A Textbook of Clinical Pharmacology and Therapeutics

INHERITEDDISEASES THATPREDISPOSE TODRUGTOXICITY 85

Key points

• Genetic differences contribute substantially to
  individual (pharmacokinetic and pharmacodynamic)
  variability (20–50%) in drug response.


• Mendelian traits that influence drug metabolism
  include:
  (a) deficient thiopurine methyltransferase (TPMT)
  which inactivates 6-MP (excess haematopoietic
  suppression);
  (b) deficient CYP2D6 activity which hydroxylates
  several drug classes, including opioids, β-blockers,
  tricyclic antidepressants and SSRIs;
  (c) deficient CYP2C9 activity which hydroxylates several
  drugs including sulphonylureas, S-warfarin,
  losartan;
  (d) acetylator status (NAT-2), a polymorphism that
  affects acetylation of drugs, including isoniazid,
  hydralazine and dapsone;
  (e) pseudocholinesterase deficiency; this leads to
  prolonged apnoea after suxamethonium, which is
  normally inactivated by this enzyme.


• Several inherited diseases predispose to drug toxicity:
  (a) glucose-6-phosphate dehydrogenase deficiency
  predisposes to haemolysis following many drugs,
  including primaquine;
  (b)malignant hyperthermia is a Mendelian dominant
  affecting the ryanodine receptor in striated muscle,
  leading to potentially fatal attacks of hyperthermia
  and muscle spasm after treatment with
  suxamethonium and/or inhalational anaesthetics;
  (c) acute porphyrias, attacks of which are particularly
  triggered by enzyme-inducing agents, as well as
  drugs, e.g. sulphonamides, rifampicin and anti-
  seizure medications.

FURTHER READING

Evans DA, McLeod HL, Pritchard S, Tariq M, Mobarek A. Inter-ethnic

variability in human drug responses. Drug Metabolism and

Disposition2001; 29 : 606–10.

Evans WE, McLeod HL. Drug therapy: pharmacogenomics – drug

disposition, drug targets, and side effects. New England Journal of

Medicine2003; 348 : 538–49.

Wang L, Weinshilboum R. Thiopurine S-methyltransferase pharmaco-

genetics: insights, challenges and future directions. Oncogene2006;

25 : 1629–38.

Weinshilboum R. Inheritance and drug response. New England Journal

of Medicine2003; 348 : 529–37.

Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside.

Nature Reviews. Drug Discovery2004; 3 : 739–48.

Wilkinson GR. Drug therapy: drug metabolism and variability among

patients in drug response. New England Journal of Medicine2005;

352 : 2211–21.