1 PHARMACOKINETICS DR.ABDUL LATIF MAHESAR KING Dr.SAUD UNIVERSITY October 2008D.

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PHARMACOKINETICS

DR.ABDUL LATIF MAHESAR

KING Dr.SAUD UNIVERSITY

October 2008D

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DRUG ABSORPTION

Is the passage of the drug through body barriers or cell membranes to reach its site of action

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Mechanism of Drug Movements Across Cell Membrane

Passive diffusion ( simple diffusion )

Active transport

Facilitated diffusion ( need carrier )

Pinocytosis (endocytosis)

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Passive diffusion Types: a) Aqueous Diffusion ( filtration through the

pores) => water soluble and low molecular weight.

B) Lipid diffusion => lipid soluble and low molecular weight.

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Charactersa. Commenestb. Non selectivec. Require no energyd. Depends on concentration gradiente. Depends on lipid/water partition coefficientf. Depends on PKa (of drug) and PH ( of the

medium.

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PKa ( is the dissociation or inization constant) is the PH at which half of the substance is ionized and half is unionized

PH is the ionization of the drug weak acids => best absorbed in stomach( because acid wont be ionized – lipid soluble – best absorption.

Note: strong acids or bases are fully ionized (polar+water soluble)- can not cross cell membrane ,given IV infusion

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Active transport Relatively not common Against concentration gradient Requires carrier + energy Specific e.g iodides Saturable with receptor Depends on lipid/water coefficient Iron absorption Uptake of levodopa by brain

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Carrier mediated Along concentration gradient Requires carrier Doesn’t need energy Selective Saturable e.g uptake of glucose .vit.B12 and

intrinsic factor.

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Endocytosis High molecular weight drugs

There is engulfment of the substrate by the cell e.g vit A,E, D ,K

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Factors affecting Drug absorption a) Drugs: 1. Molecular weight

2. PKa 3. Lipid water partition coefficient. 4. Drug formulation

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b) Patient: 1. PH of the gut

2. Rate of the gastric emptying 3. Presence of the food in the gut 4. Intestinal motility (transient time) 5. Surface area available for

absorption 6. Drug interaction

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c) Food: 1. Reduces absorption e.g

aspirin,pencillin v, tetracyclin, erythromycin

2. Increases absorption e.g propranolol, diazepam, dicoumrol

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2 .DISTRIBUTION1 .ECF (extra cellular fluid)

Plasma (5% of body weight)Interstitial fluid (16% of body weight)Lymph (1% of body weight)

2. ICF (intracellular fluid)35% sum of fluid contents of all cells in the body

3. Transcellular fluid (2%) cerbrospinal , synovial, peritoneal,pleural, digestive secretion.

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THE MAJOR BODY FLUID COMPARTMENTS

1.Intravascular(one compartment)in blood (not filtered through endothelium)

2.Extra vascular (2 compartments) i-e blood and interstitial fluid pass endothelium but not cell membranes e.g Nitroglycerine.

3.Extravascular and intracellular( multicompartment)pass endothelium and cell membranes.e.g physostigmine.

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Factors affecting distribution1. Cardiac output and blood flow. increased

cardiac output increases the distribution2. Physiological properties of the drug3. Permeablity across tissue barrier4. Plasma protein binding with drug5. Tissue binding with drug6. PH7. PKa8. Lipid solubility (fat water partition)

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Volume of distribution(vd) It is the amount of drug in the body to

the concentration of the drug in blood or plasma.

vd = amount of drug in the body Cp (concentration in plasma)

Increase in Cp ,decreased is the volume of distribution and vice versa

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Drugs with high volume of distribution

Higher concentration in tissue than in plasma

Relatively lipid soluble

Distributed intracellularly

low molecular weight → easy to cross barrier.

not efficiently removed by the hemodialysis e.g phenyton ,morphine , digoxin,tricyclic anti-depressants

cross BBB or placental barrier easily

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Drugs with low volume of distribution confined to plasma and interstitial fluids(not tissues)

Distributed in extracellular compartment mostly

High MW ,eg.heparin,insulin ,dextran

these are polar or lipid insoluble drugs e.g carbenicillin, vecuronium,gentamycin

High plasma protein binding e.g warfarin

Don’t cross BBB or placental barrier→ because of lipid insolubility

All skeletal muscle relaxants have low vd.

