Pharmacokinetics

PharmacokineticsPharmacokinetics

The dynamics of drug absorption, Distribution, The dynamics of drug absorption, Distribution, Metabolism, eliminationMetabolism, elimination

Drugs at site of administration

Drugs in plasma

Drugs in tissues Metabolism

Metabolite(s) in tissues

Drugs &/or matabolites in urine, feces, bile

Distribution

Elimination

Absorption

MetabolismMetabolism General considerations - drug metabolism General considerations - drug metabolism

(biotransformation) usually results in more water-(biotransformation) usually results in more water-soluble, more polar metabolites, thus facilitating soluble, more polar metabolites, thus facilitating their excretion by reducing renal tubular their excretion by reducing renal tubular reabsorptionreabsorption

drug metabolism does not always result in drug metabolism does not always result in detoxification and inactivation of drugs, although detoxification and inactivation of drugs, although these usually occur.these usually occur.

BiotransformationBiotransformation

1. Inactivation: most drugs and their 1. Inactivation: most drugs and their active metabolites are rendered inactive or active metabolites are rendered inactive or less active e.g. pentobarbitone , less active e.g. pentobarbitone , morphine , chloramphenicol.morphine , chloramphenicol.


2. Active metabolite from an active drug: 2. Active metabolite from an active drug: many drugs have been found to be many drugs have been found to be partially converted to one or more active partially converted to one or more active metabolite , the effects observed are the metabolite , the effects observed are the sum total of that due to the parent drug sum total of that due to the parent drug and its active metabolites .and its active metabolites .

BiotransformationBiotransformation3. Activation of a inactive drug – few 3. Activation of a inactive drug – few drugs are inactive as such and need drugs are inactive as such and need conversion in the body to one or more conversion in the body to one or more active metabolites . Such a drug is active metabolites . Such a drug is called a prodrug . The prodrug may called a prodrug . The prodrug may offer advantage over the active form in offer advantage over the active form in being more stable, having better being more stable, having better bioavailability or other desirable bioavailability or other desirable pharmacokinetics properties or less pharmacokinetics properties or less side effect and toxicity . side effect and toxicity .

Kinetics of MetabolismKinetics of Metabolism

1. First order Kinetics: Rate of drug 1. First order Kinetics: Rate of drug metabolism is directly proportional to metabolism is directly proportional to the conc. of free drug.the conc. of free drug.

2. Zero order Kinetics: Rate of drug 2. Zero order Kinetics: Rate of drug metabolism is not dependent on the metabolism is not dependent on the conc. of free drug. And rate of conc. of free drug. And rate of metabolism remain constant over time.metabolism remain constant over time.


Biotransformation reaction can be Biotransformation reaction can be classified into : classified into :

a. Nonsynthetic /.phase 1 reactions – a. Nonsynthetic /.phase 1 reactions – metabolites may be active or inactive .metabolites may be active or inactive .

b. Synthetic / conjugation / phase 2 b. Synthetic / conjugation / phase 2 reaction – metabolite is mostly inactive .reaction – metabolite is mostly inactive .

Drug Phase I

Oxidation ,

reduction

and/or

hydrolysis

Phase IIConjugation

products

Following Phase I, the drug may be activated, unchanged,

inactivated.

Conjugated drugIs usually inactive.

Some drugs directly Enter Phase II

metabolism

The biotransformation of drugsThe biotransformation of drugs

Directly

Nonsynthetic reactionNonsynthetic reaction

1. oxidation – this reaction involves 1. oxidation – this reaction involves addition of oxygen / negatively charged addition of oxygen / negatively charged radical or removal of hydrogen / positively radical or removal of hydrogen / positively charge radical . Oxidations are the most charge radical . Oxidations are the most important drug metabolizing reaction . important drug metabolizing reaction . Various oxidation reaction are : Various oxidation reaction are :


Hydroxylation , oxygenation at C, N,or S Hydroxylation , oxygenation at C, N,or S atoms ; N or O –dealkylation , oxidative atoms ; N or O –dealkylation , oxidative deamination , etc , it may cases the initial deamination , etc , it may cases the initial insertion of oxygen atom into the drug insertion of oxygen atom into the drug molecule produces short lived highly molecule produces short lived highly reactive quinone / epoxide / superoxide reactive quinone / epoxide / superoxide intermediates which then convert to more intermediates which then convert to more stable compounds .stable compounds .


