Calcium channel antagonists: part VI: Clinical pharmacokinetics of first and second-generation agents

Abstract

A survey of the pharmacokinetic properties of the three prototypical calcium antagonist agents shows that they have in common a very high rate of hepatic first-pass metabolism with, in the case of verapamil and diltiazem, the formation of an active metabolite that affects the dose during chronic therapy. Therefore, the major factor altering the pharmacokinetic properties and the dose of the drug required is the capacity of the liver to metabolize the drug, which in turn depends on the hepatic blood flow and the activity of the hepatic metabolizing systems. Hence liver disease, a low cardiac output, and coadministration of certain drugs inducing or inhibiting the hepatic enzymes, all indirectly affect the pharmacokinetic properties of the calcium antagonists. There are also other potential drug interactions of a kinetic or dynamic nature that may arise. In general, renal disease has little effect on the pharmacokinetics of calcium antagonists.

Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

“…In addition, low pH, hypoxia, and elevated K +, factors which mimic the situation in acute ischemia, enhanced the negative inotropic potency of verapamil and to a further extent that of diltiazem, but did not affect that of nifedipine [47]. Therefore, differences in negative inotropic potency may be due to different functional behavior of the Ca 2+-antagonists at the Ca 2+-channel as well as by different additional effects, such as interaction on Na +-or K+-channels [9,22,27,40].…”

“…They are thus active in both cardiac muscle and vascular smooth muscle cells [8,37,38,40,42]. Because they reduce contractility of smooth muscle cells, they are used in the treatment of hypertension as well as in coronary artery disease.…”

“…C a 2 +-antagonists are used in the treatment of hypertension as well as in ischemic heart disease mainly because of their vasodilatory properties [1,8,12,13,20,35,38,40,52]. Moreover, these compounds are reported to exhibit an important initial diuretic effect [34].…”

Conventional and Novel Pharmacotherapy of Angina Pectoris

“…Elimination half-lives of old CCBs are rather short (3-8 hours), whereas the newer ones (esp. new DHPs) have been designed to last longer in body (Opie 1989;Piepho 1991).…”

Dihydropyridine Calcium Antagonists: The Role in Current Therapy of Cardio-Vascular Diseases

“…Последнее обстоя-тельство объясняется тем, что препараты второго по-коления создают более равномерную концентрацию в крови и поэтому реже дают побочные действия. Из-вестно, что возникновение побочных эффектов анта-гонистов кальция зависит не столько от концентрации препарата в крови, сколько от быстроты ее нарастания [1,2,3]. …”