The potencies and selectivities of four calcium antagonists as inhibitors of uterine contractions in the rat in vivo.

The potencies of four calcium antagonists (nifedipine, gallopamil, verapamil and diltiazem) at inhibiting uterine contractions in vivo have been assessed in the conscious ovariectomized, post-partum rat. Their selectivities for this action, relative to their effects on blood pressure and heart rate, have been compared with salbutamol. All compounds produced a dose-dependent inhibition of intra-uterine pressure cycles. The rank order of potency was salbutamol greater than nifedipine greater than diltiazem = gallopamil greater than verapamil. All compounds produced a dose-dependent fall of mean blood pressure. The rank order of potency was salbutamol greater than nifedipine greater than gallopamil greater than verapamil greater than diltiazem. Salbutamol and nifedipine produced a tachycardia, which was very marked with salbutamol. Gallopamil, verapamil and diltiazem induced a moderate tachycardia at low doses but temporary cessation of heart beat occurred at high doses. Nifedipine and diltiazem, like salbutamol, exhibited some selectivity for inhibition of uterine contractions relative to their cardiovascular actions. Gallopamil and verapamil showed no selectivity for the uterus.     

Effects of hypoxia, elevated K+ and acidosis on the potency of verapamil, diltiazem and nifedipine in the guinea-pig isolated papillary muscle.

1 The effects of the structurally diverse calcium channel blockers verapamil, nifedipine and diltiazem were investigated on the force of contraction of guinea-pig, electrically stimulated papillary muscles in vitro. 2 Calcium channel blocking potency was assessed either as a direct negative inotropic effect or as the ability of the drugs to antagonise the positive inotropic effects of added calcium (Ca2+). By either method, the rank order of potency was found to be nifedipine greater than verapamil greater than diltiazem. 3 Various factors which mimic some of the consequences of acute ischaemia in vivo, namely low pH, hypoxia and elevated K+, in combination, but not singly, enhanced the negative inotropic potency of verapamil and to lesser extent that of diltiazem, but not that of nifedipine. 4 Whilst the various interventions, especially in combination, produced a profound negative inotropic effect themselves, this was not responsible per se for the potentiation of the negative inotropic effects of verapamil and diltiazem, since the negative inotropic effects of nifedipine and dinitrophenol were not potentiated under the 'ischaemic' conditions. 5 By use of antagonism of the positive inotropic action of exogenous Ca2+ as an alternative measure of potency, the differential influence of 'ischaemia' on calcium channel blocker potency was confirmed. The effect of verapamil was potentiated some 9 fold, that of diltiazem about 2 fold, and that of nifedipine was unchanged. 6 The differential effect of 'ischaemia' on the potencies of the calcium channel blockers was unexpected. Verapamil (but not nifedipine) is thought to bind to the calcium channel at a specific site not easily accessible from the extracellular space. 'Ischaemic' conditions may cause membranal perturbations which allow verapamil easier access to its binding site thus increasing its negative inotropic potency.     

Dynamic and kinetic differences of the vascular and myocardial effects of calcium antagonists in the rat heart

We studied the effects of nifedipine, nimodipine, verapamil, D600 (gallopamil), D888 (desmethoxyverapamil), D890 (quaternized verapamil), bepridil, and diltiazem on the coronary flow and the left ventricular pressure in the retrogradely perfused paced rat heart; in addition, we investigated the time course of onset and recovery of these effects. We found a clear difference in potency order for the vascular and cardiac effects as well as widely different kinetics of coronary flow increase and negative inotropic activity. Furthermore, positive inotropism at low doses of some calcium antagonists seemed to be related to the vascular effects of these compounds. We conclude that the rat heart contains a hydrophylic and readily accessible, vascular "dihydropyridine" site and a more hydrophobic, possibly intramembraneous or intracellular, myocardial "verapamil" site with a lower accessibility for verapamil derivatives and bepridil.     

