What is Pharmacology? • study of substances that react with living systems through chemical processes – BINDING to regulatory molecules – ACTIVATING or INHIBITING normal body responses
What is Pharmacology?• study of substances that react with
living systems through chemical processes
–BINDING to regulatory molecules
–ACTIVATING or INHIBITING normal body responses
Pharmacology: Areas of Study
Medical Pharmacology – science of substances used to prevent, diagnose & treat disease
Toxicology – deals with undesirable effects of chemicals on living systems (cells to ecosystems)
- Poisons & Organ toxicity
Pharmacology: Areas of Study
2 MAIN SUBDIVISIONS:
Pharmacokinetics – processes that determine the concentration of drugs in body fluids & tissues over time
- what the body does to the drug
Pharmacodynamics – actions of drugs on target organs
- what the drug does to the body
• Pharmacotherapeutics – use of drugs in the treatment of disease
• Pharmacogenomics – study of genetic variations that cause differences in drug response
Pharmacology: Areas of Study
DRUG - natural product, chemical substance, or
pharmaceutical preparation for administration to diagnose or treat a disease
- any substance that brings about a change in biologic functions through its chemical actions
Nature of Drugs
Synthetic1. Aspirin2. Barbiturates3. Local anesthetics
Nature of Drugs
Xenobiotics: chemicals not synthesized in the body
Nature of Drugs
isolated from natural sources or synthesized in the laboratory
drugs intended for administration to patients
Pharmaceutical Preparations
1. TABLETS AND CAPSULES 2. SOLUTIONS AND SUSPENSIONS3. SKIN PATCHES4. AEROSOL5. OINTMENTS, CREAMS, LOTIONS, AND
SUPPOSITORIES
Nature of Drugs
Routes of Administration
1. Topical Administration2. Systemic Administration
A. Enteral Administration
3. Oral4. Rectal 5. Sublingual6. Buccal
C. Transdermal Administration
D. Inhalation Administration
Nature of Drugs
B. Parenteral Administration1. Intravenous2. Intramuscular3. Subcutaneous4. Intrathecal5. Intra-articular6. Intra-dermal7. Epidural8. Insufflation (intranasal)
Drug Size
MW: 7 (Lithium) 59,050 (altepase)
MW 100-1000• drugs must be able to move from site
of administration to site of action
Nature of Drugs
Intravenous or Intra-arterial
Drug Reactivity & Drug-Receptor Bonds
1. Covalent – very stronge.g. ASA + cyclooxygenase
2. Electrostatic – more common; relatively strong (ionic bonds), weak (hydrogen bonds), very weak (van der Waals forces)
3. Hydrophobic – weak; interaction of lipid-soluble drugs with cell membrane
Nature of Drugs
Drug Reactivity & Drug-Receptor Bonds
“Drugs that form weak bonds with receptors are more selective.”
Nature of Drugs
Drug Shape
“Complementary to its receptor as a key to a lock”
Stereoisomerism
*one enantiomer may be more potent than the other
* one enantiomer more susceptible to drug-metabolizing enzymes (duration of action)
Nature of Drugs
Me-too drug
• structurally very similar to already known drugs, with only minor differences.
