Farmakokinetika Sri Wahyuni, S. Farm., Apt
Prinsip Farmakokinetika Farmasi Fkg ums
Dec 07, 2015
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Farmakokinetika
Sri Wahyuni S Farm Apt
Quiz What is pharmacokinetics
What your body does to the drug The quantitative analysis of the time course of
drug What are the steps of pharmacokinetics
Absorption Distribution Metabolism Excretion
Nasib Obat dalam Tubuh(Farmakokinetika)Apa yangterjadi padaobat setelahmasuk ke tubuh kita
4
Definition quantitative study of absorption distribution metabolism and elimination of chemicals in the body as well as the time course of these effectsSummary
- absorption- distribution- metabolism- elimination
Pharmacokinetics science that studies routes of administration absorption anddistribution bioavailability biotransformation and excretion of drugs
key factors in the drug experience
Farmakokinetik Farmakodinamik
Bioavailabilitas Aksi Obat Efek Obat
1048633Rute pemberian1048633Absorpsi1048633Distribusi- Difusi- Kelarutan lipid- Ionisasi- Ikatan depot1048633Metabolisme1048633Ekskresi
bullReseptor- Hubungandosis-respon- Antagonisme
-Efek samping-Indeks terapi-Perubahan perilaku
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Quiz What is pharmacokinetics
What your body does to the drug The quantitative analysis of the time course of
drug What are the steps of pharmacokinetics
Absorption Distribution Metabolism Excretion
Nasib Obat dalam Tubuh(Farmakokinetika)Apa yangterjadi padaobat setelahmasuk ke tubuh kita
4
Definition quantitative study of absorption distribution metabolism and elimination of chemicals in the body as well as the time course of these effectsSummary
- absorption- distribution- metabolism- elimination
Pharmacokinetics science that studies routes of administration absorption anddistribution bioavailability biotransformation and excretion of drugs
key factors in the drug experience
Farmakokinetik Farmakodinamik
Bioavailabilitas Aksi Obat Efek Obat
1048633Rute pemberian1048633Absorpsi1048633Distribusi- Difusi- Kelarutan lipid- Ionisasi- Ikatan depot1048633Metabolisme1048633Ekskresi
bullReseptor- Hubungandosis-respon- Antagonisme
-Efek samping-Indeks terapi-Perubahan perilaku
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Nasib Obat dalam Tubuh(Farmakokinetika)Apa yangterjadi padaobat setelahmasuk ke tubuh kita
4
Definition quantitative study of absorption distribution metabolism and elimination of chemicals in the body as well as the time course of these effectsSummary
- absorption- distribution- metabolism- elimination
Pharmacokinetics science that studies routes of administration absorption anddistribution bioavailability biotransformation and excretion of drugs
key factors in the drug experience
Farmakokinetik Farmakodinamik
Bioavailabilitas Aksi Obat Efek Obat
1048633Rute pemberian1048633Absorpsi1048633Distribusi- Difusi- Kelarutan lipid- Ionisasi- Ikatan depot1048633Metabolisme1048633Ekskresi
bullReseptor- Hubungandosis-respon- Antagonisme
-Efek samping-Indeks terapi-Perubahan perilaku
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
4
Definition quantitative study of absorption distribution metabolism and elimination of chemicals in the body as well as the time course of these effectsSummary
- absorption- distribution- metabolism- elimination
Pharmacokinetics science that studies routes of administration absorption anddistribution bioavailability biotransformation and excretion of drugs
key factors in the drug experience
Farmakokinetik Farmakodinamik
Bioavailabilitas Aksi Obat Efek Obat
1048633Rute pemberian1048633Absorpsi1048633Distribusi- Difusi- Kelarutan lipid- Ionisasi- Ikatan depot1048633Metabolisme1048633Ekskresi
bullReseptor- Hubungandosis-respon- Antagonisme
-Efek samping-Indeks terapi-Perubahan perilaku
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Pharmacokinetics science that studies routes of administration absorption anddistribution bioavailability biotransformation and excretion of drugs
key factors in the drug experience
Farmakokinetik Farmakodinamik
Bioavailabilitas Aksi Obat Efek Obat
1048633Rute pemberian1048633Absorpsi1048633Distribusi- Difusi- Kelarutan lipid- Ionisasi- Ikatan depot1048633Metabolisme1048633Ekskresi
bullReseptor- Hubungandosis-respon- Antagonisme
-Efek samping-Indeks terapi-Perubahan perilaku
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Farmakokinetik Farmakodinamik
Bioavailabilitas Aksi Obat Efek Obat
1048633Rute pemberian1048633Absorpsi1048633Distribusi- Difusi- Kelarutan lipid- Ionisasi- Ikatan depot1048633Metabolisme1048633Ekskresi