Uptake of calcium antagonistic drugs into muscles as related to their lipid solubilities

Calcium antagonists, e.g. bepridil and verapamil, block the Ca2+-dependent slow action potentials in frog skeletal muscle [L.M. Kerr and N. Sperelakis, J. Pharmac. exp. Ther. 222, 80 (1982)]. To determine whether the calcium antagonistic drugs may enter the fibers and exert an internal action as well, uptake of tritiated bepridil, verapamil, nitredipine, nifedipine, and diltiazem into rat extensor digitorum longus (EDL) muscles was examined. It was found that the uptake values of verapamil, nitrendipine, and bepridil were much higher than those of nifedipine and diltiazem. The order of uptake was: bepridil greater than nitrendipine greater than verapamil much greater than nifedipine greater than diltiazem. The small uptake values of nifedipine and diltiazem may represent primarily binding to the surface membrane. In frog skeletal muscle (sartorius) also, the uptake of bepridil was greater than that of verapamil, and disruption of the T-tubules by the glycerol method did not change them. The same order of drug uptake values was found for monolayer cultures of vascular smooth muscle cells (rat aorta). The order of uptake in isolated sarcoplasmic reticulum (SR) from rat skeletal muscles was: verapamil greater than nitrendipine greater than bepridil greater than nifedipine greater than diltiazem. The lipid solubility values of the calcium antagonists were measured by their partition coefficients in oil/Ringer, octanol/Ringer, and chloroform/Ringer systems. The order of lipid solubility was: bepridil greater than verapamil greater than nitrendipine greater than nifedipine much greater than diltiazem. Thus, the calcium antagonists with the highest lipid solubilities were taken up more by the muscle cells and SR. It is concluded that verapamil, bepridil, and nitrendipine enter and accumulate inside the muscle cells, whereas nifedipine and diltiazem do not permeate readily.     

Pharmacodynamic Profiles of Different Calcium Channel Blockers

Abstract: The cardiovascular effects of different calcium channel blockers (CCB), exemplified by nifedipine, verapamil and diltiazem, are not identical. Some of these differences in effect may be due to the different CCBs interacting with different calcium channel subtypes in the tissues, and/or that the drug-receptor sites are separate. The drugs also have different abilities to activate the sympathetic nervous system, nifedipine increasing and diltiazem decreasing the baroreflex sensitivity. Verapamil, but not nifedipine and diltiazem, has a postjunctional α-adrenoceptor blocking effect, and can also increase the release of noradrenaline from adrenergic nerves by blocking pre-junctional α-adrenoceptors. In addition, verapamil may have a reserpine-like action on sympathetic nerves. The vasodilator actions of CCBs are not uniform, but seem to vary between species, different vascular regions, and different agents. Mechanisms other than blockade of influx of calcium from the extracellular medium have been suggested to explain these differences, including inhibition of intracellular calcium release, blockade of postjunctional α – adrenoceptors, interaction with calmodulin, inhibition of cyclic AMP phosphodiesterase, stimulation of Na⁺ –, K⁺ -activated ATPase, stimulation of a calcium pump, and a direct interaction with the contractile proteins. The heterogeneity in pharmacodynamic profile characterizing the CCBs is conspicuous, and may be of importance when selecting agents for the treatment of various cardiovascular and non-cardiovascular disorders.     

Activation of calcium channels by novel 1,4-dihydropyridines. A new mechanism for positive inotropics or smooth muscle stimulants

The effects of the novel, 1,4-dihydropyridine derivative methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) -pyridine-5-carboxylate (Bay k 8644) are reported. In contrast to the nifedipine-like dihydropyridines, which have calcium antagonistic actions. Bay k 8644 has positive inotropic and vasoconstrictor effects. The effects and mechanism of action of Bay k 8644 have been examined in the anaesthetised dog, on the isolated perfused guinea-pig heart, and on the isolated rabbit aortic strip. In these preparations Bay k 8644 is active in the same dose range as nifedipine, but has effects diametrically opposite to those of nifedipine. There is a competitive antagonism between Bay k 8644 and nifedipine, whereas verapamil and diltiazem produce only a functional, non-competitive inhibition of the effects of Bay k 8644. We conclude that a specific dihydropyridine receptor exists, which may bind both nifedipine and Bay k 8644. In contrast to nifedipine Bay k 8644 stimulates the calcium influx into the cell.     