• generic drug with an identical formulation and stated indications as a drug previously approved by the FDA
• chemically related to the prototype, or other chemical compounds which have an identical mechanism of action
Side Effects
nuisance; tolerated to gain benefit of therapeutic effecte.g. dry mouth & sedation of antihistamine
Adverse Effects
undesired and may be harmful e.g. persistent diarrhea
Toxic Effects
Poisoning, extremely harmful & may be life-threatening
Nature of Drugs
Processes:Absorption – entrance of a drug into
the bloodstreamDistribution – various tissues & organsMetabolism – biotransformationElimination – excretion of drug (renal,
intestinal, respiratory)
PHARMACOKINETIC PRINCIPLES
Absorption
Permeation-Movement through barriers separating
compartments
-Oral drug intestinal wall capillary wall BBB walls of capillaries perfusing the brain
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
1. Aqueous diffusion – drugs diffuse through aqueous channels
• large aqueous compartments (interstitial space, cytosol) • epithelial membrane tight junctions & endothelial
pores (MW 20,000-30,000)
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
2. Lipid diffusion – most important limiting factor in permeation
- lipid:aqueous partition coefficient determines how readily drug moves between aqueous & lipid media
- Ability of weak acid & weak base to move from aqueous to lipid media or vice versa varies with the pH of the medium
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
Electrostatic charge of ionized molecule attracts water dipoles polar, water-soluble & lipid-insoluble complex
Weak acid – neutral molecule that can reversibly dissociate into an anion & proton
C8H7O2COOH C8H7O2COO- + H+
Neutral ASA ASA anion
Weak base – neutral molecule that forms cation by combination with a proton
C12H11O2CIN3NH3+ C12H11O2CIN3NH2
+ H+
Pyrimethanine cation Neutral Pyrimethanine
PHARMACOKINETIC PRINCIPLES
ACID
PHARMACOKINETIC PRINCIPLES
BASE
Mechanisms of Permeation
Law of Mass Action = these reactions move to the left in acidic environment (low pH, excess protons) & to the right in alkaline environment
C8H7O2COOH C8H7O2COO- + H+
Neutral ASA ASA anion
C12H11O2CIN3NH3+ C12H11O2CIN3NH2
+ H+
Pyrimethanine cation Neutral Pyrimethanine
Mechanisms of Permeation
3. Special Carriers– for molecules that are too large or too insoluble to lipid (peptides, AA, glucose)
- facilitated diffusion & active transport
- selective, saturable , inhibitable
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
ABC – ATP- binding cassette family- Less selective & expel foreign molecules
1. P-glycoprotein or MDR1 (multi-drug resistance type 1) transporter
Brain, testes, drug-resistant neoplastic cells
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
2. MDRP (MDR protein) transporters- for excretion of drugs & metabolites in urine &
bile- plays a role in resistance of tumors to
chemotherapeutic drugs
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
SLC (Solute carrier) family- important in uptake of Neurotransmitters
NET (Norepinephrine transporter)SERT (Serotonin transporter)VMAT (Vesicular monoamine transporter)
PHARMACOKINETIC PRINCIPLES
Mechanisms of Permeation
4. Endocytosis/Exocytosis– for molecules that are too large & impermeant
e.g. B12 (intrinsic factor) Fe (transferrin)
Neurotransmitters
PHARMACOKINETIC PRINCIPLES
Absorption
Bioavailability – fraction of unchanged drug reaching systemic circulation following administration
IV – 100%IM, SC, Transdermal - < 100%Oral, Rectal - < 100%
PHARMACOKINETIC PRINCIPLES
Factors affecting Bioavailability
A. Extent of Absorption
Incomplete – Low Bioavailability
Oral administration – incompletely absorbed in the gutHydrophilic drug– cannot cross CMHydrophobic drug– can’t cross water layer adjacent to cell
Reverse transporter P-glycoprotein– pumps drug out of gut wall back into
gut lumen- inhibition of transporter (grapefruit juice) increases absorption
PHARMACOKINETIC PRINCIPLES
Factors affecting Bioavailability
B. First-Pass Effect- portal blood delivers drug to the liver prior to entry in systemic circulation
Alternative RoutesSublingualTransdermalRectal – lower rectum insertion enter vessels
that drain into IVC
PHARMACOKINETIC PRINCIPLES
Direct access to systemic veins
Summary
Factors controlling Rate of absorption:
1.Degree of ionization2.Surface Area3.Blood flow4.Gastric emptying time & GI motility
PHARMACOKINETIC PRINCIPLES
Distribution
Volume of Distribution (V)- Defined with respect to blood, plasma, or water
- An apparent volume necessary to contain the amount of drug homogenously found in blood, plasma, or water
- Can vastly exceed physical volume of the body
PHARMACOKINETIC PRINCIPLES
0.6 L/kg
0.04
L/k
g
0.4 L/kg
0.2L/kg
Distribution
Volume of Distribution
V = Amount of drug (dose)C plasma conc.
e.g. A 500 mg New drug was administered . The plasma concentration is 0.01mg/ml. What is the V?