Oxidative reaction are mostly carried by Oxidative reaction are mostly carried by a group of monooxygenases in the a group of monooxygenases in the liver , which is the final step involve a liver , which is the final step involve a cytochrome P-450 heamoproteins , cytochrome P-450 heamoproteins , NADPH , cytochrome P- 450 reductase NADPH , cytochrome P- 450 reductase and Oand O22 . There are 30 – 100 cytochrome . There are 30 – 100 cytochrome

P 450 isoenzymes differing in their P 450 isoenzymes differing in their affinity for various substrates . affinity for various substrates .

Microsomal enzyme oxidation Microsomal enzyme oxidation systemsystem

Oxidation is the addition of oxygen and/or the removal of hydrogen. Most oxidation steps occur in the endoplasmic reticulum. Common reactions include :- Alkyl group ----> alcohol

for example phenobarbitone Aromatic ring ----> phenol

Oxidation

ReductionAddition of a hydrogen or removal of oxygen.

azo (-N=N-) or nitro groups (-NO2) ---> (-NH2) amines


2. Reduction – This reaction is the 2. Reduction – This reaction is the converse of oxidation and involves converse of oxidation and involves cytochrome P 450 enzymes working in the cytochrome P 450 enzymes working in the opposite direction . Drugs primarily opposite direction . Drugs primarily reduced are chloralhydrate , reduced are chloralhydrate , chloramphenicol , halothane .chloramphenicol , halothane .


3. Hydrolysis – This is cleavage of drug 3. Hydrolysis – This is cleavage of drug molecule by taking up a molecule of molecule by taking up a molecule of water .water .

Ester + HEster + H22O O Acid + alcohol Acid + alcohol

Similarly amides and polypeptides are Similarly amides and polypeptides are hydrolysed by amidases and peptidases .hydrolysed by amidases and peptidases .

esterase

HydrolysisAddition of water with breakdown of molecule. In blood plasma (esterases) and liver Esters ---> alcohol and acid

for example aspirin to salicylic acid


Hydrolysis occurs in liver , intestines , Hydrolysis occurs in liver , intestines , plasma and other tissues . Ex- choline plasma and other tissues . Ex- choline esters , procaine , lidocaine .esters , procaine , lidocaine .

4. Cyclization – this is formation of ring 4. Cyclization – this is formation of ring structure from a straight chain compound , structure from a straight chain compound , e.g. proguanil.e.g. proguanil.


5. Decyclization --- This is opening up of 5. Decyclization --- This is opening up of ring structure of the cyclic drug molecule , ring structure of the cyclic drug molecule , e.g. barbiturate , phenytoin . This is e.g. barbiturate , phenytoin . This is generally minor pathway.generally minor pathway.

Enzyme InductionEnzyme Induction

An interesting feature of some of these An interesting feature of some of these chemically dissimilar drug substrates is chemically dissimilar drug substrates is their ability , on repeated their ability , on repeated administration ,to induce cytochrome administration ,to induce cytochrome P450 by enhancing the rate of its P450 by enhancing the rate of its synthesis or reducing its rate of synthesis or reducing its rate of degradation .degradation .


A large number of drugs can cause an A large number of drugs can cause an increase over time in liver enzyme activity. increase over time in liver enzyme activity.

This in turn can increase the metabolic rate of This in turn can increase the metabolic rate of the same or other drugs. Phenobarbitone will the same or other drugs. Phenobarbitone will induce the metabolism of itself, phenytoin, induce the metabolism of itself, phenytoin, warfarin, etc. Cigarette smoking can cause warfarin, etc. Cigarette smoking can cause increased elimination of theophylline and increased elimination of theophylline and other compounds. Dosing rates may need to other compounds. Dosing rates may need to be increased to maintain effective plasma be increased to maintain effective plasma concentrations. concentrations.


induction results in an acceleration of induction results in an acceleration of metabolism and usually in a decrease in the metabolism and usually in a decrease in the pharmacologic action of the inducer and pharmacologic action of the inducer and also of coadministered Drugs.also of coadministered Drugs.

however in the case of drugs metabolically however in the case of drugs metabolically transformed to reactive metabolites ,enzyme transformed to reactive metabolites ,enzyme induction may exacerbate metabolite –induction may exacerbate metabolite –mediated tissue toxicity.mediated tissue toxicity.

Enzyme inhibition Enzyme inhibition

Certain drugs substrate may inhibit Certain drugs substrate may inhibit cytochrome P450 enzyme activity . cytochrome P450 enzyme activity . Imidazole-containing drugs such as Imidazole-containing drugs such as cimetidine and ketoconazole bind tightly to cimetidine and ketoconazole bind tightly to the heme iron of cytochrome P450 and the heme iron of cytochrome P450 and effectively reduce the metabolism of effectively reduce the metabolism of endogeneous substrate .endogeneous substrate .

