Calcium antagonists: past, present and future - a personal view

Calcium antagonists are now widely used in the management of patients with a variety of cardiovascular disorders, including angina pectoris and hypertension. The prototype of the group – the phenylalkylamine-based verapamil – lacked tissue specificity within the cardiovascular system. Its introduction triggered the search for other calcium antagonists with improved tissue selectivity and resulted in the introduction of a variety of dihydropyridine based compounds including nifedipine, nisoldipine, nitrendipine and felodipine. These drugs exhibited improved tissue selectivity relative to verapamil, but possessed unfavourable pharmacokinetic profiles resulting in short duration of action, short plasma half-lives and rapid onset of action. The resultant unfavourable side effects limited the efficacy of these compounds and although the introduction of slow release formulations attenuated some of the problems encountered during their use the search for a tissue selective calcium antagonist with an intrinsically favourable pharmacokinetic profile continued, resulting in the development of amlodipine. Although a dihydropyridine, amlodipine differs from its predecessors in having a strongly ionized side-chain and an ability to insert directly into membranes lipid bilayers. This therefore provides the prototype of a third generation of calcium antagonists characterised by possessing a favourable pharmacokinetic profile (slow onset and prolonged duration of action coupled with a long plasma half-life) due to its own molecular structure. For purposes of classification verapamil can be regarded as the prototype of the first generation of calcium antagonists, nifedipine as the prototype of the second generation (improved tissue selectivity) whilst amlodipine is the prototype of a third generation (retained tissue selectivity with an intrinsically favourable pharmacokinetic profile). Clinically amlodipine is an effective blood pressure lowering agent in hypertensives, where it also reverses left ventricular hypertrophy. Surprisingly amlodipine’s safety extends to its long-term use in hypertensives with severely compromised left ventricular function – including chronic heart failure associated with non-ischaemic, dilated cardiomyopathy. J Clin Basic Cardiol 1999; 2: 155–61.