bullReseptor- Hubungandosis-respon- Antagonisme
-Efek samping-Indeks terapi-Perubahan perilaku
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
7
Concentration of a drug at its site of action is a fundamental determinant of its pharmacologic effects
Drugs are transported to and from their sites of action in the blood ndash because of that the concentration at the active site is a function of the concentration in the blood
The change in drug concentration over time in the blood at the site of action and in other tissues is a result of complex interactions of multiple biologic factors with the physicochemical characteristics of the drug
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Pharmacokinetics Drug molecules interact with target sites to
effect the nervous system The drug must be absorbed into the bloodstream and
then carried to the target site(s) Pharmacokinetics is the study of drug
absorption distribution within body and drug elimination Absorption depends on the route of administration Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
Drug elimination is accomplished by excretion into urine andor by inactivation by enzymes in the liver
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
ADME
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Processes that Determine Drug Processes that Determine Drug PKPK
Absorption how the drug enters the blood The amount of acid in stomach or amount of food changes
the amount of drug absorbed This is why some drugs must be taken with or without food or
can not be taken with antacids
Distribution how the drug travels in the blood and how it goes into and out of other areas of the body
Metabolism how the body changes a drug usually in intestine and liver
Drug Elimination how the body gets the drug out via kidneys through urine or via liver though stool
httpwwwthebodycomcontentart875html
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Routes of Administration
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Carajalur pemberian(Routes of administration)
1048698 Bagaimana dan di mana obat memasuki tubuh akan menentukan seberapa banyak obat mencapai
tempat aksinya dan pada gilirannya menentukan besarnya efek
1048698 Jalur pemberian dapat mempengaruhi absorpsi obat1048698 Yang menentukan adalah Luas permukaan absorpsi Banyaknya membranbarrier yang harus dilewati Banyaknya obat yang terdegradasi Jumlah ikatan dengan depot
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Macam cara pemberian obat 1048698 bull Intravenous Injections (iv) 1048698 bull Intramuscular Injections (im) 1048698 bull Subcutaneous Administration (sc) 1048698 bull Intraperitoneal Injections (ip) 1048698 bull Inhalation 1048698 bull Oral Administration (po) 1048698 bull Other (eg Sublingual Topical
Transdermal etc)
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Injeksi subcutaneous
Sublingual Injeksi Intramuscular
Intra vena Inhalasi ip
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Anestesi epidural pada akan melahirkan
Anestesi epidural pada ibu yangakan melahirkan
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Sebelum dapat memberikanefek obat harus masuk kedalam sirkulasi sistemik
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Routes of administration
Time course of drug blood levels depends on route of administration They are also associated with differential duration of drug effect
bullCp maxbullTmaxbullOnsetbullClbullT12
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Overview
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Liberation Applies to drugs given orally Components
Release of drug from pill tablet capsule Dissolving of active drug in GI fluids
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Ex Enteric coated Ex Enteric coated aspirin slows absorption in aspirin slows absorption in
stomach vs non-coatedstomach vs non-coated
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Absorption Movement from administration site into
circulation
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Absorpsi Obat
Adalah perpindahan obat dari tempat pemberian menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemikpembuluh darah obat harus dapat melintasi membranbarrier merupakan faktor terpenting bagi obat untuk mencapai tempat aksinya ( misal otak jantunganggota badan lain)
Obat harus dapat melewati berbagai membran sel (misalnya sel usus halus pembuluh darah sel glia di otak sel saraf)