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Physiological barriers Blood brain barrier (BBB) Placental barrier

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Placental barrier Drugs cross placenta by simple diffusion

lipid soluble drugs readily (easily) enter the fetal blood

In mother if given Morphine → respiratory depression in the fetus Warfarin → hemorrhage ( if taken in the 1st

3months → congenital malformation) Anti-thyroid drugs → neonatal goiter

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Passage of drugs in to CNS and CSF Controlled by BBB

lipid soluble drugs e.g general anesthetics , CNS depressants, antibiotics chloramphenicol and sulphadiazine.

Inflammation as in meningitis ( in meningitis → permeability is increased e.g penicillin ,gentamycin.

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Binding of Drugs Tissue binding ( some drugs posses and affinity for certain

tissues and get accumulated in there like :

1. Bone e.g tetracycline and heavy metals such as lead ( which combine with collagen)

2. Fat :drugs like thiopental and ether

3. Salivary and thyroid glands: Iodides

4. Liver: quinacrine ( 300 time more in liver) chloroquine with nucleic acid

5. Hair and Skin: arsenic( combines with keratin)

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Plasma Protein Binding Albumin:acidic drugs bind with albumin

such as warfarin,phenetoin, aspirin ,sulphonamides

Globulin : Basic drugs such as quinidine ,diazepam

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Drugs exists in Bound form Unbound or free form Bound drugs

Not available for combination with receptorNo pharmacological actionNot available for metabolismNot available for excretionlong duration of actionmay lead to clinically important drug - drug

interaction

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Unbound Drug Pharmacologically active Available for metabolism Available for excretion Has short duration of action.

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Displacement some drugs can compete with each other for the

same site on the plasma protein and displace drugs thus increasing their concentrations to toxic level.

e.g. Warfarin-strong + tolbutamide- weak → hypoglycemia (warfarin is binding where tolbutamide is free +effect)

Aspirin –strong + warfarin-weak → bleeding

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Termination of the drug Biotransformation Excretion Redistribution

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Resdistribution: resdistribution of the drug from its site of

action to other tissues e.g thiopental

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METABOLISM Drug metabol(biotransformation) It is the chemical reactions which lead to modification of drugs Sites of metabolism - Hepatic:

microsomes ,mitochondria, cytoplasm

- Extrahepatic: lung ,blood ,skin , GIT,

kidney.

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Microsomes: Microsomal enzyme system→ mixed

function oxidase → mono-oxigenase. its components:

cytochrome P450Flavinoprotein NADPHMolecular oxygen, Mg

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Mitochondria:mono-amine oxidase enzyme (MAO)Acetylation

Cytoplasm:Alcohol dehydrogenase

Blood (plasma)EstrasesAmidasesCatechol-o methyltransferases(COMT)

Intestinal Mucosa and Lumen:GIT flora:Glucouronidase ,Asoreductases.

GIT mucosa : Monoamime oxidase (MAO) , Suphatase

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Types of Metabolic ReactionPhase I reaction (non-synthetic)Phase II reaction (synthetic)

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Phase I Reaction: Make the drug more polar → more water solulble.(oxidation –reduction- hydrolysis) Oxidarion reaction:

introduces functional group (OH,NH2,SH) Can be mirosomal or nonmicrosomal

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Microsomal: Drug + O2 +NADPH+H→changed drug +H2O +NADPH e.g. 1. Aliphatic hydroxylation

Phenobarbital→hydroxyphenobarbital2. Aromatic hydroxylation

Phenacetin→ 2-hydroxyphenacitin (paracetamol)3. Oxidation of amine

Aniline → nitrobenzene4. sulphoxidation

Parathione → paroxon

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Non-microsomal: oxidation by soluble enzyme in cytosol or

mitochondria of cells e.g 1. dehydrogenases and oxidases

Ethanol → acetaldehyde → acetic acid.Methanol → formaldehyde → formic acid

CH3CH2OH→ CH3CHO→CH3COOH

2. monoamide oxidase(noradrenaline) 3. Hypoxanthine → xanthine → uric acid

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Reduction Reactions: Microsomal or non-microsomal

Microsomasl:nitrobenzene → aniline

NO2 →NH2 Non-Microsomal:

Chloral hydrate → trichloroethanol

Hydrolysis:Non-microsomal ONLY

Ester-C-O and amides-C-N Acetylcholine → choline +acetate(ester) Procainamide (lidocaine) (amide)

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Characteristics of Phase I Products (Result of Drug Metabolism)

1 .Inactivation (abolish the activityOxidation of Phenobarbital and alcohol

Hydrolysis of acetylcholine2 .conversion of active drug to another active one.

