[Clinical development of therapy with two antihypertensive agents in fixed combination]

Changing the blood pressure brings counter-regulatory effects into play which may impair the antihypertensive efficacy of treatment targeted at a single blood pressure regulatory factor. Thus, diuretics stimulate the renin angiotensin and catecholamine systems and, in some cases, vasopressin. Arteriolar vasodilators stimulate the sympathetic nervous system and renin-angiotensin system, while blockade of the renin-angiotensin system itself triggers a reactive release of renin which may then serve to restore normal circulating angiotensin II levels. Rational combinations can therefore be developed to neutralize the effects of counter-regulation and achieve blood pressure control at lower drug doses and hence with fewer side-effects. Such combinations can also be prescribed in steadily increasing doses of each drug, to achieve blood pressure control by a process of 3-stage titration. The stringent rules governing the clinical development of such combinations are reviewed: formulation, pharmacokinetics, pilot studies, factorial design, high-risk patients. One advantage of combination therapy is that it enhances compliance, as an entire treatment is contained in a single pack of drugs. A disadvantage is the potential multiplicity of combinations between the five or six major classes of antihypertensive drug.