Drug Metabolism and Interactions Flashcards
Why are genetic polymorphisms of drug metabolism important?
Genetic variation can alter response to drug therapy. For example, ACEi may prevent the occurrence of diabetes in homozygous carriers of the 1166A variant of angiotensin 1 receptor gene, but not heterozygotes and non carriers.
Genetically determined enzyme activity may alter individual susceptibility to adverse drug reactions.
What drugs show changes in adverse effects with acetylator responses?
Slow acetylator response (occurring in around 50% of Caucasians) may be associated with adverse side effects due to higher drug concentrations:
- drug-induced lupus
- isoniazid induced peripheral neuropathy
Rapid acetylators have an increased propensity to adverse drug effects due to the actions of excess drug metabolites, for example, hepatitis due to a metabolite of isoniazid.
What is drug-induced lupus?
This is associated with a slow acetylator response and possession of HLA DR4.
In contrast to autoimmune SLE, the incidence is equal in men and women and laboratory findings include antibodies to histone and single-stranded DNA.
What are the clinical features of drug-induced lupus?
Arthralgia
Butterfly rash
Pleurisy
Renal involvement (except with hydralazine) and neuropsychiatric manifestations are unusual
What drugs cause lupus-like syndrome?
Beta blockers Hydralazine Phenytoin Chlorpromazine Isoniazid Procainamide Lithium Methyldopa Sulphonamides Tetracyclines
What drugs induce liver enzymes?
Drugs that induce liver enzymes increase their metabolism (and decrease the effectiveness) of other drugs.
Enzyme induction normally takes several days to be clinically apparent due to the time required to synthesise new enzyme.
Drugs that cause this effect can be remembered by "PC BRAS" Phenytoin Carbamazepine Barbiturates Rifampicin Alcohol (chronic, not acute) Sulphonylureas/ St Johns Wart
What drugs may be affected by enzyme induction?
Hydrocortisone
Oral contraceptive pill
Phenytoin
Warfarin
What drugs are inhibitors of liver enzymes?
A small number of drugs are capable of inhibiting hepatic enzyme systems and the effect may be immediate.
Enzyme inhibition can slow the metabolism of other drugs, thereby increasing their plasma concentration and the risk of adverse events.
Drugs capable of inhibiting liver enzymes may be remembered by "AODEVICCES" Allopurinol Omeprazole Disulfiram Erythromycin Valproate Isoniazid Ciprofloxacin Cimetidine Acute ethanol intoxication Sulphonamides
What drugs may be affected by liver enzyme inhibition?
Carbamazepine Ciclosporin Phenytoin Theophylline Warfarin
What can cause failure of the combined oral contraceptive pill?
Any condition that leads to impaired absorption of the components of the pill (e.g. traveller’s diarrhoea) can result in its failure as a contraceptive.
Oestrogenic component of the oral contraceptive pill may be metabolised more rapidly in the presence of liver enzyme inducers leading to pill failure. Enzyme inhibitors have no clinically significant effect.
Pill failure can also result from concurrent antibiotics use. For example, ampicillin, amoxicillin and tetracyclines may eradicate gut flora that deconjugates bile salts, therefore interrupting enterohepatic cycling of the oestrogen component. Prior to 2011, additional precautions where advised for 7 days after antibiotics were used in patients taking the COC. This advice is no longer required except for rifampicin.