Enzyme inhibition Enzyme inhibition

Alternately some drugs can inhibit the Alternately some drugs can inhibit the metabolism of other drugs. Drug metabolism of other drugs. Drug metabolism being an enzymatic process metabolism being an enzymatic process can be subjected to competitive inhibition. can be subjected to competitive inhibition. For example, warfarin inhibits tolbutamide For example, warfarin inhibits tolbutamide elimination which can lead to the elimination which can lead to the accumulation of drug and may require a accumulation of drug and may require a downward adjustment of dose. downward adjustment of dose.

Synthetic reaction Synthetic reaction 1.Glucuronide conjugation – this is the most 1.Glucuronide conjugation – this is the most important synthetic reaction . Compounds with important synthetic reaction . Compounds with a hydroxyl or carboxylic acid group are easily a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is conjugated with glucuronic acid which is derived from glucose . Ex- chloramphenicol , derived from glucose . Ex- chloramphenicol , aspirin , morphine . Not only drug but aspirin , morphine . Not only drug but endogenous substrate like bilirubin , steroidal endogenous substrate like bilirubin , steroidal hormones and thyroxin utilized this pathway.hormones and thyroxin utilized this pathway.

Diagram of entero-hepatic Diagram of entero-hepatic circulationcirculation

liver

gutunconjugateddrug

biliary tract

to circulation

conjugated drug

bacteria

portal vein absorption

Synthetic reactionSynthetic reaction

2. Acetylation – Compounds having amino or 2. Acetylation – Compounds having amino or hydrazine residues are conjugated with the hydrazine residues are conjugated with the help of acetyl coenzyme – A , e.g. help of acetyl coenzyme – A , e.g. sulfonamides , isoniazid , hydralazine . sulfonamides , isoniazid , hydralazine . Multiple genes control the acetyl transferases Multiple genes control the acetyl transferases and rate of acetylation shows genetic and rate of acetylation shows genetic polymorphisn .polymorphisn .


Methylation – The amine and phenols can be Methylation – The amine and phenols can be methylated , methionine and cysteine acting as methylated , methionine and cysteine acting as methyl doners , e.g. adrenaline , histamine , methyl doners , e.g. adrenaline , histamine , nicotinic acid .nicotinic acid .

4. Sulfate Conjugation :The phenolic and steroid 4. Sulfate Conjugation :The phenolic and steroid compounds are sulfated by sulfokinase.compounds are sulfated by sulfokinase.

5. Glycine conjugation – salicylates and 5. Glycine conjugation – salicylates and other drugs having carboxylic acid group other drugs having carboxylic acid group are conjugated with glycine , but this is not are conjugated with glycine , but this is not a major pathway of metabolism.a major pathway of metabolism.

6. Glutathione conjugation:6. Glutathione conjugation:

7. Ribonucleoside / nucleotide synthesis :7. Ribonucleoside / nucleotide synthesis :


Elimination/ ExcretionElimination/ Excretion

Excretion is the passage out of systemically absorbed drug.

Drugs and their metabolites are excreted in –

1. Urine

2. Faeces

3. Exhaled air

4. Saliva and sweat

5. Milk

Elimination via the kidneyElimination via the kidney Depends on

- blood flow to kidney (normal 1500ml/min)

- glomerular filtration rate (normal 100mls/min)- active secretion of drugs into the kidney

tubule- passive reabsorption back into the tubule

Therefore those with a poor renal function will not eliminate so well

- renal failure or dysfunction elderly or neonates

Elimination by the kidneyElimination by the kidney

drug filtered some drugs activelysecreted

some drugsreabsorbed

Drug elimination via the Drug elimination via the liverliver

Depends onblood flow to the liveractivity of the enzyme in the liver

Liver enzymes will chemically alter the drug to form ‘metabolites’ which are:inactivate orequally or more active than the parent drug

Drug elimination and the liverDrug elimination and the liver

Metabolites are eventually eliminated via the kidney as they become more water soluble

Factors which may reduce elimination via the liverelderly have poorer blood flowneonates have a low liver enzyme activitysome drugs reduce liver enzyme activityany extensive liver damage

