Calcium Antagonists: Pharmacologic Agents in Search of New Clinical Indications

Abstract

The broad availability of new pharmacologic agents is usually followed by both the search for similar compounds with more specific and refined actions and the expansion of clinical applicability for these agents. During the last twenty years extensive investigations have revealed that calcium (Ca) antagonists hold a multifaceted pharmacodynamic potential that includes not only the antiarrhythmic and antihypertensive effects of the drug but also the protection against excessive Ca entry into the cells of the cardiovascular system and subsequent cell damage. The physiologic age-dependent Ca accumulation in the arterial wall, which inevitably appears after the second decade, reaches maximal values in the age group of eighty-one to ninety years when the aortic wall exhibits a total Ca content that is 100 times higher than in arteries of infants. In animals we also find age-dependent accumulation of Ca in the arterial wall that is severely aggravated by uncontrolled diabetes or hypertension. Fleckenstein has shown that this arterial calcinosis can be prevented by chronic administration of Ca antagonists. Furthermore, Fleckenstein has demonstrated that excessive Ca overload of myocardial tissue constitutes a basic pathologic process in the development of cardiac necroses—brought about by extreme beta-adrenergic drive (overdoses of catecholamines), high doses of vitamin D3, dihydrotachysterol, alimentary factors such as K or Mg deficiency, or genetic defects (hereditary cardiomyopathy). Even cardiac hypertrophy, either idiopathic or as a consequence of hypertension, can be prevented by the action of Ca antagonists. In addition, the uncontrolled Ca entry into the cell constitutes an important etiologic factor in microstructural impairment of the myocytes due to ischemia—hence Ca antagonists are successfully used as cardio-protective agents in cardioplegic solutions. More recently the tissue-protection action of Ca antagonists has also been proven to be effective in renal transplantation and inhibition of toxic liver injury. It can be concluded that Ca antagonists have an antiatherosclerotic, anticalcinotic, and tissue-protective potential that opens a wide spectrum of applications both prophylactic and therapeutic, especially in the cardiovascular field.