Drug Metabolism

Question 0

Paracetamol

Answer 0

Small % metabolised by isoforms CYP3A4 and 2E1-> produced a toxic compound

• > normally mopped u by glutathione
• > in overdose too much NAPQ1 toxic metabolite is produced for the body to deal with

Question 1

Elimination

Answer 1

Removal of parent drug from the body
Water soluble-> liver or kidney excretion
Lipid soluble-> liver metabolism-> water soluble
Volatile-> lung excretion

Question 2

Drug metabolism phase 1

Answer 2

Introduction or unmasking of functional group, some increase in water solubility
Oxidations-> microsomal mixed function oxidase system-> ER of liver -> CYP’s
RH+NADPH+O2->CYP450-> ROH+NADPH+H2O
P459 cycle-> Fe2+ (RH), ->Fe2+OOH(RH) ->FE2+(ROH)-> ROH and Fe2+
Aromatic hydroxylation-> propranolol
Aliphatic hydroxylation-> ibuprofen
N and O dealkylation-> diazepam, codeine
Deamination-> oxygenation intermediate-> amphetamine
S-oxidation-> promethazine
Oxidative dehalogenation-> halothane

Question 3

Important forms of CYP450

Answer 3

1A2-> inducible eg smoking
2C9-> genetic variation, inducible
2C19-> genetic variation 
2D6-> genetic variation
2E1-> inducible, alcohol
3A4-> inducible

Question 4

Non P450

Answer 4

Oxidations:
Alcohols-> ethanol dehydrogenase
Amines-> mono amine oxidises 
Reductions:
Nitro reduction-> chloramphenicol
Reductive dehalogenation-> halothane
Hydrolysis:
Esters-> esmolol
Amides-> lidocaine

Question 5

Phase 2 reactions

Answer 5

Conjugation with endogenous chemical at functional centre
Large increase in water solubility by increased polarity
Glucuronidation-> adds OH-> morphine, paracetmol
-> adds COOH-> naproxen
-> adds NH2-> dapsone
Sulphination-> adds OH-> paracetamol
Glycine conjugation-> adds OH-> salicyclic acid
Acytalation-> add NH2-> sulphonamides
Via transferases
Requires energy

Question 6

Enzyme induction by other drugs

Answer 6

Increase rate of enzyme activity mediated by new protein synthesis-> inducers
Alters rate of metabolism of inducer itself and other drugs given concurrently
Important if drug treatment is chronic or small therapeutic range
Rifampicin -> reduces warfarins anticoagulant effect
Phenytoin-> OCs-> reduced contraceptive effect
Cigarette smoke-> theophylline-> reduced bronchodilation

Question 7

Enzyme inhibition

Answer 7

Decrease rate of enzyme activity
Usually due to non specific nature of enzymes
Erythromycin-> inhibits CYP450-> increases warfarin conc
Inhibition of disopyramide metabolism hetocanazole -> arythrmias
Cimetidine retards oxidation hepatic drug metabolism by binding P450

Question 8

Other factors effecting drug metabolism

Answer 8

Age-> decreased levels of drug metabolism at both extremes of age
Liver disease-> decreased drug metabolism in acute viral hepatitis and chronic liver disease
Genetic factors