Drug-Drug and Pharmacogenetic Interactions

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What are the possible mechanisms by which medications or supplements affect antihypertensive medication effectiveness?

The mechanisms by which medications or supplements may impact antihypertensive effectiveness include modulating the metabolism of the antihypertensive medication and activating molecular mechanisms which counteract the targeted blood pressure–lowering mechanisms. Drug metabolism is mediated, in part, by the cytochrome P450 proteins, which are monooxygenases which participate in activation, inactivation, and clearance of drugs. Cytochrome P450 3A4 (CYP3A4), for instance, participates in the oxidation, inactivation, and removal from the circulation for a number of drugs including dihydropyridine calcium channel blockers such as nifedipine. Rifampin, an antibiotic often used in the treatment of tuberculosis, causes an induction of CYP3A4 which leads to decreased systemic concentrations of nifedipine and worsening hypertension. Nonsteroidal antiinflammatory drugs (NSAIDs), by contrast, lead to increased blood pressure without altering drug metabolism. NSAIDS inhibit the cyclo-oxygenase pathway of arachidonic acid metabolism and decrease the formation of prostaglandins which modulate blood pressure though a number of mechanisms including altered tubular secretion of salt and water and modulation of the renin-angiotensin-aldosterone system. The overlap between these mechanisms and those modulated by thiazide diuretics and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) results in attenuated activity of these classes of antihypertensives in the presence of NSAIDS. Additional mechanisms are presented in Table 39.1 . Antihypertensive medications affected by cytochrome P450 are listed in Table 39.2 .

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