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


      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


      Hepatitis, cirrhosis, heavy metal poisoning – impaired metabolism

Drug Excretion


       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


       Volatile general anesthetics

       Paraldehyde, alcohol – partially excreted by lungs


       Hepatocytes actively secrete drugs and their metabolites into bile

       Doxycycline, cefaperazone  - high conc in bile

       Enterohepatic circulation


       Enterocyte transporters/ passive diffusion

       Drug/ metabolite secreted into lumen

       Cassia, senna, heavymetals


       Small quantity

       Arsenic, mercury


       Iodides & metallic salts in saliva

       Lead sulfide deposits in gum


       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:


       Metabolism in liver

       Renal excretion

       Protein binding

       Modifying mol. structure

       By retarding:


       Metabolism in liver

       Renal excretion

       Protein binding

       Modifying mol. structure


       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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