Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine.

The calcium antagonists are a heterogeneous class of drugs which block the inward movement of calcium into cells through 'slow channels' from extracellular sites. By inhibiting phase 0 depolarisation in cardiac pacemaker cells and phase 2 plateau in myocardium, and by depressing calcium ion flux in smooth muscle cells of blood vessels, these agents may exert profound effects on the cardiovascular system, particularly in susceptible individuals or in overdose. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilatation may result. Pharmacokinetic features of calcium antagonists include rapid and complete absorption from the gastrointestinal tract, with extensive first-pass hepatic metabolism yielding generally low bioavailability. The volume of distribution is generally large and protein binding is high. Elimination is almost entirely by the liver. Impaired renal function does not affect pharmacokinetics. Verapamil is the most potent inhibitor of cardiac conduction and contractility, with diltiazem also showing such effects. Nifedipine is the most potent vasodilator, but only occasionally impairs the sinus node or AV conduction. Significant pharmacodynamic effects are common during combination therapy with calcium antagonists, especially verapamil and beta-blockers. Verapamil may significantly elevate serum digoxin concentrations and may exert additive negative effects on chronotropism and dromotropism when this combination is used. Overdoses of calcium entry blockers are becoming more frequent and reflect an extension of the known pharmacodynamic profile of these agents. Typical features include confusion or lethargy, hypotension, sinus node depression and cardiac conduction defects. Onset of symptoms may be delayed if a sustained release preparation is ingested. Management of calcium antagonist overdose includes gut decontamination with lavage and activated charcoal. All symptomatic patients and patients with a history of ingesting a sustained release preparation should be admitted for ECG monitoring. If bradycardia and/or conduction defects contribute to hypotension, atropine or isoprenaline (isoproterenol) may accelerate the ventricular rate. Transvenous pacing may be required. Depressed myocardial contractility usually responds well to calcium chloride or calcium gluconate administration, but further inotropic support may be required. Peripheral vasodilation should be managed with intravenous fluids and a pressor agent such as dopamine or norepinephrine (noradrenaline).     

Effects of KT-362, a new calcium release blocker, on vascular selectivity and hemodynamic actions in anesthetized dogs

Pharmacological properties of 5-(3-((2-(3,4-dimethoxyphenyl)ethyl)-amino)-1- oxopropyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate (KT-362), a newly synthesized calcium release blocker, were studied by comparing its vascular selectivity and cardiovascular actions with those of verapamil, a calcium entry blocker. The relaxing effect of KT-362 in rabbit femoral and basilar artery strips contracted with norepinephrine was greater than that in aortic and coronary artery strips. In anesthetized mongrel dogs, KT-362 (0.1-3.0 mg/kg, i.v.) decreased the mean blood pressure, heart rate and total peripheral resistance in a dose-dependent manner, while cardiac output increased slightly despite a decrease in left ventricular pressure. This is consistent with the data on verapamil. Both i.a. and i.v. injections of KT-362 produced a marked dose-dependent increase in vertebral and femoral blood flow. Pretreatment of atropine, propranolol or diphenhydramine exerted no significant effect on the KT-362-induced vasodilation. Verapamil caused a marked increase in the vertebral and coronary blood flows after the injections, but only a slight increase in femoral blood flow. KT-362 at the dose of 10 mg/kg, i.v., had no significant effect on the PQ interval on the electrocardiogram in anesthetized dogs, but 0.1 mg/kg of verapamil increased this interval significantly. These results suggest that KT-362 has properties similar to calcium entry blockers such as verapamil on systemic hemodynamic actions except for the reactivity of vasculatures.     

