Pharmacology of calcium antagonists

doi:10.1016/0002-9149(85)90798-2

The American Journal of Cardiology

Volume 55, Issue 7, 15 March 1985, Pages C3-C7

https://doi.org/10.1016/0002-9149(85)90798-2 Get rights and content

Abstract

Although the calcium antagonists verapamil, nifedipine, diltiazem and bepridil are structurally diverse, they share, to a variable extent, several pharmacologic properties. These effects are presumably the result of dose-related inhibition of transmembrane calcium ion flux through the slow channel. In diseased tissue, other routes of calcium entry may also be inhibited, and intracellular sites of action also are now strongly suspected. The calcium antagonists tend to relax vascular smooth muscle in a dose-dependent and site-specific manner. Effective coronary vasodilation is found with each agent; peripheral vasodilation is most pronounced with nifedipine, followed, in descending order of potency, by verapamil, diltiazem and bepridil. Atrioventricular conduction is also inhibited by diltiazem, bepridil and verapamil, whereas nifedipine paradoxically has no effect at therapeutic doses. The calcium antagonists also reduce muscle contractile force, but again in variable degrees. Negative inotropy is significant with verapamil and minimal with diltiazem and bepridil. Nifedipine often causes a reflex increase in contractility and heart rate. At therapeutic doses, bepridil has additional properties: it appears to affect sodium and perhaps potassium channels, producing a quinidine-like effect, and it prolongs the refractory period. Experimentally, bepridil has also been found to extend the duration of the action potential, raise the ventricular fibrillation threshold and possess both class I and class IV antiarrhythmic activity at relatively small doses. If documented clinically, bepridil may prove to be an effective antiarrhythmic as well as antianginal agent.

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There are more references available in the full text version of this article.