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Mekanisme perpindahantransport obat 1048698 Difusi pasif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi tinggi ke konsentrasi rendah merupakan mekanisme transport sebagian besar
obat 1048698 Transport aktif Perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier mekanisme transport obat-obat tertentu
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Difusi Pasif Transport Aktif
Senyawa lipofilik Senyawa hidrofilik carrier
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Difusi pasif Tergantung pada bull ukuran dan bentuk molekul obat bull kelarutan obat dalam lemak bull derajat ionisasi obat
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Pengaruh kelarutan obat dalam lipid
1048698 Membran sel tersusun oleh molekul lipid (lemak) 1048698 Akibatnya obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble) 1048698 Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)
angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air 1048698 P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium)
1048698 Pow = (CoilCwater)equilibrium 1048698 P gt 1 lipofilik P lt 1 hidrofilik 1048698 Dengan demikian faktor utama kelarutan dalam lipid adalah derajat
ionisasi
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Derajat ionisasi
Adalah banyaknya obat yang terionkan (menjadi bermuatan)
ketika dilarutkan dalam air Faktor penentu utama ionisasi 1048698 Sifat asam-basa obat asam lemah atau basa
lemah (sebagian besar obat adalah asam lemah atau basa lemah)
1048698 Sifat asam-basa cairan solven (pelarut)-nya asam atau
basa (obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Contoh obat dan sifat keasamannyaBasa Diazepam Klordiazepoksid Trimetoprim Morfin Norepinefrin Dopamin Propranolol Amfetamin Klorokuin
Asam Levodopa Penisilin Aspirin Metotreksat Sulfametoksazol Klorotiazid Fenobarbital Fenitoin Asam askorbat
Makin basa
Makin asam
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Aturan Molekul akan menjadi kurang bermuatan (tidak terionisasi )
jika
berada pada suasana pH yang sama dan akan lebih bermuatan jika
berada di pH yang berbeda Semakin bermuatan suatu molekul akan semakin sulit
menembus membran Semakin kurang bermuatan suatu molekul akan lebih
mudah menembus membran Dapat menjadi prediktor terhadap sifat absorpsi obat Contoh
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi di lambung atau usus
Mengapa
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Factors Affecting LiberationAbsorption Formulation factors
Tablet disintegration Inert ingredient
solvent effects Solubility Drug pH Concentration
Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food
other drugs
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Lipid Bilayer
Small uncharged
Large uncharged
Small charged ions
H2O urea CO2 O2 N2
Glucose Sucrose
H+ Na+ K+ Ca2+ Cl- HCO3
-
DENIED
DENIED
Swoosh
Membranes and Absorption
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
Aspirin is an acidic drug In the stomach will it exist mostly in ionized or non-ionized form
NON-IONIZED
A real live actual clinical question
WhyWhy
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Lipid Bilayer
How will this affect aspirin absorption
Ionized form (charged) Ionized form (charged) A-
Ionized form (uncharged) Ionized form (uncharged) HA HA
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Moral of the story
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments
Basic drugs are best absorbed from basic environments
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
So
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipacidify the environment
To absorption of an acidic drughellipalkalanize the environment
To absorption of an acidic drughellipalkalanize the environment
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Absorpsi pada Blood-Brain Barrier(sawar darah otak)
Agar dapat menembus sawar darah otak
suatu obat harus Tetap tidak terionkan pada pH darah Memiliki koefisien partisi yang tinggi (larut dalam lipid) Atau menggunakan bantuan suatu
mekanisme transport (misalnya L-DOPA)
Khusus untuk obat-obat yang tempat aksinya ada di otak ia harusdapat menembus sawar darah otak
Guna sawar darah otak melindungi otak dari bahan-bahan yangmungkin berbahaya
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Contoh
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Distribution Rate of perfusion Plasma protein (albumin) binding Accumulation in tissues Ability to cross membranes
Blood-brain barrier Placental barrier
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Distribution The movement of drug from the blood
to and from the tissues