Efficacy of the novel calcium antagonist R(+)-semotiadil in limiting the ventricular rate during atrial flutter in isolated guinea pig hearts

Ca2+ antagonists slow the ventricular rate by blocking conduction in the anterograde direction through the atrioventricular (AV) node. The aim of this study was to investigate the efficacy of the novel Ca2+ antagonist semotiadil compared with verapamil and diltiazem on the filtering capacity of the AV node during simulated atrial flutter in isolated guinea-pig hearts perfused by the method of Langendorff. During sinus rhythm, semotiadil as well as verapamil and diltiazem induced comparable depressant effects on AV-nodal conduction time and, during tachycardia, a comparable enhancement of this effect. The time constant (tau-on) for the drug-specific rate-dependent effect on AV-nodal conduction slowing was longest in the presence of verapamil compared with the long tau-on of semotiadil and the short tau-on of diltiazem. Verapamil and semotiadil exhibited a significantly greater effect than diltiazem on the mean ventricular cycle length (VCLmeun), on the maximal ventricular cycle length (VCLmax) and on the standard deviation of the VCL (SD(VCL)) during atrial flutter. Therefore the kinetics of the rate adaptation of AV-nodal conduction time in the presence of Ca2+ antagonists predicts the filtering capacity of the AV node during atrial flutter. Semotiadil has a verapamil type of action on ventricular cycle length during atrial flutter, whereas the disadvantageous prolongation of maximal VCL as well as the dispersion of VCL with semotiadil was only about half those found with verapamil.     

Cardiac electrophysiologic effects of McN-5691, a new calcium-channel blocking antihypertensive agent.

The purpose of this study was to evaluate the cardiac electrophysiological effects of McN-5691, a new calcium-channel blocking antihypertensive drug. In anesthetized dogs, the primary electrophysiological effect of McN-5691 was dose-related prolongation of AV-nodal conduction time and refractoriness (0.1-1.0 mg/kg i.v.), which correlated with McN-5691 plasma levels. There were no significant effects on atrial or ventricular conduction times, QTc, or ventricular monophasic action potential duration. This profile was similar to that of verapamil. McN-5691 caused concentration-related, rate-dependent reductions in Vmax and amplitude of slow-response action potentials in guinea pig papillary muscle: ED-20% for depression of Vmax was 0.72 +/- 0.32 microM. Verapamil was more potent in depressing these action potentials: ED-20% for depression of Vmax was 0.03 +/- 0.01 microM. McN-5691 also caused rate-dependent reduction in Vmax and amplitude of canine Purkinje fiber action potentials, but only at relatively high concentrations: ED-20% for depression of Vmax was 55 +/- 12 microM. McN-5691 also reduced the action potential duration (0.3-30 microM) without affecting the slope of phase 4 depolarization and the maximum diastolic potential. Verapamil also reduced Vmax in Purkinje fibers (ED-20% for depression of Vmax was 32 +/- 3 microM) and shortened the action potential duration. The results show that McN-5691 has cardiac electrophysiological effects consistent with blockade of the slow inward calcium current, and that this activity occurs at concentrations well below those having local anesthetic activity. In addition, its lower potency in comparison to verapamil in depressing slow responses suggests a lesser propensity for negative inotropic effects.     

The haemodynamic effect of verapamil

Summary The haemodynamic effect of verapamil has been studied in twelve patients during diagnostic cardiac catheterisation. The dose administered was 0.1 mg/kg body-weight given as an i. v. injection followed immediately by continuous infusion of 0.005 mg/kg body-weight per minute for thirty minutes. The total amount of verapamil administered varied between 13.0 and 21.6 mg. Brachial and pulmonary artery pressure, cardiac output, stroke volume, heart rate and peripheral vascular resistance were studied as well as atrioventricular conduction. — In patients in sinus rhythm no significant haemodynamic effects were observed, despite a significant increase in the atrioventricular conduction time. One patient developed second degree atrioventricular block, and several others showed first degree blocks. Two digitalized patients with atrial fibrillation were examined. Their results differed as they showed significant decreases in ventricular rate, blood pressure and cardiac output despite some increase in stroke volume. — On the basis of these results it was concluded that verapamil does not seem to have any haemodynamically unfavourable effects in the doses used. However, until further experience has been gained, verapamil should be used with caution in patients with atrial fibrillation who have already been digitalized. Verapamil should also be used with great care in persons with disturbed atrioventricular conduction and should not be given at all to patients with AV block of the second and third degree.     

