Pharmacokinetic and pharmacodynamic aspects of the choice of components of combination therapy.

Several different strategies may underlie the development of combination products for the treatment of hypertension or other disease states. Some of these approaches may be more rational and justifiable than others. Amongst those which can clearly be justified are: (1) improved convenience (and compliance) in patients with an established need for two separate treatments; (2) increased efficacy over monotherapy; (3) reduced side-effects over monotherapy; (4) increased efficacy and reduced side-effects. As far as relevant pharmacokinetic issues are concerned, it is advisable to avoid pharmacokinetic interactions between the two components based on either induction or inhibition of drug metabolism or modification of protein binding as these will add unpredictable variability to the response to the drugs. Compatible if not similar pharmacokinetics are only of relevance if there is a close correlation between plasma concentration and effect for both components independently. Of more importance are dynamic issues, including the mechanism of action. It is preferable to use drugs with differing complementary mechanisms rather than identical mechanisms. It is not essential that the drugs have a similar duration of effect but the dose frequency will be determined by the drug with the shortest duration of effect. These principles provide a sound basis for the development of combination regimens in hypertension including an ACE-inhibitor with a thiazide diuretic and also the combination of a beta-blocker with a dihydropyridine calcium antagonist. The combinations have been established to have a role in the management of hypertension.