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Distribusi -- Ikatan depot
1048698 Adalah ikatan suatu obat dengan suatu bagian tidak aktif seperti albumin (pada darah) otot tulang lemak atau liver
Perlu diingat bahwa
1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempat
aksinya (reseptor)
1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat dengan bekerja di tempat aksinya menghasilkan efek
1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalam darah digambarkan dgn persamaan sbb
D + A harr DA
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Efek ikatan depot terhadap efek terapi
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Plasma Protein Binding Many drugs bind to plasma proteins in the blood
steam Plasma protein binding limits distribution A drug that binds plasma protein diffuses less
efficiently than a drug that doesnrsquot
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
warfarin (Coumadin) is highly protein bound (99) Aspirin warfarin (Coumadin) is highly protein bound (99) Aspirin binds to the same site on serum proteins as does Coumadin binds to the same site on serum proteins as does Coumadin If a patient on Coumadin also takes aspirin what will happenIf a patient on Coumadin also takes aspirin what will happen
The available Coumadin will increase
Plasma Protein Binding
1) Why2) Why do we care
1) Why2) Why do we care
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
The blood brain barrier consists of cell tightly The blood brain barrier consists of cell tightly packed around the capillaries of the CNS packed around the capillaries of the CNS What characteristics must a drug possess to What characteristics must a drug possess to easily cross this barriereasily cross this barrier
Non-protein bound non-ionized and highly lipid soluble
Blood-Brain Barrier
WhyWhy
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Metabolism (Biotransformation) Two effects
Transformation to less active metabolite Enhancement of solubility
Liver = primary site Liver disease
Slows metabolism Prolongs effects
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Metabolisme(biotransformasi) Suatu proses kimia di mana suatu obat diubah di dalam tubuh menjadi
suatumetabolitnya Organ metabolisme utama liverhepar
Hasil metabolisme bisa Lebih atau kurang aktif inaktif atau tidak
berubah dalam kaitannya dengan aktivitasnya
umumnya menjadi bentuk yang kurang aktif
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Hepatic lsquoFirst-Passrsquo Metabolism Affects orally administered drugs Metabolism of drug by liver before drug
reaches systemic circulation Drug absorbed into portal circulation must
pass through liver to reach systemic circulation
May reduce availability of drug
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
First-Pass Metabolism Obat yang digunakan secara oral akan melalui liverhepar
sebelum masuk ke dalam darah menuju ke daerah lain dari tubuh
(mis Otak jantung paru-paru jaringan lainnya) Di dalam liver terdapat enzim khusus (yaitu sitokrom P450) yang
akan mengubah obat menjadi bentuk metabolitnya Metabolit umumnya menjadi lebih larut dalam air (polar) dan akan
dengan cepat diekskresikan keluar tubuh (melalui urin feses
keringat dll) Hal ini akan secara dramatik mempengaruhi kadar obat dalam
plasma obat-obat yang mengalamifirst past metabolism akan
kurang bioavailabilitasnya efek berkurang
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Oral Administration
Intestines
Liver
IntravenousAdministration
Metabolism
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)1048698 Oxidasi reduksi hydrolysis alkilasi dealkilasi Metabolitnya bisa lebih aktiftidak dari pada senyawa
asalnya Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II) Konjugasi (glukoronidasi sulfatasi) Penggabungan suatu obat dengan suatu molekul lain Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Skema metabolisme obat
Absorpsi Metabolisme Eliminasi
Fase I Fase II
Obat A Konjugasi
Obat B
Obat C
Obat D
aktif
aktif
inaktif
inaktif
Konjugasi
Konjugasi
Lipofilik Hidrofilik
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Faktor yang mempengaruhi metabolismeobat1 Induksi enzim dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri atau obat lain yang dimetabolisme oleh enzim yang
sama dapat menyebabkan toleransi
2 Inhibisi enzim kebalikan dari induksi enzim biotransformasi obat
diperlambat bioavailabilitas meningkat efek menjadi lebih
besar dan lebih lama
3 Kompetisi (interaksi obat) terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh alcohol dan barbiturates)