PHARMACOKINETIC PRINCIPLES
= 500 mg 0.01 mg/ml
= 50000 ml or 50L
Distribution
PHARMACOKINETIC PRINCIPLES
COMPARTMENT EXAMPLE OF DRUGSTotal body water Ethanol: Small water solubleExtracellular water Gentamicin: Large water soluble Blood Heparin: Strongly plasma
protein-bound large moleculesFat DDT : highly lipid solubleBone Lead, Fluoride: ions
DistributionBinding to Plasma Proteins
- Use to achieve ideal therapeutic regimen:
1. sufficient amount of drug reach site of action to bring desired effect
2. drug should not disappear too rapidly in site of action
PHARMACOKINETIC PRINCIPLES
Distribution
Binding to Plasma Proteins1. Albumin – most important; high affinity to drugs
2. Glycoproteins
3. Lipoprotein
4. Globulins
PHARMACOKINETIC PRINCIPLES
Distribution
Factors Affecting Rate of Distribution:
1. Extent of binding – free drug (unbound) able to distribute
2. Ability to diffuse through CM – lipophilic
3. Degree of perfusion – higher perfusion, faster equilibrium
Lung - 10 Kidney - 4Heart - 0.6 Brain - 0.5Muscle – 0.025 Fat - 0.003
PHARMACOKINETIC PRINCIPLES
Distribution
Factors Affecting Rate of Distribution:
4. Properties of tissue membrane
Blood Brain Barrier – tightly joined capillaries covered by foot-like processes of astrocytes
Placental Barrier – separates fetal & maternal blood
- lipid-soluble drugs diffuse easily; water-soluble drugs diffuse poorly
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Why is this necessary?
1. Active organic drugs tend to be lipophilic & remain unionized or partially ionized in physiologic pH; readily reabsorbed in nephron
2. Lipophilic compounds are strongly bound to albumin & not readily filtered
3. Prolonged duration of action if termination is through renal excretion
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Site:KidneysBrain Skin GI tract
Gastric acid - penicillinDigestive enzymes – insulinEnzymes in intestinal wall – catecholamines
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Site:Plasmae.g. succinylcholine
lidocaine
Lungs e.g. converts Angiotensin I to Angiotensin II
Liver - principal organ of metabolism e.g. isopreterenol, meperidine, morphine
PHARMACOKINETIC PRINCIPLES
hydrolyzed by pseudocholinesterase
Drug Biotransformation
Major Categories
Phase I Reactions- convert parent drug to a more polar metabolite by introducing or
unmasking a functional group (-OH, -NH2, -SH) to be readily excreted
Oxidations DeaminationDesulfuration ReductionsHydrolyses
e.g. Isoniazid – N-acetyl conjugate hydrolyzed to isonicotinic acid
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Major Categories
Phase II Reactions
- those not readily eliminated undergo subsequent reaction in which endogenous substrate combine with newly incorporated functional group to form highly polar conjugate
Glucuronic acid Acetic acidSulfuric acid Amino acid
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Phase II Reactions- relatively faster - previously terminal inactivation events or “true
detoxification”- May precede Phase I reaction
Conjugates- Polar molecules readily excreted & often inactive- Involves high-energy intermediates & specific
transfer enzymes
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Subcellular Site:
Endoplasmic reticulumMitochondriaCytosolLysosomesPlasma membraneMicrosomes – lamellar membranes of ER reform
into vesicles after homogenization & fractionation of cell
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Transferases – located in microsomes or cytosol1. UDP (uridine 5’diphosphate)-glucoronosyl transferase – most dominant