PREVENTIVE EFFECT OF A NEW CALCIUM ANTAGONIST, MONATEPIL, ON DRUG-INDUCED ISCHAEMIC ELECTROCARDIOGRAPHIC CHANGES IN RATS

1. The preventive effects of monatepil, a new calcium antagonist with α₁-adrenoceptor blocking activity, on ischaemic electrocardiographic changes in rat models of vasospastic angina were evaluated and compared with those of the existing calcium antagonists (diltiazem, verapamil, nicardipine and nifedipine). 2. In order to assess the contribution of the α₁-adrenoceptor blocking action of monatepil to its anti-vasospastic action, the anti-ST depression effect of prazosin, an α₁-adrenoceptor blocker, was also examined. 3. Monatepil given orally (3–30 mg/kg) inhibited vasopressin (0.2 IU/kg, i.v.)-induced ST depression which is considered to indicate ischaemic electrocardiographic changes in a vasospastic angina. This effect of monatepil was more potent and long-lasting than that of diltiazem, and was similar to that of verapamil and nicardipine. At a dose of 30 mg/kg, monatepil produced a significant inhibition, even at 7 h after administration. 4. Monatepil given intravenously (0.3 mg/kg) exerted a significant inhibitory effect on methacholine (16 μg/kg, intracoronary arterial administration; i.c.a.)-induced ST elevation which seems to be caused by coronary vasospasm. This effect was more potent or equipotent to those of the existing calcium antagonists. 5. These results indicate that monatepil produces the preventive effect on the drug-induced ischaemic electrocardiographic changes in rats and suggest that monatepil may have potential for the treatment of vasospastic angina.     

Direct effects of diltiazem, nifedipine and verapamil on peripheral sympathetic nerve function, cardiac impulse conduction and cardiovascular function in anesthetized dogs subjected to ganglionic blockade

The Ca2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P less than 0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct beta-adrenoceptor stimulation by isoproterenol (0.1 microgram/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25-35 V, 5 ms), but not high frequency (10 Hz, 25-35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical use of Ca2+ blockers as compared to other direct-acting vasodilators.     

Calcium Channel blockers: Spectrum of Side Effects and Drug Interactions

Abstract: Calcium antagonists are a chemically heterogenous group of agents with potent cardiovascular effects which are beneficial in the treatment of angina pectoris, arterial hypertension and cardiac arrhythmias. The main side effects for the group are dose-dependent and the result of the main action or actions of the calcium antagonists, i.e. vasodilatation, negative inotropic effects and antiarrhythmic effects. Pronounced hypotension is reported for the main calcium antagonist drugs; verapamil, diltiazem and nifedipine. While conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, tachycardia, headache and flush are more frequent after nifedipine. Constipation is relatively frequent after verapamil while nifedipine is reported to induce diarrhea in som patients. Idiosyncratic side effects are rare but have been reported from the skin, mouth, musculoskeletal system, the liver and the central nervous system. These side effects include urticarial rashes, gingival hyperplasia, arthralgia, hepathotoxicity and transistory mental confusion or akathisia. Verapamil, diltiazem and possibly also nifedipine have been reported to increase serum digoxin concentrations but the clinical relevance of these drug interactions are not clear. Furthermore, verapamil and diltiazem may potentiate the effects of β-adrenergic blocking drugs and verapamil may also potentiate the effects of neuromuscular blocking drugs. It is concluded that side effects after calcium antagonist drugs are mostly trivial and transient although they may sometimes be relatively common. Clinically relevant drug interactions are few. Judged from the point of efficacy and safety, calcium antagonists will have a major place in the future pharmacotherapy of several cardiovascular disorders.     

Evidence for a role of inhibition of sympathetic neurotransmission in the cardiovascular effects of intravenously administered verapamil

The effects of intravenous administration of verapamil, nifedipine and diltiazem on sympathetic stimulation-induced increase in heart rate (HR) and blood pressure (BP) have been investigated in chloralose-anaesthetized and artificially-ventilated cats. Verapamil (300 μg kg⁻¹ i.v.) produced a significant inhibition of sympathetically-induced tachycardia and pressor responses. The same dose of verapamil did not significantly alter adrenaline (2 μg kg⁻¹ i.v.) induced increase in HR and BP. In contrast, neither the sympathetically-induced nor the adrenaline-induced pressor and tachycardiac responses were significantly affected by nifedipine or diltiazem. These results demonstrate that peripherally administered verapamil but not nifedipine and diltiazem can inhibit cardiovascular sympathetic neurotransmission and this can possibly contribute to its effects on HR and BP.     

Comparison of the cardiovascular effects of trans-diclofurime with different types of calcium antagonists in conscious spontaneously hypertensive rats.