Diagram of first pass effectDiagram of first pass effect(excretion)(excretion)

liver

gut

biliary tract

to circulation

metabolised drug

portal vein

unmetaboliseddrug

Diagram of entero-hepatic Diagram of entero-hepatic circulation and elimination of drugcirculation and elimination of drug

liver

gutunconjugateddrug

biliary tract

to circulation

conjugated drug

bacteria

portal vein absorption

ClearanceClearance

Drug clearance principles are similar to the Drug clearance principles are similar to the creatinine clearance which is defined as the creatinine clearance which is defined as the rate of elimination of creatinine in the urine rate of elimination of creatinine in the urine relative to its serum concentration. At the relative to its serum concentration. At the simplest level, clearance of a drug is the simplest level, clearance of a drug is the factor that predicts the rate of elimination is factor that predicts the rate of elimination is relation to the drug concentration:relation to the drug concentration:

CL= Rate of elimination / CCL= Rate of elimination / C

The systemic clearance, CL, is a measure of the efficiency with which a drug is irreversibly removed from the body

Elimination of drug from the body may involve process occurring in the Kidney, the lung, liver and other organs.

Dividing the rate of elimination at each organ by the concentration of drug presented to its yields the respective clearance at that organs. Added together, these separate clearance equal total systemic clearance:

CL renal = Rate of elimination kidney / C ----(i)

CL liver = Rate of elimination liver / C -----(ii)

CL other = Rate of elimination other / C ---(iii)

CL systemic =CL renal + CL liver + CL other ---(iv)

Half LifeHalf LifeHalf life (tHalf life (t1/21/2) is the time required to change the ) is the time required to change the amount of drug in the body by one half during amount of drug in the body by one half during elimination or during a constant infusion. In the elimination or during a constant infusion. In the simplest case --- and the most useful in designing simplest case --- and the most useful in designing drug dosage regimens--- the body may be drug dosage regimens--- the body may be considered as a single compartment of a size equal considered as a single compartment of a size equal to the volume of distribution (Vto the volume of distribution (Vdd). While the organ of ). While the organ of elimination can only clear drug from the blood or elimination can only clear drug from the blood or plasma in direct contact with the organ, this blood or plasma in direct contact with the organ, this blood or plasma is in equilibrium with the total volume of plasma is in equilibrium with the total volume of distribution. distribution.

Thus , the time course of drug in the body will depend on both the volume of

distribution and the clearance.

t1/2 = 0.7 * Vd / CL

LOADING DOSELOADING DOSEWhen the time to reach steady state is When the time to reach steady state is

appreciable, as it is for drugs with long appreciable, as it is for drugs with long half-lives, it may be desirable to administer half-lives, it may be desirable to administer a loading dose that promptly raises the a loading dose that promptly raises the concentration of drug in plasma to the concentration of drug in plasma to the target concentration. target concentration.

This is a single or few quickly repeated This is a single or few quickly repeated doses given in the beginning to attain doses given in the beginning to attain target concentration rapidly.target concentration rapidly.

LOADING DOSELOADING DOSEIn theory, only the amount of the loading In theory, only the amount of the loading

dose need be computed--- not the rate of dose need be computed--- not the rate of its administration--- and, to a first its administration--- and, to a first approximation, this is so. approximation, this is so.

The volume of distribution is the proportionality factor that relates the

total amount of drug in the body to the concentration in the plasma (Cp) ; if a loading dose is to achieve the target

concentration,

Loading dose= Amount of the body immediately following the loading dose

=Vd * TC /F

For the theophylline example, the loading dose will be 350 mg (35 L *10

mg/L) for a 70 kg person. For most drugs, the loading dose can be given as

a single dose by the chosen route of administration.

Maintenance DoseMaintenance Dose In most clinical situations, drugs are In most clinical situations, drugs are

administered in such a way as to maintain a administered in such a way as to maintain a steady state of drug in the body, ie, just enough steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug drug is given in each dose to replace the drug eliminatedeliminated since the preceding dose. Thus since the preceding dose. Thus calculation of the appropriate maintenance dose calculation of the appropriate maintenance dose is a primary goal. is a primary goal.

This dose is one that is to be repeated at This dose is one that is to be repeated at specified intervals after the attainment of target specified intervals after the attainment of target Cpss so as to maintain the same by balancing Cpss so as to maintain the same by balancing the eliminationthe elimination

Maintenance DoseMaintenance Dose Clearance is the most important Clearance is the most important

pharmacokinetic term to be considered in pharmacokinetic term to be considered in defining a rational steady state drug dosage defining a rational steady state drug dosage regimen. regimen.