Effect of perhexiline on atrioventricular nodal function of anesthetized dogs

We investigated the effects of perhexiline, a calcium-antagonistic vasodilator, on atrioventricular (AV) conduction in anesthetized open-chest dogs and in isolated, blood-perfused AV node preparations of the dog. Perhexiline, 3 mg/kg, prolonged the AV conduction time from 103.0 +/- 4.4 to 115.3 +/- 4.0 msec (p less than 0.05) in dogs with intact cardiac nerves. In dogs on which vagotomy and stellectomy had been performed, basal AV conduction time was 119.0 +/- 5.0 msec; 3 mg/kg of perhexiline barely prolonged it (121.0 +/- 7.0 msec). Thus, the negative dromotropic effect of perhexiline was abolished by denervation. The functional refractory period of the AV node was also lengthened with 3 mg/kg of perhexiline in the nerve-intact dogs (from 246.0 +/- 15.7) to 270.0 +/- 15.5 msec), but was scarcely affected by perhexiline in the cardiac denervated dogs (from 296.7 +/- 15.7 to 303.2 +/- 13.6 msec). Verapamil, 0.1-0.3 mg/kg, exerted a negative dromotropic effect in both innervated and denervated hearts. A direct inhibitory effect of perhexiline on AV conduction was observed in isolated blood-perfused AV node preparations, but it was much weaker when compared with that of verapamil.     

Electrophysiologic effects of verapamil metabolites in the isolated heart.

The electrophysiologic effects of the metabolites of verapamil are unknown and may contribute to the observed differences between intravenous and oral verapamil. We examined the electrophysiologic effects of verapamil and its metabolites (norverapamil, N-dealkylverapamil (D617), and N-dealkylnorverapamil (D620)) at estimated, free therapeutic concentrations, in the retrogradely perfused, isolated rabbit heart. Verapamil at 5 and 10 ng/ml significantly prolonged anterograde (11 and 27%, respectively) and retrograde (10 and 25%, respectively) atrioventricular (AV) nodal block cycle lengths. Anterograde and retrograde AV nodal conduction times and refractory periods were also prolonged. Norverapamil at 100 ng/ml had qualitatively similar effects equivalent to 20-50% that observed with verapamil at 10 ng/ml. D620 had small but statistically significant effects on some AV nodal parameters. D617 had no effect. The combination of verapamil plus its principal metabolite, norverapamil, had additive effects. None of the compounds had any measurable effect on atrial conduction, His-Purkinje conduction, or atrial refractoriness. Ventricular refractoriness was significantly prolonged only by norverapamil. In conclusion, some of the metabolites of verapamil have important electrophysiologic AV nodal effects and may contribute to the clinical effects observed during chronic oral verapamil dosing.     

Effects of verapamil on accessory pathway properties and induction of circus movement tachycardia in patients with the Wolf-Parkinson-White syndrome

The electrophysiological effects of 0.2 mg/kg of intravenously administered verapamil (mean plasma level, 51.3 ng/ml) were evaluated using intracardiac recordings and electrical stimulation in 10 patients with the concealed or manifest Wolff-Parkinson-White syndrome. Verapamil produced a minimal effect on both the antegrade and retrograde effective refractory periods of the accessory pathway and the retrograde conduction time over the accessory pathway, but significantly lengthened the intranodal conduction time as well as the effective and functional refractory periods of the atrioventricular (AV) node. Reproducible sustained circus movement tachycardia was initiated in 8 patients before administration of verapamil and in 2 after verapamil. The sustained tachycardia could no longer be initiated in 6 patients because of an increase in AV nodal refractoriness. In 4 patients, atrial echoes were induced at longer premature beat intervals due to a greater AV conduction delay of the atrial impulse. The cycle length of the tachycardia was lengthened in 2 patients, reflecting an increase in the A-H interval after verapamil administration. In conclusion, these results show that verapamil has no apparent effect on either antegrade or retrograde accessory pathway properties and suggest that verapamil does indeed prevent sustained circus movement tachycardia by increasing the AV nodal refractoriness in some patients with the Wolff-Parkinson-White syndrome.     

