Clinical Pharmacology and Therapeutics

INHERITED DISEASES THAT PREDISPOSE TO DRUG TOXICITY 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 antiseizure
medications.
FURTHER READING
Evans DA, McLeod HL, Pritchard S, Tariq M, Mobarek A. Inter-ethnic
variability in human drug responses. Drug Metabolism and
Disposition 2001; 29: 606–10.
Evans WE, McLeod HL. Drug therapy: pharmacogenomics – drug
disposition, drug targets, and side effects. New England Journal of
Medicine 2003; 348: 538–49.
Wang L, Weinshilboum R. Thiopurine S-methyltransferase pharmacogenetics:
insights, challenges and future directions. Oncogene 2006;
25: 1629–38.
Weinshilboum R. Inheritance and drug response. New England Journal
of Medicine 2003; 348: 529–37.
Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside.
Nature Reviews. Drug Discovery 2004; 3: 739–48.
Wilkinson GR. Drug therapy: drug metabolism and variability among
patients in drug response. New England Journal of Medicine 2005;
352: 2211–21.