At steady state (SS), the dosing rate (rate in) must equal the rate of

elimination (rate out). Substitution of the target concentration (TC) for

concentration (C) predicts the maintenance dosing rate:

Dosing rate ss = Rate of elimination ss

= CL*TC

Thus, if the desired target concentration is known, the clearance in that patient will determine the dosing rate. If the drug is

given by a route that has a bioavailability less then 100%, then the dosing rate predicted by above equation must be

modified. For oral dosing

Dosing rate oral = Dosing rate / F oral

If intermittent doses are given, The maintenance dose is calculated from

maintenance dose=Dosing rate* Dosing interval

Tissue storageTissue storage

Brain--- Chlorpromazine, Brain--- Chlorpromazine, acetazolamide, isoniazid.acetazolamide, isoniazid.

Retina --- Chloroquine .Retina --- Chloroquine .

Iris--- Ephedrine, atropine .Iris--- Ephedrine, atropine .

Tissue storageTissue storage

Bone and teeth– Tetracyclines, heavy Bone and teeth– Tetracyclines, heavy metals .metals .

Adipose tissue--- Thiopentone, ether, Adipose tissue--- Thiopentone, ether, minocycline , phenoxybenzamine, minocycline , phenoxybenzamine, DDTdissolve in neutral fat due to high lipid DDTdissolve in neutral fat due to high lipid solubility , remain stored due to pore blood solubility , remain stored due to pore blood supply of fat . supply of fat .

Biotransformation Biotransformation

Biotransformation mean chemical alter Biotransformation mean chemical alter action of the drug in the body . It is needed action of the drug in the body . It is needed to render non polar components polar so to render non polar components polar so that they are not reabsorbed in the renal that they are not reabsorbed in the renal tubules and are excreted . Most tubules and are excreted . Most hydrophilic drugs , e.g. streptomycin, hydrophilic drugs , e.g. streptomycin, neostigmine , decamethonium , etc are not neostigmine , decamethonium , etc are not biotransformed and are excreted biotransformed and are excreted unchanged .unchanged .


Mechanism which metabolize drugs have Mechanism which metabolize drugs have developed to protect the body from developed to protect the body from ingested toxins . The primary site for drug ingested toxins . The primary site for drug metabolism is liver , others are – kidney metabolism is liver , others are – kidney intestine , lungs and plasma . intestine , lungs and plasma . Biotransformation of drugs may lead to the Biotransformation of drugs may lead to the following :following :

1.1.

Unique characteristics of the Unique characteristics of the oral routeoral route

Influences of gastric emptying, mucosal Influences of gastric emptying, mucosal surface area, and drug inactivation important surface area, and drug inactivation important for oral routefor oral route

Small intestine usually most important Small intestine usually most important because of large surface area (folds of because of large surface area (folds of Kerckring, villi, microvilli)Kerckring, villi, microvilli)

Clinical advantagesClinical advantages

Safest routeCheapest routeBest patient acceptance

DisadvantagesDisadvantagesDelayed effectPatient cooperation requiredUnique problems with GI toxicity

Absorption of drugs (2)Absorption of drugs (2)

From oral, sublingual, or rectal mucosa: From oral, sublingual, or rectal mucosa: passive diffusion.passive diffusion.May bypass first-pass inactivation May bypass first-pass inactivation

From the lungs: passive diffusionFrom the lungs: passive diffusionrapid absorption, dependent on particle size (6 µm rapid absorption, dependent on particle size (6 µm

cutoff)cutoff)

Absorption of drugs (3)Absorption of drugs (3)

From injection sites: subcutaneous tissues, From injection sites: subcutaneous tissues, muscle or fat, absorbed by diffusion and muscle or fat, absorbed by diffusion and affected by blood flowaffected by blood flow

From miscellaneous sites: skin, spinal canal, From miscellaneous sites: skin, spinal canal, tooth pulptooth pulp

Intravenous, intraarterial injection avoids Intravenous, intraarterial injection avoids absorptionabsorption

BioavailabilityBioavailability

Clinical pharmacology of differential Clinical pharmacology of differential absorptionabsorption

Related termsRelated termsbiologic equivalencechemical equivalencetherapeutic equivalence

DistributionDistribution

Absorbed drugs leave capillary wall quickly Absorbed drugs leave capillary wall quickly and freely (via filtration and diffusion) to enter and freely (via filtration and diffusion) to enter interstitial fluid; blood flow being important in interstitial fluid; blood flow being important in the regional distribution of drugsthe regional distribution of drugs