1. Trans-diclofurime has been shown to be a potent group II calcium antagonist in in vitro and in vivo test systems. In contrast to the dihydropyridines, group II calcium antagonists have a reduced propensity to cause reflex tachycardia due to well-balanced inhibitory effects in smooth muscle and heart. Since effects on autonomic reflexes are more reliably assessed in conscious animals, the cardiovascular effects of trans-diclofurime have been examined and compared to those of nifedipine, verapamil and diltiazem in the conscious spontaneously hypertensive rat (SHR). 2. Each SHR had an indwelling catheter in the femoral artery to record mean arterial pressure (MAP) and heart rate (HR) and a cannula in the femoral vein for drug infusion over 1 min. 3. Nifedipine (0.1-3.0 mumol kg-1 i.v.) caused dose-related falls in MAP accompanied by dose-related increases in HR. Trans-diclofurime and verapamil (0.3-3.0 mumol kg-1 i.v.) also caused dose-related decreases in MAP, but significant tachycardia was only seen at 1.0 and 3.0 mumol kg-1. Trans-diclofurime (0.3 mumol kg-1) induced a significant fall in HR. Diltiazem (1.0-10.0 mumol kg-1 i.v.) induced dose-related falls in MAP, significant bradycardia was evident with 1.0 mumol kg-1 and tachycardia with 10 mumol kg-1. Trans-diclofurime and diltiazem induced less tachycardia than nifedipine and verapamil for equivalent falls in MAP. 4. These results suggest that trans-diclofurime is a potent antihypertensive agent in conscious SHR and, like diltiazem, the hypotensive effects are associated with less tachycardia than is usually apparent with calcium antagonists such as nifedipine or verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential actions of calcium antagonists on calcium binding to cardiac sarcolemma

The action of four calcium antagonistic drugs, including verapamil, bepridil, nifedipine, and diltiazem, on calcium binding to cardiac sarcolemma from guinea pig was tested. It was found that verapamil (10^?6 to 10^?5 M) inhibited calcium binding to a great extent. Bepridil at the same concentrations was less potent than verapamil in the depression of calcium binding. Nifedipine and diltiazem did not affect sarcolemmal calcium binding. The differential action of the calcium antagonistic drugs was discussed.     

Defining the Role of Calcium Channel Antagonists in Heart Failure Due to Systolic Dysfunction

Calcium channel antagonists (CCAs) may either be divided into the dihydropyridines (e.g. amlodipine, felodipine, isradipine, lacidipine, nilvadipine, nifedipine, nicardipine etc.), the phenylalkylamines (e.g. verapamil) and the benzothiazepines (e.g. diltiazem) according to their chemical structure, or into first generation agents (nifedipine, verapamil and diltiazem) and second generation agents (subsequently developed dihydropyridine-derivatives). Second generation CCAs are characterized by greater selectivity for calcium channels in vascular smooth muscle cells than the myocardium, a longer duration of action and a small trough-to-peak variation in plasma concentrations. Heart failure is characterized by decreased cardiac output resulting in inadequate oxygen delivery to peripheral tissues. Although the accompanying neurohormonal activation, leading to vasoconstriction and increased blood pressure, is initially beneficial in increasing tissue perfusion, prolonged activation is detrimental because it increases afterload and further reduces cardiac output. At the level of the myocyte, heart failure is associated with increased intracellular calcium levels which are thought to impair diastolic function. These changes indicate that the CCAs would be beneficial in patients with heart failure. There has been a strong interest and increasing experience in the use of CCAs in patients with heart failure. Despite potential beneficial effects in initial small trials, findings from larger trials suggest that CCA may have detrimental effects upon survival and cardiovascular events. However, this may not necessarily be a ‘class b’ effect of the CCAs as there is considerable heterogeneity in the chemical structure of individual agents. Clinical experience with different CCAs in patients with heart failure includes trials that evaluated their effects on hemodynamic parameters, exercise tolerance and on symptomatology. However, the most relevant results are those from randomized clinical trials that assessed mortality as the primary endpoint. First generation CCAs have direct negative inotropic effects and even sustained release formulations have not proved any beneficial effect upon survival. With second generation CCAs, some benefit on hemodynamic parameters has been observed but none on survival, alone or in combination with ACE inhibitors. It is noteworthy that although amlodipine had a neutral effect on morbidity and mortality in large, randomized, placebo-controlled trials in patients with heart failure, the drug was well tolerated. There is no specific indication for CCAs (first or second generation) in patients with systolic heart failure, alone or in combination with ACE inhibitors, but amlodipine may be a considered in the management of hypertension or coronary artery disease in patients with heart failure.     