Diazepam →oxydiazepamCodeine ,heroin → Morphine

Phenylbutazone → oxyphenylbutazonePropranolol → 4-hydroxypropranolol

3 .conversion of drug to toxic metabolites:Paracetamol → acetaminopen (hepatic toxicity)

Halothane → metabolite hepatotoxicity 4 .Activation of pro-drug

Chloral hydrate → trichloral hydrate 5 .Product might undergo phase II

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Phase II Conjugation Reaction (Synthetic reaction)

Glucuronide conjugationAminoacid eg.glycine

Acetylation reaction e.g CO-CH3

Sulphate conjugation SO4

Methylation reaction e.g CH3Noradrenaline → adrenaline

ALL is non-microsomal enzyme Except glucouronidation (catalyzed by glucouronyl transferase )

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Characteristics of Phase II Products

Product = Conjugate Pharmacologically inactive More water soluble→ to be excreted More readily excreted in urine

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Modulation of Liver Microsomal Enzymes

Induction Inhibition

Liver Microsomal InducersAlcohol

BarbituratesCigarette smoking

PhenytoinRifampicin

SpironalactoneGriseofulvin

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Enzyme Induction results in Increase metabolism of the inducer Tolerance: decreased pharmacological action of the

drug Increase the metabolism of co-administered drug (drug

interaction)Barbiturate +Warfarin

Phenytoin + Oral contraceptivesRifampicin + Hydrocortisone

Increased metabolite- mediated tissue toxicityParacetamol and phenacetin

As therapy ( phenobarbitone + hyperbilirubinemia)

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Liver Microsomal InhibitorsCimetidine

Erythromycinketoconazole

MetronidazoleProbenecid

Enzyme inhibition may Retard the metabolism and excretion of the inhibitor

and co-administered drugs

Prolong the action of the inhibitor and co-administered drugs→ increased pharmacological activity.

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First Pass Metabolism A drug can be metabolized before the drug reaches the

systemic circulation so the amount reaching systemic circulation is less than the amount absorbed

Where ? Liver ,gut wall, lungResult:

low bioavailabilityShort duration of action

How is it given e.g

MorphineSalbutamol

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4 .EXCRETION Main routes of excretion

Renal excretionBiliary excretion

Minor routes of excretionExhaled air

Salivary secrtetionsSweat MilkTears

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Renal excretion: Glomerular filtration Active tubular secretion Passive tubular reabsorption Alteration in tubular PH

e.g : gentamycin , ampicillin ,benzylpencillin ,digoxin

Contraindicaited: in case of renal failure

in case of elderly

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Glomerular filtration Only free drug (not bound to albumin) Low molecular weight drug( below 20000) renal plasma flow = 600ml /min GFR 20% of renal plasma flow = 125 ml/min

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Active Tubular secretion: Characters:

Selective

Require energy carrier Against concentration gardient Clearance to plasma protein bound drugsTypes

System for acidic drugsSystem for basic drugs

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System for Acidic Drugs:e.g. of acidic drugs:

salicylates,sulphonamides,penicillin,glucouronide conjugate, sulphate conjugate.

Blocked by : probenicid (inhibitor)→ carrier will carry this drug so ,

acidic drugs → long duration of action + blocker will excertion.

System for Basic Drugs:e.g

catecholamines,atropine ,morphine ,quinine ,neostigmine.

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Passive tubular reabsorption

Non ionized form (lipid soluble) can be reabsorbed back into systemic circulation

and excretion will be low

Ionized drugs are poorly reabsorbed and so rapidly excereted.

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Alteration in urine PHUrine is normally slightly acidic and favors

excretion of basic drugsAcidification of urine→ increased excretion

of basic drugsAlkalization of urine → increased excretion

of acidic drugs.

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Acidification of urine:by

ammonium chlorideascorbic acid

Alkalization of urineby

Sodium bicarbonateSodium lactateSodium citrate.

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Biliary excretion

Is important for some drugs that are metabolized in the liver

e.g :digoxin

Biliary excretion is useful in treating biliary infection

It plays a role in the removal of conjugated metabolites particularly glucouronides

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Enterohepatic CirculationBile passes into the intestine where drug if lipid soluble is

reabsorbed again and cycles is repeated.

Glucouronides are hydrolyzed in intestine liberating free drugs that can be reabsorbed back

This prolongs the action the druge.g. morphine , ethinyl estradiol ,

thyroxine

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Drug clearance