4 Perbedaan individu karena adanya genetic polymorphisms
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Consequences Of Metabolism Drug metabolism = Drug inactivation The metabolite may have
Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties not seen with the parent drug
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Elimination
Kidneys = primary site Mechanisms dependent upon
Passive glomerular filtration Active tubular transport
Partial reabsorption Hemodialysis
Renal disease Slows excretion Prolongs effects
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Eliminasiekskresi
Obat akan dieliminasi dari dalam tubuh dalam bentuk metabolitnya
atau bentuk tidak berubah Organ ekskresi utama adalah ginjal urin Namun bisa juga melalui paru-paru keringat air liur
feses ASI
T12 (half-life) waktu yangdibutuhkan obat sehinggakonsentrasinya dalam darah menjadi separonya
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Active Tubular Transport
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
Probenecid is moved into the urine by the same transport pump that moves many antibiotics Why is probenecid sometimes given as an adjunct to antibiotic therapy
It competes with the antibiotic at the pump and slows its excretion
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
A patient has overdosed on phenobartital A patient has overdosed on phenobartital Phenobarbital is an acid If we lsquoalkalinalizersquo the Phenobarbital is an acid If we lsquoalkalinalizersquo the urine by giving bicarbonate what will happen urine by giving bicarbonate what will happen to the phenobarbital molecules as they are to the phenobarbital molecules as they are filtered through the renal tubulesfiltered through the renal tubules
They will ionize
Urine pH and Elimination
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Non-ionized
HA H+ + A-
How will this affect phenobarbital reabsorption by the kidney
Decreased reabsorptionDecreased reabsorption
Increased eliminationIncreased elimination
Ionized
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Thank U Matur Nuwun
See U Next week
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
ADME - Summary
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
PK DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sm
a C
on
cen
trati
on
3000
Cmax Maximum concentration ndash may relate to some side effects
AUC Area under the curve (filled area) = overall drug exposure
Cmin minimum or trough concentrations may relate with efficacy of HIV drugs
httpwwwthebodycomcontentart875html
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Drug Levels amp ResistanceDrug Levels amp Resistance
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
How Do Drug Interactions HappenHow Do Drug Interactions Happen
They occur due to changes in the pharmacokinetics
of a drug Changes in the absorption distribution
metabolism and excretion (ADME) of a drugToxic
Effective
Ineffective
0 6 12 18 24 TIME
Conce
ntr
ati
on
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Concentration versus Time Profiles
One-Compartment Model Assumes body as one compartment 1
Two-Compartment Model
Central compartment (drug entry and elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dose
Broadly the concentration ndash time profiles can be viewed as two different ways
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment
This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
The distribution phase for aminoglycosides is only 15-30 minutes therefore we can use a one-compartment model with a high degree of accuracy
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Drugs which exhibit a slow equilibration with peripheral tissues are best described with a two compartment model
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Vancomycin is the classic example its distribution phase is 1 to 2 hours Therefore the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose
Rate of drug accumulation at any time dDBODYdt= dDABSdt - dDELIMdt
Absorption PhasedDABSdt gt dDELIMdt
At time of peak drug concdDABSdt = dDELIMdt
Post-absorption PhasedDABSdt lt dDELIMdt
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
05hr
02hr
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
B AmsdenCHEE 440
Open one-compartment model
process of distribution to each compartment is much faster than absorption into blood and elimination
drug concentration everywhere in the compartment is equal (CSTR)
elimination processes are pseudo-1st order
D
ka
DBCp
kel
Vd
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