e.g. coupling of UDP derivative of glucuronic acid with bilirubin (Glucuronidation)
2. Sulfotransferase- sulfation of PAPS (3’phosphoadenosine 5-
phosphosulfate)
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Transferases 3.GSH (glutathione) transferase
- GSH conjugation 4. N-acetyl transferase
e.g. Isoniazid – N-acetyl conjugate - acetylation
5. Methyltransferase- transmethylases methylation
Epoxide Hydrolases – water conjugation
PHARMACOKINETIC PRINCIPLES
Absorption
Drug
Metabolism Elimination
Lipophilic
Drug
Phase I Phase II
Conjugate
Conjugate
Conjugate
Drug metabolite with modified activity
Inactive drug metabolite
Hydrophilic
Drug
Drug Biotransformation
Metabolism to Toxic Products
- Compounds metabolically transformed to reactive intermediates that are toxic to various organs
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation
Acetaminophen
Glucuronidation Sulfation
Non-toxic Reactive Non-toxic Glucuronide Intermediates Sulfate (N-acetylbenzoiminoquinone)
+ GSH Neucleophillic conjugation cellular proteins
Mercapturic Acid Liver Cell Death conjugate
PHARMACOKINETIC PRINCIPLES
CYP1 CYP3A4
Drug Biotransformation: Variables in Differences
1. Genetics
Genetic polymorphissm- genetic factors influence enzyme levels- occurrence of variant allele at population
frequency ≥ 1% - resulting to altered expression &/or
function activity of gene product
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation: Variables in Differences
1. Genetics
Autosomal Recessive Traits
e.g. Succinylcholine –metabolized half rapidly in persons with deficiency
of pseudocholinesterase or butyrylcholinesterase (BCHE)
INH – slow acetylators phenotype - 50% Caucasians, less common in Asians
- high incidence of INH-induced peripheral neuritis
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation: Variables in Differences
2. Age – increase toxicity in extreme ages
Neonate – deficiency in UGT Glucoronide formation - adult value at 3-4yo
Elderly – decline of liver to recover from injury
3. SexMale – faster metabolism
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation: Variables in Differences
4. Diseases
Liver diseases – impaired hepatic drug-metabolizing enzymes
Cardiac diseases – impaired hepatic blood flowPulmonary diseases – reduced hepatic
metabolismEndocrine diseases
Hypothyroidism - reduced hepatic metabolismHyperthyroidism – increased hepatic metabolism
PHARMACOKINETIC PRINCIPLES
Drug Biotransformation: Variables in Differences
5. Nutritional & environmental charcoal-broiled foodcruciferous vegetables
grapefruit - inhibitor
cigarette smokepesticides
PHARMACOKINETIC PRINCIPLES
inducers
inducers
Drug Excretion
Common Pathways:Sweat SalivaMilk
Respiratory - role not significant in excretion- when drugs are metabolized into products
that can be exchanged from blood into respiratory system
- excreted by lungs
PHARMACOKINETIC PRINCIPLES
Drug ExcretionCommon Pathways:
GI - after oral administration, portion of drug is unabsorbed & is excreted in the feces
Enterohepatic pathway lipid soluble drug liver bile intestine blood
liver
PHARMACOKINETIC PRINCIPLES
Drug Excretion
Common Pathways:Renal
- blood filtered & reabsorbed- urinary waste products & nonabsorbable form are
excreted- excretion of drug & metabolite: water soluble
Acidic drug – basic urineBasic drug – acidic urine
PHARMACOKINETIC PRINCIPLES
Fruits VegetablesNa2HCO3
Protein rich foodProbiotics
Drug Excretion
Clearance: measure of the body to eliminate the drugs: factor that predicts rate of elimination in relation to
drug concentration: defined in respect to blood, plasma or unbound in water