Binding to plasma proteins (mostly to albumin and, Binding to plasma proteins (mostly to albumin and,

for basic drugs, for basic drugs, 11-acid glycoprotein)-acid glycoprotein) major distribution site highest drug concentrations usually found in blood; serve

as drug depots, thus prolonging half-life of drugs pharmacologic effects and toxic manifestations affected

by hypoalbuminemia and copresence of other drugs also bound effectively to albumin

Central nervous system: permeable to lipid-Central nervous system: permeable to lipid-soluble drugs only; limited permeability to soluble drugs only; limited permeability to water-soluble drugs when inflamedwater-soluble drugs when inflamed

Placental transfer: limited by blood flow, not Placental transfer: limited by blood flow, not by a "barrier"by a "barrier"

Fat tissue: depot for thiopental and Fat tissue: depot for thiopental and chlorinated hydrocarbon insecticides (e.g., chlorinated hydrocarbon insecticides (e.g., DDT)DDT)

Sites for metabolism and excretion: liver, Sites for metabolism and excretion: liver, kidney, intestine, lungskidney, intestine, lungs

Redistribution: especially important for IV Redistribution: especially important for IV injection of lipophilic drugsinjection of lipophilic drugs

Redistribution of thiopental Redistribution of thiopental after intravenous injectionafter intravenous injection

Drug clearanceDrug clearanceDrug clearance principles are similare to the Drug clearance principles are similare to the clearance concepts of the renal physiology in which clearance concepts of the renal physiology in which creatinine clearance is defined as the rate of creatinine clearance is defined as the rate of elimination of creatinine of the urine relative to its elimination of creatinine of the urine relative to its serum concentration. At the simplest level clearance serum concentration. At the simplest level clearance of a drug is the factor that predicts the rate of of a drug is the factor that predicts the rate of elimination in relation to the drug concentration.elimination in relation to the drug concentration.

Rate of eliminationCL=

ConcentrationConcentration

CleranceClerance

Elimination pof drug from the body may Elimination pof drug from the body may involve processes occur the kidney, the involve processes occur the kidney, the lung, the liver, and other organs.lung, the liver, and other organs.

Rate of elimination Kidney

CL=ConcentrationConcentration

Half life: Half life:

Half life t1/2 is the time required to change Half life t1/2 is the time required to change the amount of drug in the body by one half the amount of drug in the body by one half during elimination.during elimination.

Distribution of drugsDistribution of drugs

Does not generally target the site of actionDoes not generally target the site of action Is diluted in the blood stream and carried Is diluted in the blood stream and carried

to all parts of the bodyto all parts of the bodyTissue concentration depends onTissue concentration depends on

physico-chemical propertiesphysico-chemical propertiese.g. lipid solubility, crossing blood/brain e.g. lipid solubility, crossing blood/brain barrierbarrier

blood flowblood flow

Volume of distributionVolume of distribution

DefinitionDefinition

Reflection of the amount left in the blood Reflection of the amount left in the blood stream after all the drug has been absorbedstream after all the drug has been absorbed

if drug is ‘held’ in the blood stream it will have if drug is ‘held’ in the blood stream it will have a small volume of distributiona small volume of distribution

if very little drug remains in blood steam has a if very little drug remains in blood steam has a large volume of distributionlarge volume of distribution

Penetration into brain and Penetration into brain and CSFCSF

The capillary endothelial cells in brain have The capillary endothelial cells in brain have tight junction and lack large intercellular tight junction and lack large intercellular pores . Further , an investment of neural pores . Further , an investment of neural tissues covers the capillaries . Together they tissues covers the capillaries . Together they constitute the so called blood – brain barrier . constitute the so called blood – brain barrier . A similar blood – CSF barrier is located in the A similar blood – CSF barrier is located in the choroid plexus: capillaries are lined by choroid plexus: capillaries are lined by choroidal epithelium having tight junction . choroidal epithelium having tight junction .

Penetration into brain and Penetration into brain and CSFCSF

Both these barriers are lipoidal and limits Both these barriers are lipoidal and limits the entry of non – lipid soluble drugs , e.g. the entry of non – lipid soluble drugs , e.g. Streptomycin, neostigmine etc. only lipid Streptomycin, neostigmine etc. only lipid soluble drugs , therefore , are able to soluble drugs , therefore , are able to penetrate and have action on the central penetrate and have action on the central nervous system . nervous system .

