Effect of calcium antagonists

Fig. 2. Effect of calcium antagonists (CA) on a cardiac cell. Top typical cardiac action potential. The calcium (slow) inward current flows during the characteristic plateau phase (phase 2) of the action potential. This calcium influx is selectively inhibited by CA. Activation of the sarcoplasmic reticulum (SR) and other cellular calcium pools occurs via Ca + and Na+ ions which flow into the cell. The SR and other pools donate activator Ca + ions which stimulate the contractile proteins. The presence of tubular systems (invaginations), which are characteristic of cardiac tissues, results in considerable enlargement of the cellular surface, thus enabling an effective influx of Na+ and Ca + ions. Inhibition of the calcium inward flux by a CA causes diminished activation of the contractile proteins.

Data on the effect of calcium antagonists on cardiovascular disease risks in patients with hypertension are available from one moderate-to-large scale randomized, placebo-controlled trial. In the Systolic Hypertension in Europe (Syst-Eur) trial, nitrendipine-based therapy produced an approximate 10/5 mmHg reduction in SBP-DBP in patients with systolic hypertension and a 42% reduction in the risk of stroke. Similar results were observed in two large, nonrandomized, placebo-controlled trials (with alternate treatment assignment), i.e. the Shanghai Trial of Nifedipine in the Elderly and the Systolic Hypertension in China (Syst-China) trial. 

Knight CJ et al. Different effects of calcium antagonists, nitrates and beta blockers on platelet function Possible importance for the treatment of unstable angina. Circulation 1997 95 125-132. 

Ueno S, Hara Y. Lambert-Eaton myasthenic syndrome without anti-calcium channel antibody adverse effect of calcium antagonist diltiazem. J Neurol Neurosurg Psychiatry 1992 55(5) 409-10. 

Gasic S, Eichler HG, Korn A. Effect of calcium antagonists on basal and digitalis-dependent changes in splanchnic and systemic hemodynamics. Clin Pharmacol Ther 1987 41(4) 460-6. 

Amano J, Suzuki A, Sunamori M, and Tofukuji M. 1995. Effect of calcium antagonist diltiazem on renal function in open heart surgery. Chest 107 1260-1265. 

Case-control smdies with calcium blockers suggest an increased risk for MI and cancer." " " The relationship to cancer appears to be weak to nonexistent, whereas the risk for MI is probably real and related to the type of drug used and the relationship to recent MI. Shorter-acting calcium blockers can activate the sympathetic nervous system and in patients with recent MI or significant CAD may induce ischemia. This effect has not been shown for longer-acting products. The hemodynamic effect of calcium antagonists is complementary to /3-blockade, and consequently, combination therapy is rational, but clinical trial data do not support the notion that combination therapy is always more effective." " ... 

Neumayer HH, Kunzendorf U, Schreiber M. Protective effects of calcium antagonists in human renal transplantation. Kidney Int (SuppI) 1992 36 S87-S93. 

Sabbatini M, Leonardi A, Testa R. et al Effect of calcium antagonists on glomerular arterioles in sponta-... 

C. Calcium can reverse the negative inotropic effects of calcium antagonists however, depressed automaticity and atrioventricular nodal conduction velocity and vasodilation may not respond to calcium administration. 

These drugs were developed as coronary vasodilating agents and were used for that purpose for some time, until it was discovered that they inhibit the contractile effect of calcium on smooth musculature and cardiac muscle, and that they affect calcium channels on the cell surface that permit calcium ions to enter. At first, they were called calcium antagonists however, later on this class of compounds was given the preferred name of calcium channel blockers. 

Fig. 3. Haemodynamic effects of different types of calcium antagonists. Drawn lines nifedipine and other rapidly an short-acting dihydropyridines. Dotted lines verapamil and diltiazem. MAP = mean arterial pressure HR = heart rate CO = cardiac output TPR = total peripheral resistance UE = urinary excretion of Na and H2O. Note the reflex tachycardia, provoked by nifedipine.

Fig. 4. Schematic presentation of the mechanism of calcium antagonists with respect to their beneficial effect in angina pectoris. The final result is an improvement of the imbalance between myocardial oxygen demand and supply. TPR = total peripheral resistance HR = heart rate.

Hollt, V., M. Kouba, M. Dietel, and G. Vogt. 1992. Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. Biochem Pharmacol 43 2601. 

Although noradrenergic terminals normally contain too little dopamine for presynaptic dopamine heteroreceptors to become activated, and despite the fact that the hippocampus is only sparsely innervated by dopaminergic fibers (Bischoff et al. 1979), the release of [3H]-noradrenaline in rabbit (Jackisch et al. 1985) and rat (Monnet 2002) hippocampus was inhibited by endogenous dopamine as shown by the facilitatory effect of D2 antagonists. Voltage-sensitive calcium channels seem to play a role in the dopaminergic inhibition of noradrenaline release (Monnet 2002). 

Kang W, Yun HY, Liu KH et al. (2004) Determination of beni-dipine in human plasma using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Tech-nol Biomed Life Sci 805 311-314 Krebs R (1982) Effects of calcium entry antagonists in hypertension. Clin Exp Hypertens 4 272-284... 

Johnson, GJ, Leis, LA, Francis, OS, Adenosine potentiates the inhibitory effects of calcium channel antagoniste on human platelet aggregation induced by thromboxane A, or U46619. Thromb Bes 1990, 5 139-148. 

Treatment still remains difficult, because few clinical studies are available. High doses of calcium antagonists are recommended, but their frequent side effects have to be taken into account, particularly with a cardiac output of <2 1/min. (146) In severe cases, pulmonary pressure reduction by permanent infusion of epoprostenol over several weeks or long-term administration of oxygen may be helpful. Good experience has been made with the endothelin-receptor antagonist bosentan (2 x 125 mg/day). (36) (s. p. 338 )... 

Andersson KE. Effects of calcium and calcium antagonists on the excitation-contraction coupling in striated and smooth muscle. Acta Pharmacol Toxicol (Copenh) 1978 43(Suppl 1) 5-14. 

Mibefradil is a member of a class of calcium antagonists that specifically block the T-type calcium channel. It was marketed as an antihypertensive and antianginal drug with an adverse effects profile similar to that of placebo (1) and a favorable pharmacokinetic profile, allowing once-a-day dosage (2). 

Zhang Y, Xiao H. 1998. Antagonistic effect of calcium, zinc and selenium against cadmium induced chromosomal aberrations and micronuclei in root cells of Hordeum vulgare. Mutat Res 420 1-6. 

Pernow, J., Svenberg, T. Lundberg, J.M. (1987b) Actions of calcium antagonists on pre- and postjunctional effects of neuropeptide Y on human peripheral blood vessels in vitro. Eur. J. Pharmacol. 136, 207-218. 

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