Pharmacogenomics & Special Populations

Pharmacogenomics: inherited differences in drug handling

Principle. Inherited polymorphisms in metabolizing enzymes (CYP450, NAT2, TPMT), transporters, or drug targets shift drug levels and response, explaining idiosyncratic toxicity or non-response at standard doses. Metabolizer phenotypes range from poor to intermediate, normal, and ultrarapid. Poor metabolizers accumulate active parent drug; ultrarapid metabolizers may fail therapy, or dangerously over-activate a prodrug.

NAT2 slow acetylators. Clear isoniazid, hydralazine, procainamide, dapsone, and sulfonamides slowly. Higher levels cause drug-induced lupus (HIP: Hydralazine, Isoniazid, Procainamide; marked by anti-histone antibodies) and isoniazid peripheral neuropathy from pyridoxine depletion, prevented with vitamin B6.

TPMT. Thiopurine methyltransferase inactivates azathioprine and 6-mercaptopurine. With low or absent activity, 6-thioguanine nucleotides accumulate and cause life-threatening myelosuppression, so TPMT (and NUDT15) status is checked before dosing.

CYP2C19 and clopidogrel. Clopidogrel is a prodrug that CYP2C19 converts to an active thiol metabolite, which irreversibly blocks the platelet P2Y12 receptor. Loss-of-function alleles (*2, *3) create poor metabolizers with less platelet inhibition and more stent thrombosis; use prasugrel or ticagrelor instead. Omeprazole inhibits CYP2C19 and can blunt clopidogrel, so pantoprazole is preferred.

CYP2D6 and codeine. CYP2D6 converts codeine to morphine. Poor metabolizers (two loss-of-function alleles) get no analgesia; ultrarapid metabolizers (gene duplication) form excess morphine and risk respiratory depression, which is dangerous in breastfed infants of ultrarapid mothers and in children after tonsillectomy. Tramadol also depends on CYP2D6 for its opioid activity.

G6PD deficiency and HLA-linked reactions

G6PD deficiency. X-linked recessive and the most common enzyme deficiency worldwide. G6PD generates NADPH, which keeps glutathione reduced; without it red cells cannot withstand oxidative stress. Triggers: oxidant drugs (dapsone, primaquine, sulfonamides, nitrofurantoin, TMP-SMX), infection, and fava beans. Episodic hemolysis appears a few days after exposure, with dark urine; the smear shows Heinz bodies (denatured hemoglobin) and bite cells (left after splenic macrophages pit them out).

HLA screening. Some severe hypersensitivity reactions are predicted by HLA alleles, so testing before the first dose prevents them:

• HLA-B*57:01: abacavir hypersensitivity (screen before use; avoid if positive)
• HLA-B*15:02: carbamazepine or phenytoin Stevens-Johnson syndrome/TEN in Asian patients
• HLA-B*58:01: allopurinol SJS/DRESS

Pregnancy and teratogens

Labeling. The old FDA letter categories (A, B, C, D, X) were replaced in 2015 by narrative labeling (PLLR), but category X remains a useful board shorthand for "contraindicated": isotretinoin, warfarin, thalidomide, methotrexate, statins, and misoprostol. Organogenesis (weeks 3–8) is the highest-risk window.

Anticoagulation in pregnancy. Heparin and LMWH are large and polar and do not cross the placenta, so they replace warfarin; DOACs are avoided.

Kidney and liver disease

Renal impairment. Estimate clearance (Cockcroft-Gault) and, for renally eliminated drugs, reduce the dose or extend the interval and follow levels: aminoglycosides, vancomycin, digoxin, lithium, and gabapentin. The loading dose is usually unchanged. Avoid nephrotoxins such as NSAIDs, IV contrast, and aminoglycosides.

Hepatic impairment. Reduced oxidative (phase I) metabolism and low albumin raise the levels and free fraction of hepatically cleared, protein-bound drugs. Choose agents that bypass oxidation, such as lorazepam and oxazepam among benzodiazepines.

Neonates, children, and the elderly

Neonates. Immature UDP-glucuronosyltransferase cannot conjugate chloramphenicol, which accumulates and causes gray baby syndrome (cardiovascular collapse). Sulfonamides and ceftriaxone displace bilirubin from albumin, risking kernicterus. Higher total body water enlarges the distribution volume of hydrophilic drugs.

Elderly. Lower renal and hepatic clearance, lower serum albumin, and more body fat, which raises Vd and prolongs the half-life of lipophilic drugs such as diazepam. Polypharmacy multiplies interactions. The Beers criteria flag benzodiazepines, anticholinergics, first-generation antihistamines, and sulfonylureas as risky. Rule: start low, go slow.