Influence of extracellular calcium and calcium antagonists on contractions induced by potassium and prostaglandin F2 alpha in isolated cerebral and mesenteric arteries of the cat.

1 The effects of a number of calcium antagonists (diltiazem, nifedipine, nimodipine and verapamil) have been studied on feline isolated pial arteries contracted by potassium (127 mM) or prostaglandin F2 alpha (PGF2 alpha, 2.5 microM) and mesenteric arteries contracted by potassium (127 mM). 2 Withdrawal of Ca2+ from the extracellular medium for 30 min reduced the contractile response to potassium in cerebral vessels by 92% and in mesenteric vessels by 96%. Subsequent addition of Ca2+ caused reproducible contractions which were inhibited by both nifedipine and nimodipine. 3 The four calcium antagonists relaxed the isolated middle cerebral artery contracted either by potassium or PGF2 alpha, and mesenteric arteries contracted by potassium, in the following order of potency: nimodipine greater than nifedipine greater than verapamil greater than diltiazem. 4 Nimodipine was more potent than nifedipine in cerebral arteries, and more potent in cerebral than in mesenteric arteries. Otherwise, the potassium-contracted cerebral and mesenteric vessels showed no major differences in sensitivity to calcium antagonists.     

Effects of calcium channel blockers on ouabain-induced oscillatory afterpotentials in organ-cultured young embryonic chick hearts

Ouabain induces oscillatory afterpotentials (OAPs) in organ-cultured young (3 day old) embryonic chick hearts. Since increased [Ca]i resulting from an inhibition of the Na pump by ouabain triggers oscillatory movements of Ca2+ (i.e. OAPs) intracellularly, Ca2+ influx through the cell membrane, which tends to increase [Ca]i, may be important in developing the OAPs. Therefore, in the present experiments, effects of calcium channel blockers on ouabain-induced OAPs in organ-cultured 3 day old embryonic chick hearts were examined. Automaticity was suppressed by elevating [K]o to 6 mM. To induce the OAPs, the preparations were stimulated (0.5 Hz) in the presence of ouabain (2.5-6.3 microM). The calcium channel blockers (10 microM) depressed the OAPs in the following order of potency: bepridil greater than verapamil greater than nifedipine greater than diltiazem. This order of potency of the calcium channel blockers in depressing the OAPs was the same as that for drug penetration into the cells, but different from that for depressing slow action potentials: nifedipine greater than diltiazem greater than verapamil greater than bepridil (our previous findings). These results suggest that an intracellular site of action of the calcium channel blockers is important for depression of the OAPs, and suppression of the slow inward Ca2+ current cannot be the sole mechanism for suppression of the OAPs by these drugs.     

Inhibitory effects of diltiazem, verapamil, nifedipine, and nicardipine on sympathetic tachycardia in decentralized hearts of anesthetized dogs.

Intravenous diltiazem (10-300 micrograms/kg), verapamil (10-300 micrograms/kg), nifedipine (1-100 micrograms/kg) and nicardipine (1-100 micrograms/kg) inhibited the tachycardia caused by cardiac sympathetic nerve stimulation (SNS, 0.5-4 Hz) in decentralized hearts of anesthetized dogs. The dose range of each drug required to inhibit the SNS-induced tachycardia was almost equivalent to that required to produce the increase in coronary blood flow and the decrease in blood pressure. Nifedipine and nicardipine were equi-active and about 10 times more potent than diltiazem and verapamil in inhibiting the SNS-induced tachycardia. They produced a slight but dose-dependent slowing of the resting heart rate. The negative chronotropic potency was approximately nicardipine, verapamil greater than nifedipine, diltiazem. Bay K 8644 (30 micrograms/kg) antagonized the inhibitory effects of diltiazem (100 micrograms/kg) and nifedipine (30 micrograms/kg) on the SNS-induced tachycardia. Tachycardia induced by intracoronary norepinephrine (0.03-0.3 micrograms) was suppressed by diltiazem (30-300 micrograms/kg) and nifedipine (10-100 micrograms/kg). The inhibitory effects of calcium entry blocking drugs on the sympathetic tachycardia appear to be explained by the interference of the beta-adrenoceptor-mediated increase in slow inward current in the sinoatrial (SA) node. It is also suggested that other mechanisms different from calcium entry blocking action contribute to the negative chronotropic response to these calcium entry blocking drugs.     

