Pharmacokinetics
Content
• Enzyme induction and inhibition
• Factors affecting drug metabolism
• First and zero order kinetics
Intended Learning Outcomes
At the end of this lecture, student will be able to
• Describe enzyme induction and inhibition
• Give examples for clinically significant enzyme induction and inhibition
• Explain the factors affecting drug metabolism, differentiate between first and zero order kinetics
Enzyme induction
• Repeated administration of drug
• Stimulates smooth ER
• Enhanced microsomal activity
• Increase metabolism
• Decreased pharmacological response
• Prominent in liver
Clinical relevance of Enzyme induction
• Clinical consequences of increased drug metabolism
• Decreased effect - if metabolite inactive
• Leads to drug toxicity
– Ethanol drinkers prone to liver toxicity
• Knowledge can be used for therapeutic benefits
– Induction of fetal hepatic glucuronyl transferase
Enzyme inducers
• CYP3A4: Phenobarbitone, carbamazepine, phenytoin, pioglitazone
• CYP3A4: CYP2C9: Rifampicin, Phenobarbitone
• CYP1A2: Smoking, omeprazole, charcoal broiled meat
• CYP2E1: Chronic ethanol intake, isoniazid
Enzyme inhibition
• Inhibition of metabolism
• Increase the concentration
• Rapid process, usually reversible
• Sometimes irreversible – secobarbital overdose
• Chloramphenicol, erythromycin: hepatic MFOs - phenytoin, warfarin
• Disulfiram, tolbutamide: Aldehyde dehydrogenase –Alcohol, phenytoin
Clinical relevance of Enzyme inhibition
Potentially adverse consequences:
• Severe respiratory depression with morphine + MAOIs
• Enhanced bleeding tendency with dicoumarol + cimetidine
Therapeutically beneficial consequences:
• Levodopa + carbidopa
• Aversion of alcohol with disulfiram
• Reversal of Skeletal muscle paralysis due to dtc by neostigmine
Factors affecting in drug metabolism
• Age
– Low microsomal activity, GT activity, Above 60 yrs reduced hepatic blood flow
• Sex: Male rat – increased microsomal activity
• Species: Rabbits – increased atropine esterase activity
• Race: Chinese – headache, palpitation after alcohol
• Drug - drug interactions
• Genetic variation
– Slow acetylators + isoniazid – peripheral neuropathy
– Fast acetylators + isoniazid – Hepatotoxicity
– Pseudocholine esterase + succinyl choline – Prolonged apnoea
• Nutrition and diet
– Rich in protein, low in CH - ↑metabolism
– Starvation – Enzyme inhibition
• Disease
– Hepatitis, cirrhosis, heavy metal poisoning – impaired metabolism
Drug Excretion
Kidneys
• Passive Glomerular Filtration
– Unbound fraction of ionized drugs
– Reabsorbed by diffusion
– Small amount appears in urine
– Molecular weight < 20, 000 MW
• Active tubular secretion
– Weak acids and bases – actively secreted
– By carrier mediated systems
– Transporters such as P-gp & MRP2
– Secretion of weak organic acid (Penicillin) – inhibited by probenecid
• Tubular reabsorption
– Bidirectional process
– Drugs diffuse depending upon drug conc, lipid solubilty & pH
– Weak acids quickly eliminated in alkaline urine (Salicylates)
– Weak bases in acidic urine (Amphetamine, pethidine)
• Net renal excretion = [GF + T. secretion] – T. Reabsorption
Lungs
• Volatile general anesthetics
• Paraldehyde, alcohol – partially excreted by lungs
Bile
• Hepatocytes actively secrete drugs and their metabolites into bile
• Doxycycline, cefaperazone - high conc in bile
• Enterohepatic circulation
Intestine
• Enterocyte transporters/ passive diffusion
• Drug/ metabolite secreted into lumen
• Cassia, senna, heavymetals
Skin
• Small quantity
• Arsenic, mercury
Saliva
• Iodides & metallic salts in saliva
• Lead sulfide deposits in gum
Milk
• Passive diffusion
• More lipid soluble and less protein bound compound
Kinetics of Elimination
• Elimination: Metabolic inactivation + excretion
• Clearance: Theoretical volume of plasma from which the drug is removed in unit time
• CL = Rate of elimination / Plasma conc.
• Loading dose: single dose/ series of doses to achieve therapeutic drug conc.
• Maintenance dose: to maintain the steady state conc.
• Zero order (Linear kinetics)
• Rate of elimination remains constant
• Irrespective of drug conc.
• First order (Exponential kinetics)
• Rate of elimination ∝ drug conc.
• CL remains constant (constant fraction)
Mixed order kinetics
• Saturation kinetics/ Michaelis menton kinetics
• Phenytoin, digoxin, warfarin, tolbutamide, aspirin
• Smaller dose: 1st order
• Higher dose: Zero order
• Metabolising enzyme / elimination process - saturated
Kinetics of Elimination – Half life
• Plasma half life
• Time taken for its plasma conc. to be reduced to half of its original value
• Biological half life
• Time duration in which the principal pharmacological effect of drug decline by half
Methods of prolonging drug action
• By retarding:
• Absorption
• Metabolism in liver
• Renal excretion
• Protein binding
• Modifying mol. structure
• By retarding:
• Absorption
• Metabolism in liver
• Renal excretion
• Protein binding
• Modifying mol. structure
Summary
• Enzyme induction: slow irreversible process
• Enzyme inhibition: Rapid and mostly reversible
• Enzyme inducers: Phenobarbitone, phenytoin
• Enzyme inhibitors: chloramphenicol, erythromycin
• Zero order (Linear kinetics): Rate of elimination remains constant, Irrespective of drug conc.
• First order (Exponential kinetics):Rate of elimination ∝ drug conc, CL remains constant (constant fraction)
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