Pharmacogenetics and blood dyscrasias

Pharmacogenetic differences in the handling of and response to drugs can markedly alter the risk of severe idiosyncratic adverse drug reactions, including neutropenia, agranulocytosis and aplastic anaemia. Inherited deficiencies of drug metabolizing enzymes can shunt the metabolism of drugs to metabolites which are directly toxic (e.g. 6-mercaptopurine metabolism to 6-thioguanine nucleotides) or towards electrophilic metabolites which can kill cells and/or lead to a host immune response (e.g. sulphonamide metabolism to hydroxylamine metabolites). Defects in detoxification pathways (e.g. glutathione conjugation) similarly can predispose patients to adverse outcomes. The advent of molecular screening tools to define individual (rather than population) risk may lead to the use of clinical laboratory tests to identify/predict idiosyncratic adverse drug reactions.