Volume of distribution- Volume of distribution- advancedadvanced

Formula for volume of distributionFormula for volume of distribution

V=D

C

V= volume of distributionD= dose (assuming all a

absorbed)C= concentration in blood

stream

If you know the volume of distribution it is possible to calculate the concentration in the blood stream for a particular dose

Volume of distribution advancedVolume of distribution advanced

Suppose there is a drug that gives a plasma Suppose there is a drug that gives a plasma concentration of 0.1mg/ml after giving a 1 concentration of 0.1mg/ml after giving a 1 gram bolus dose IVgram bolus dose IV

V=1000mg/0.1 = 10 litres

Usually expressed as litres/kg body wt.If this was a 50Kg personV=0.5L/Kg

Decline in renal function with Decline in renal function with ageage

Decline in renal function with Decline in renal function with ageage

0 1 10 20 30 40 50 60 70 80

S1

0

20

40

60

80

100

120

140

160

Ap

pro

xiam

te G

FR

m

l/min

/1.7

3m2

Age (years)

Change in Glomerular Filtration Rate with age

Diagram of entero-hepatic Diagram of entero-hepatic circulation circulation (advanced)(advanced)

liver

gutunconjugateddrug

biliary tract

to circulation

conjugated drug

bacteria

portal vein

Change in plasma concentrationChange in plasma concentration

Rate of elimination proportional to amount in body

Con

cent

ratio

n (m

g/L)

Time (hours)

Log

Con

cent

ratio

n (m

g/L)

Time (hours)

Half LifeHalf Life

Half-life is the time taken for the concentration of drug in blood to fall by a half

0

10

20

30

40

50

60

70

80

90

100

110

0 1 2 3 4 5 6 7 8 9

Time (hours)

Co

nce

ntr

atio

n (

mg

/L)

Accumulation and therapeutic Accumulation and therapeutic windowwindow

0

1

0.5

1.5

0.75

1.75

0.875

1.875

0.9875

1.9875

0.99275

1.99275

0.996375

1.996375

0

1

0.75

1.75

1.32

2.32

1.74

2.74

2.055

3.055

2.29

3.29

2.46

3.46

0

0.5

1

1.5

2

2.5

3

3.5

4

0 1 2 3 4 5 6 7 8

Time (hrs)

Lo

g C

on

ce

ntr

ati

on

(m

g/L

)

Half life = 1 hour

Half life= 2 hours

Toxicity

Therapeutic

Inject 1g stat druggives 1mg/L

Section 3: Section 3: TherapeuticsTherapeutics

Translating the pharmacological actions Translating the pharmacological actions of drugs into beneficial effects for of drugs into beneficial effects for patientspatients

Therapeutic and adverse effectsTherapeutic and adverse effects

Therapeutic or adverse effectsTherapeutic or adverse effects the result of a drug’s pharmacological actionsthe result of a drug’s pharmacological actions

Important considerationsImportant considerationshow drug action may be modifiedhow drug action may be modifiedhow both therapeutic and adverse effects may how both therapeutic and adverse effects may

be mediatedbe mediatedspeed of onset and duration of actionspeed of onset and duration of action interactions between drugs and disease statesinteractions between drugs and disease states

Quantitative aspects of drug Quantitative aspects of drug actionaction

Response alters as the dose changesResponse alters as the dose changesdefined by the shape of the dose response defined by the shape of the dose response

curvecurve

Partial agonist

Full agonistResponse

Dose (log)

Drugs that activate receptorsDrugs that activate receptorspossess both affinity and efficacypossess both affinity and efficacy full agonists have high efficacyfull agonists have high efficacypartial agonists have lower efficacypartial agonists have lower efficacy

Efficacy or potencyEfficacy or potency terms that are often confusedterms that are often confusedefficacy is the capacity to produce an effectefficacy is the capacity to produce an effect

Drugs that are antagonistsDrugs that are antagonistshave affinity but not efficacyhave affinity but not efficacymay be competitive or non-competitivemay be competitive or non-competitive

Drug efficacy Drug efficacy

The ability of a drug to produce an effectThe ability of a drug to produce an effect refers to the maximum therapeutic effectrefers to the maximum therapeutic effectadverse effects may make the maximum adverse effects may make the maximum

unobtainable unobtainable

Classes of analgesic differ in their efficacyClasses of analgesic differ in their efficacymorphine is a high efficacy analgesic morphine is a high efficacy analgesic nefopam is a moderate efficacy analgesicnefopam is a moderate efficacy analgesicmorphine gives more pain relief than nefopam morphine gives more pain relief than nefopam

irrespective of the dose of nefopam givenirrespective of the dose of nefopam given

Drug potencyDrug potency

Amount of drug in relation to its effectAmount of drug in relation to its effect drugs may differ in potency, but have similar efficacydrugs may differ in potency, but have similar efficacy