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Among the various antihypertensive drugs available in the market literature study reveals that slow acting nifedipine is the safe antihypertensive drug for the treatment of preeclampsia [9–11]. Nifedipine is a calcium-channel blocking agent of the dihydropyridine type that is mainly used in the treatment of angina pectoris and systemic hypertension [12]. It is also used as second line treatment for preeclampsia and premature labor.
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In order to improve the predictability of dissolution testing new apparatuses have been proposed that mimic hydrodynamic and mechanical conditions in the gastrointestinal tract. In this study tested were four different nifedipine extended release (ER) formulations using the paddle apparatus and the reciprocating cylinder as pharmacopoeial test devices as well as two newly developed test apparatuses: the rotating beaker apparatus and the dissolution stress test apparatus. Investigated were Adalat OROS in strengths of 30 and 60 mg, and two hydrophilic matrix formulations: 60 mg nifedipine Coral and Nifedipin Sandoz 40 mg retard. The results demonstrate that the dissolution characteristic of the ER tablets is strongly dependent on the applied test conditions. The dosage form related food effects for Coral 60 mg tablets that were previously observed in human bioequivalence studies could be predicted with the two non-compendial dissolution test devices. The dissolution of Sandoz 40 mg tablets was very sensitive to all applied test conditions. The stable drug delivery characteristics of Adalat OROS observed in numerous in vivo studies was also observed in all of the dissolution tests. In conclusion, the present study shows that besides pH dependency the aspect of the mechanical robustness may be an essential factor affecting the dissolution characteristic of hydrogel matrix formulations.
Validation of a guinea pig Langendorff heart model for assessing potential cardiovascular liability of drug candidates
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Cardiac liabilities represent a major cause of recent withdrawal of marketed drugs and also for the high attrition rate evidenced during late stage drug development. To identify molecules with potential cardiovascular risks early in drug development, a screening model of ex vivo Langendorff hearts has been validated with 26 reference compounds of various chemical and therapeutic classes.
The hearts of adult guinea pigs were maintained by retrograde perfusion in Langendorff mode, beating spontaneously at sinus rhythm or paced via the right atrium at 200 and 300 beats per minute. Multiple parameters consisting of hemodynamic function (coronary and left ventricle pressure), cardiac electrophysiology (electrocardiogram and monophasic action potential) and indices of arrhythmogenesis (triangulation, reverse-use dependence, repolarization dispersion and beat-to-beat instability), together with overt arrhythmia were evaluated simultaneously. Ascending concentrations up to either 100-fold of the determined hERG IC₅₀ or nominally 100 µM were routinely tested utilizing 4–6 hearts per compound.
Each compound exhibited a unique cardiovascular profile: (i) the majority displayed concentration and heart rate-dependent mixed-ion channel or multiple-target effects that frequently resulted in bradycardia, atrioventricular block, negative inotropy, coronary vasodilatation, and QRS widening. (ii) Compounds associated with high arrhythmogenic risk in the clinic exhibited more “positive signals” at concentrations within 30-fold of their maximal therapeutic free plasma concentration than those with less arrhythmogenic potential. (iii) For several potent torsadogens, proarrhythmic indices other than the prolongation of QT/QTc and MAP duration appeared more sensitive in representing proarrhythmic liability. (iv) A scoring system was developed to assist in the rank-ordering of potential cardiotoxicants.
The cardiovascular action of reference compounds profiled by this isolated heart model was generally consistent with their known mechanisms and, except for the sinus heart rate, correlated well with that observed in the clinic. Further, the overall cardiac liability estimated by the scoring system matched the clinical documentation, suggesting this model could serve as a valuable tool in early cardiovascular drug safety assessment.
Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95
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The observation of a greater efficacy with time was further explored by continuous presence of the drug in experiments comparing RESPIR 4-95 and the voltage operated calcium channel antagonist nifedipine. It is well established that calcium is necessary for contraction in smooth muscle fibers and that voltage operated l-type calcium channel antagonists, such as verapamil or nifedipine, can relax many types of smooth muscle effectively [11]. However, it has also been shown that airway smooth muscle is unexpectedly insensitive to the relaxing effect of this type of substances [12,13], which has led to the conclusion that airway smooth muscle has other types of calcium channels that are mainly responsible for calcium entry [14].
Current drugs including beta-agonists have limited smooth muscle relaxant effects on human small airways. Yet this is a major site of obstruction in asthma and chronic obstructive pulmonary disease (COPD).
This study explores human small airway relaxant effects of RESPIR 4-95, a novel chemical analogue (capsazepinoid) to capsazepine. Capsazepine was recently shown to relax small airways in a way which was independent of its TRPV₁ antagonism and independent of current bronchodilator drug mechanisms.
In vitro preparations of human small airways, 0.5–1.5 mm in diameter and responding with reproducible contractions to leukotriene D₄ (LTD₄) for 12 h, were used.
RESPIR 4-95 reversibly prevented LTD₄-induced contractions as well as relaxed the established tonic contraction by LTD₄. RESPIR 4-95 exhibited marked improvements over the reference capsazepinoid, capsazepine, by being 10 times more potent, exhibiting twice as long duration of action after wash-out (9 h), and inhibiting equally well LTD₄-, histamine-, prostaglandin D₂ (PGD₂)-, and acetylcholine (ACh)-induced contractions. RESPIR 4-95 was distinguished from l-type calcium channel antagonist nifedipine by its greater efficacy and potency and by exhibiting increased relaxant effect by repeated exposures. Furthermore, RESPIR 4-95 was more efficacious and longer acting than the long-acting beta-agonist formoterol.
Efficacy, potency, duration of action, and inexhaustibility of its relaxation of human small airways make RESPIR 4-95 an interesting lead compound for further developments aiming at drug treatment of small airway obstruction in asthma and COPD. Further work is warranted to unveil the molecular biology behind its relaxant actions.
Protection of cardiomyocytes by pinacidil during metabolic inhibition and hyperkalemia
1999, European Journal of Pharmacology
The objective of this study is to understand the mechanism underlying the cardioprotective effects of pinacidil, an ATP-sensitive K⁺ channel (K_ATP) opener. We examined the effects of 10 μM pinacidil in cultured chicken cardiomyocytes. Pinacidil caused a concentration-dependent delay in metabolic inhibition-induced increase in intracellular calcium concentration ([Ca²⁺]_i) and creatine phosphokinase release, and this action was antagonized by glyburide, a K_ATP blocker. Neither verapamil, an L-type Ca²⁺ channel blocker, nor bepridil, a Na⁺–Ca²⁺ exchange inhibitor, affected the time course of increase in [Ca²⁺]_i induced by metabolic inhibition. Pinacidil did not have an effect on the amplitude of K⁺-induced increase in [Ca²⁺]_i, but accelerated the rate of decline following peak stimulation. In contrast, glyburide reduced the amplitude of K⁺-induced increase in [Ca²⁺]_i and prolonged the rate of decline. These results provide direct evidence that pinacidil protects cardiomyocytes from metabolic inhibition-induced injury by cyanide (CN) through a delay in the onset of increase in [Ca²⁺]_i, rather than by inhibition of the L-type Ca²⁺-channels or by alteration of Na⁺–Ca²⁺ exchange.
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Pharmacology of calcium antagonists

Abstract

Some membrane interactions with bepridil, a new antianginal agent

J Pharm Exp Ther

Supraventricular antidysrhythmic and electrophysiological effects of bepridil, a new antianginal agent

J Cardiovasc Pharmacol

Effects of antiarrhythmic drugs on ventricular fibrillation thresholds of normal and ischaemic myocardium in the anaesthetized rat

Br J Pharmacol

Effects of bepridil on electrophysiological properties of guinea-pig ventricular muscles

Br J Pharmacol