In vivo canine cardiac electrophysiologic profile of 1,4-benzodiazepine IKs blockers

Previous cardiac electrophysiologic studies of blockers of the slowly activating delayed rectifier (IKs) current have focused primarily on ventricular repolarization. This report summarizes an extensive in vivo cardiac electrophysiologic profile of four 1,4-benzodiazepine IKs blocker analogues (L-761334, L-763540, L-761710, and L-768673) in dogs. At 3.0 mg/kg intravenously, all four analogues elicited 14.5%-21.4% increases in ventricular refractoriness and 19.2%-22.6% increases in QTc interval. Concomitant 11.1%-13.5% increases in atrial refractoriness were noted with all four analogues. Decreases in sinus heart rate of 8.4%-17.3% were noted with all four compounds. No effects on atrial, His Purkinje, ventricular conduction or atrial and ventricular excitation were observed. One analogue, L-761710, significantly delayed atrioventricular (AV) nodal conduction (40.7+/-17.4% increase in atrial-to-His interval) and increased the AV conduction system functional refractory period 19.9+/-6.2%. The lack of effect of the other three 1,4-benzodiazepine IKs blockers on AV nodal function at dosages producing comparable effects on atrial and ventricular refractoriness suggest that the AV nodal effects of L-761710 were unrelated to IKs blockade. These findings indicate IKs plays important roles in both atrial and ventricular refractoriness as well as pacemaker function in the dog heart, suggesting potential utility for IKs blockers in the treatment of atrial and ventricular arrhythmias.     

The effects of aging on the electrophysiologic and hemodynamic responses to nifedipine in isolated perfused hearts.

Age effects on responses to calcium channel blockade with nifedipine were studied in isolated Langendorff-perfused Fischer 344 rat hearts. Responses to 25 min of perfusion with nifedipine concentrations of 0, 25, 50, 75, and 100 ng/ml were studied in hearts from 11 mature (6 months) and 13 senescent (23-27 months) male F344 rats. Nifedipine produced significant increases in the atrial cycle length (p less than 0.001), paced atrioventricular (AV) conduction time (p less than 0.001), AV Wenckebach cycle length (p less than 0.001), left ventricular (LV) diastolic pressure (p less than 0.001), and decreases in LV systolic pressure (p less than 0.001) and peak dP/dt (p less than 0.001) in hearts from both mature and senescent rats. Greater decreases in the atrial rate (p less than 0.05) and depression of peak dP/dt (p less than 0.05) were detected in senescent vs. mature rat hearts. No age difference in responses of AV conduction parameters were detected although increases in the AV Wenckebach cycle length appeared to be greater in senescent hearts at concentrations greater than 75 ng/ml.     

Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine.

1. It was investigated whether the calcium antagonistic coronary drugs verapamil and nifedipine have similar antiarrhythmic properties. Their effects on functional refractory period and contractile force in the isolated left guinea pig atrium were compared. To assess their influence on myocardial excitability the relation between threshold voltage and pulse duration was studied in the left guinea pig atrium. Furthermore, the influence on AV conduction was investigated in the conscous dog in haemodynamically equieffective dose ranges. 2. Verapamil as well as nifedipine cause a dose-dependent prolongation of the functional refractory period in the isolated left guinea pig atrium. The slope of the dose-response curve of nifedipine is, however, significantly less steep than that of verapamil. Maximum prolongation of refractory period which can be induced by nifedipine is significantly inferior to that occurring after verapamil; under nifedipine this prolongation is, however, accompanied by a significantly greater reduction in contractility. 3. In the isolated left guinea pig atrium the voltage-duration curve is shifted to the right and the chronaxia value is significantly increased by verapamil. Even in the highest dose possible nifedipine has no effect on atrial excitability. 4. In the conscious dog verapamil considerably prolongs AV conduction time whereas a moderate yet dose-dependent shortening of PQ duration is observed with equieffective nifedipine doses regarding the decrease in blood pressure and increase in heart rate. 5. The results indicate that nifedipine does not exert antiarrhythmic effects comparable to those of verapamil.     

