DRUG-INTERACTIONS WITH ANTIHYPERTENSIVE D RUGS

Numerous of pharmacokinetic and pharmacodynamic interactions with anti hypertensive drugs have to be considered. In this review, interactions are analysed in the major organ sites of these interactions and in ca rdiovascular target sites of arterial hypertension, with respect to th e major antihypertensive drugs. Many antihypertensive drugs are metabo lized in the liver (calcium antagonists, liposoluble beta-blockers, an d some ACE-inhibitors) via the cytochrome-oxidase system. Phenytoin, b arbiturates, and rifampin can accelerate the breakdown of these drugs; conversely, cimetidine, which inhibits oxidase system, can increase a ntihypertensive drug levels, resulted in greater therapeutic effect. H epatic blood flow can be modified by propranolol and nifedipine with o pposite effects. When combined with nifedipine the breakdown of propra nolol is accelerated because of an increase of hepatic blood flow. In the kidney, some anti-hypertensive agents interact with other cardiova scular drugs by competing for renal clearance; calcium antagonists alt er the renal clearance of digoxin, but the mechanism remains unclear. In vascular muscle cells, excess vasodilatation or vasoconstriction ca n be observed. The combination of an alpha(1)-blocking agent with a di hydropyridine can induce hypotension, which is sometimes severe. Non-s teroidal antiinflammatory drugs (NSAIDs) are able to lessen the antihy pertensive effects of beta-blockers, diuretics and ACE-inhibitors, via vascular prostaglandin inhibition. The cardiac pharmacodynamic intera ctions of beta-blockers and calcium antagonists, verapamil and diltiaz em, at the sino-atrial node, atrio-ventricular node, conduction system and myocardium are well established and must be avoided. The main int eractions with beta-blockers concern calcium antagonists, class I anti arrhythmic drugs and NSAIDs. With calcium antagonist interactions with beta-blockers, digitalis, class I antiarrhythmic, alpha-blocking agen ts, cyclosporin, and cimetidine have to be particularily considered. I nteractions with loop and thiazide diuretics concern ACE-inhibitors an d NSXIDs, and with potassium-sparing diuretics, mainly ACE-inhibitors. With ACE-inhibitors the risk of renal impairment and hyperkaliemia mu st be underlined when associated to excessive diuretic therapy, NSAIDs and heparin, particularly in diabetics. Beneficial interactions may o ccur through synergic effects, leading to fixed combinations of two an tihypertensive drugs; a greater efficacy and a better tolerance are ex pected because of potentiation and lower doses.