Opioid analgesic have different potenciesOpioid analgesic have different potencieshydromorphone 1.3mg is equivalent to hydromorphone 1.3mg is equivalent to

morphine 10mgmorphine 10mghydromorphine is more hydromorphine is more potent potent than morphine than morphinebut both drugs can achieve the but both drugs can achieve the samesame max max

effect effect

ExcretionExcretion

Renal excretionRenal excretioninvolves glomerular filtration and tubular

reabsorption and secretion

excretion increased by decreasing tubular

reabsorption, thus basic drugs are excreted better in acidic urine, acidic drugs better in alkaline urine

clinical application—aspirin and barbiturate poisonings are treated by alkalization of patients’ urine by giving sodium bicarbonate

OthersOthers

BileLungFecesSaliva (pp. 24-25, Table 2-1)SweatMilk

Time Course of Drug ActionTime Course of Drug Action

General rulesGeneral rules Compartment modelsCompartment models

Single-compartmentMultiple-compartment

Exceptions to general rulesExceptions to general rules

General rulesGeneral rules

Plasma concentration related to degree of Plasma concentration related to degree of receptor binding, thus magnitude of drug receptor binding, thus magnitude of drug effecteffect

Disposition processes usually first orderDisposition processes usually first orderElimination usually slower process than Elimination usually slower process than

absorption or distributionabsorption or distribution

First-order process:First-order process:dC/dT = k•C (constant fraction)

Zero-order process:Zero-order process:dC/dT = k (constant amount)

Capacity limited process:Capacity limited process:low C, first-order; high C, zero-order

Single-compartment modelSingle-compartment model

Vd

BodyAbsorption Elimination

ka ke

C = D/Vd or Vd = D/C

Single compartment model: no Single compartment model: no absorption, first-order absorption, first-order

eliminationelimination

Clearance (CL): the measurement of blood Clearance (CL): the measurement of blood cleared of the drug by elimination per unit cleared of the drug by elimination per unit time (as in units of mL/sec). It and the time (as in units of mL/sec). It and the volume of distribution (Vvolume of distribution (Vdd) create the ) create the dependent variable Tdependent variable T1/21/2. They are related by . They are related by the following formula:the following formula:

T1/2 = 0.693Vd/CL

With renal excretionWith renal excretion

C•Cl = U•V

Where C = plasma concentration, Cl = clearance, U = urinary concentration, and V = urinary volume

Cl = U•V/C

Drug disappearanceDrug disappearance usually follows first-order kinetics (exponential decay),

with a constant fraction (not amount) of drug being eliminated per unit of time

the process is independent of the kind and amount of drug

half-life (T1/2), not dose, is the primary factor in prolonging drug effects

Overriding importance of half-Overriding importance of half-life on duration of drug effectlife on duration of drug effect

Drug accumulation with repeated Drug accumulation with repeated dosingdosing

Multicompartment modelsMulticompartment models

combine kinetics of redistribution and combine kinetics of redistribution and eliminationelimination

provide best description of drugs with high provide best description of drugs with high lipid solubility and drugs given intravenouslylipid solubility and drugs given intravenously

Two-compartment modelTwo-compartment model

pH - pKa = log baseacid

Henderson-Hasselbach Henderson-Hasselbach equationequation

For an acidic drug: acid = HA; base = A-

For a basic drug: acid = BH+; base = B

Theoretical absorption of Theoretical absorption of aspirin and codeine for dental aspirin and codeine for dental

painpain

Specialized Specialized transporttransport

Nonspecific active transport of drugs , Nonspecific active transport of drugs , their metabolities and some their metabolities and some endogenous products occurs in renal endogenous products occurs in renal tubules and hepatic sinusoids which tubules and hepatic sinusoids which have separate mechanisms for organic have separate mechanisms for organic acid and organic bases . Certain drugs acid and organic bases . Certain drugs have been found to be actively have been found to be actively transported in the brain and choroid transported in the brain and choroid plexus also .plexus also .


3. Hydrolysis – This is cleavage of drug 3. Hydrolysis – This is cleavage of drug molecule by taking up a molecule of molecule by taking up a molecule of water .water .

Ester + HEster + H22O O Acid + alcohol Acid + alcohol

Similarly amides and polypeptides are Similarly amides and polypeptides are hydrolysed by amidases and peptidases .hydrolysed by amidases and peptidases .

esterase

Pharmacokinetics

Documents

inactive drug

rate of drug metabolism

active metabolites

free drug

drug molecule

parent drug

rate of metabolism

various oxidation reaction