Nifedipine, diltiazem, bepridil and verapamil uptakes into cardiac and smooth muscles

Vogel et al. (1979; J. Pharmacol. Exp. Ther. 210, 378) reported that one calcium antagonist, bepridil, exerted an effect internally as well as its effect on blocking Ca2+ entry in cardiac muscle. Therefore, the uptakes of tritiated nifedipine, diltiazem, bepridil, and verapamil by cat ileal smooth muscle, chick embryonic ventricular muscle, and rabbit papillary muscle were investigated. It was found that the uptakes of verapamil and bepridil by the muscles were much higher than those of nifedipine and diltiazem. The uptake of bepridil was substantially greater than that of verapamil; thus, the order of uptake was: bepridil greater than verapamil much greater than nifedipine greater than diltiazem. The cardiac muscles accumulated at least 2-fold greater amount of calcium antagonists than the smooth muscle. The amount of a given calcium antagonist accumulated by a muscle was not a function of the ability of that calcium antagonist to inhibit Ca2+ uptake into the muscle, since nifedipine and diltiazem were more potent in depressing Ca2+ uptake, but had the smallest uptakes. The calcium antagonists were more effective in depressing Ca2+ uptake into smooth muscle than into cardiac muscle. Calculation indicates that internal drug concentration at steady state for both cardiac and smooth muscles was either equal to (diltiazem) or much higher than the drug concentration in the medium (bepridil and verapamil). It is concluded that bepridil and verapamil enter and accumulate in the muscle cells, whereas nifedipine and diltiazem permeate more slowly into the muscles. The ability of all four drugs to enter the muscle cells confers the possibility that these calcium antagonists may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum.     

Diproteverine (BRL 40015): a new type of calcium antagonist with potential antianginal properties

The calcium channel-blocking activity and associated cardiovascular effects of diproteverine, a novel compound derived from papaverine, were investigated. Electrophysiological measurements in sheep Purkinje fibres showed diproteverine to reduce the amplitude of the slow action potential (IC30 = 2 microM) and to shorten the duration of the fast action potential at 50% repolarisation (IC30 = 2.5 microM). Higher concentrations (4-5 times) were required to block block the sodium channel, as assessed by a reduction in Vmax of the fast action potential. Papaverine was found to possess marginal membrane channel-blocking activity and to be much more potent than diproteverine as a cAMP-phosphodiesterase inhibitor. The most significant haemodynamic property of diproteverine, seen in anaesthetised dogs and conscious dogs pretreated with atropine, was to cause a reduction in heart rate. This appeared to be a particular feature of diproteverine as the other calcium antagonists studied produced either a smaller decrease in heart rate or tachycardia as a reflex response to hypotension. In a chronic myocardial infarct model in dogs, diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischaemic area of the myocardium. Diproteverine resembled diltiazem in its effects on coronary blood flow, with both these agents being preferable to nifedipine and verapamil, which caused coronary steal in this model. The combination of the reduction in heart rate, to lower cardiac oxygen demand, with the beneficial action on coronary blood flow should result in diproteverine being particularly beneficial for the treatment of angina pectoris.     

Investigation of the mechanism of negative inotropic activity of some calcium antagonists

An attempt was made to discriminate between calcium entry blockade and other calcium antagonistic mechanisms involved in the negative inotropic activity of nifedipine, verapamil, diltiazem, flunarizine, lidoflazine, and bepridil in isolated guinea pig hearts. For this purpose, we used the calcium entry promoter Bay K 8644 as a tool to modulate the process of calcium entry at the sarcolemmal level. The calcium ionophore A 23187 was employed to increase intracellular calcium content without interfering with calcium channels. Bay K 8644 interacted with nifedipine, verapamil, and diltiazem; however, only a small inhibitory effect on the negative inotropic responses of flunarizine, lidoflazine, and bepridil was observed. The positive inotropic response of A 23187 was not influenced by nifedipine and was only slightly decreased by verapamil or diltiazem. After addition of flunarizine, lidoflazine, or bepridil, however, the positive inotropic effect of A 23187 was completely abolished. These results suggest that the negative inotropic effects of the calcium entry blockers are not only the result of calcium entry blockade. Apparently, an additional calcium antagonistic effect also plays a role for flunarizine, lidoflazine, and for bepridil and, to a lesser degree, for verapamil and diltiazem.     

Calcium antagonists. Pharmacokinetic properties

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.