CL = Rate of Elimination (mg/min) C (mg/ml)
e.g. A 1 liter of water contains 1000mg drug. After an hour 100mg of drug has been removed. What is the clearance of this drug?100 ml/hr
PHARMACOKINETIC PRINCIPLES
Drug Excretion
Clearance : dividing rate of elimination at each organ by conc. of drug yields respective clearance, together equal total systemic clearance
CL kidney = Rate of Elimination kidney
C
CL liver = Rate of Elimination liver
C
CL other = Rate of Elimination other
C
CL systemic = CL kidney + CL liver + CL other
PHARMACOKINETIC PRINCIPLES
Drug Excretion
First-order elimination : constant over concentration range
: elimination is not saturable: rate of drug elimination is directly
proportional to concentration
PHARMACOKINETIC PRINCIPLES
Dru
g C
once
ntra
tion
(%m
ax)
Time
100 – -
80 – -
60 – -
40 – -
20 – -0
- - - - - - - - -
Dru
g C
once
ntra
tion
(%m
ax)
Time
100 .0 –
10.0 –
1.0 -
0.1
- - - - - - - - - -
Drug Excretion
Zero-order elimination• Capacity-limited elimination • Mixed-order, saturable, dose or
concentration dependent• Nonlinear or Michealis-Menten elimination
PHARMACOKINETIC PRINCIPLES
Dru
g C
once
ntra
tion
(%m
ax)
Time
100 – -
80 – -
60 – -
40 – -
20 – -0
- - - - - - - - -
Dru
g C
once
ntra
tion
(%m
ax)
Time
100
1 0 - - - - - - - - - -
Drug Excretion
Steady state concentration (Css)•In multiple dosing or constant infusion, drug will accumulate until amount administered per unit time is equal to amount eliminated per unit time
PHARMACOKINETIC PRINCIPLESPl
asm
a C
once
ntra
tion
(%of
st
eady
sta
te)
Time
100 – - 75 – - 50
– - 25
– -0
- - - - - - - - -
1 2 3 4 5 6 7 8
Drug Excretion
Flow Dependent Elimination• Drugs are cleared readily• Elimination depend primarily on rate of
drug delivery to organs of elimination• Blood flow is main determinant of drug
delivery
PHARMACOKINETIC PRINCIPLES
Drug Excretion
Half life• Time required to change the amount of
drug in the body by ½ during elimination or constant infusion
• Time course will depend on V & CL
t1/2 = 0.7 x V CL
PHARMACOKINETIC PRINCIPLES
Elimination can be described by exponential process, time taken for 2-fold decrease is proportional to log 2 (0.7)
Drug Excretion
Half life• Indicates time required to attain 50% steady state or to
decay 50% from steady state
PHARMACOKINETIC PRINCIPLESPl
asm
a C
once
ntra
tion
(%of
st
eady
sta
te)
Time (half lives)
100 – - 75 – - 50
– - 25
– -0
- - - - - - - - -1 2 3 4 5 6 7 8
Drug accumulation in constant rate of infusion
Drug elimination after constant rate of infusion reached steady state
Drug Accumulation
• Whenever drug doses are repeated, drug will accumulate in the body until dosing stops
• Detectable if dosing is shorter than 4 half-lives• Inversely proportional to fraction of a dose lost in each
dosing interval
PHARMACOKINETIC PRINCIPLES
Drug Excretion
Average concentration (Cav)•In repeated doses, concentration fluctuates around a mean (Css) with peak & trough values
PHARMACOKINETIC PRINCIPLESPl
asm
a C
once
ntra
tion
(%of
st
eady
sta
te)
Time
100 – - 75 – - 50
– - 25
– -0
- - - - - - - - -1 2 3 4 5 6 7 8
Peak
Trough Css
PHARMACODYNAMIC PRINICPLES:
Objectives:
1. Identify the different target proteins and discuss their mechanisms of drug-receptor interactions
2. Discuss the concepts of affinity, intrinsic activity, selectivity and specificity
3. Describe signal transduction mechanisms, the different types of G-proteins, and second messenger system
4. State the occupancy theory and receptor inactivation theories
5. Describe the different dose-response curves and the pharmacologic parameters derived from these curves