Atenolol, its cardioselective property for adrenergic beta-receptor blocking action and effect on the cardiac function (author's transl)

Cardioselective property of the beta-adrenoceptor blocking action of atenolol and its effect on the AV conduction, the atrial muscle refractory period and the cardiac contractility were studied in comparison with these of propranolol. A ratio of pA2 values obtained in the isolated right-atrial preparations and the isolated tracheal preparations of guinea pigs demonstrated that atenolol was highly cardioselective, while propranolol was non-selective. This cardioselective property of atenolol was confirmed in in vivo experiments using guinea pigs. Atenolol increased the AV conduction time and decreased the cardiac contractility dose-dependently in anesthetized dogs of which the heart was electrically driven at fixed rates. At 140 beats/min, AV block was observed at 10 mg/kg, i.v. in 3 of 8 dogs, and further increase in a dose ti 30 mg/kg resulted in acute heart failure in one of remaining 5 dogs, while propranolol, though showing a tendency to be less potent in depressing AV conduction in a dose range less than 0.3 mg/kg, produced a state of heart failure in 2 of 5 dogs at 3 mg/kg, i.v. and AV block in all of the remainder at 10 mg/kg, i.v. Functional refractory period of AV node as well as functional and effective refractory period the the atrial muscle were increased dose-dependently by atenolol and propranolol. There were no significant differences between both drugs regarding these effects. Further increase in a pacing rate to 160 and 180 beats/min augmented the depressing effect of both drugs on the AV conduction.     

Effect of gradual rise in plasma calcium concentration on the impairment of atrioventricular nodal conduction due to verapamil

The possible reversal by calcium of the inhibitory action of verapamil on the atrioventricular (AV) node was investigated in anesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitory electrode and the AV node effective refractory period measured by the extrastimulus method. Calcium infusion was effective against the impairment of AV nodal conduction induced by verapamil, provided it remained moderate: the gradual rise in the plasma calcium concentration counteracted the effects of an infusion of verapamil on conduction time and effective refractory period in the AV node, as long as it did not exceed 5 mmol/L. However, beyond this level, calcium appeared less and less capable of reversing the effects of verapamil. Thus, the protective action of calcium had a bell-shaped dose-response curve, with the optimum at 5 mmol/L. This biphasic influence is consistent with the opposite opinions previously given concerning the antagonism between calcium and calcium blockers, depending on whether hypercalcemia brought into play was mild or major. In any case, the prominent role played by calcium in the slow inward current in the AV node accounts for the antagonism, observed in vivo, between calcium and verapamil. The pacemaker activity of the sinoatrial (SA) node was less influenced by both calcium blocker and calcium.     

Hemodynamic and electrocardiographic actions of the new intracellular calcium antagonist, KT-362, in the conscious dog

Effects of the intracellular calcium antagonist, KT-362, on systemic and coronary hemodynamics and the electrocardiogram were evaluated in chronically instrumented, awake dogs during intravenous infusion or bolus administration. Both methods of administration resulted in systemic hypotension, tachycardia and decreases in left ventricular pressure and peak positive left ventricular dP/dt. KT-362 produced a transient increase in mean coronary blood flow velocity only during bolus injection, while subendocardial segment shortening was depressed only by drug infusion. Prolongation of QRS duration and the QT interval (corrected for change in heart rate, QTc) also occurred during drug infusion. The results suggest that the hemodynamic effects of intracellular calcium antagonism by KT-362 are qualitatively similar to those of other calcium channel blocking agents which inhibit extracellular calcium influx. In contrast, the actions of KT-362 on cardiac conduction may be different from those of other slow channel calcium blocking agents.     

Oral verapamil and calcium infusion in patients with sick sinus syndrome

Electrophysiologic and circulatory effects of a single oral dose of verapamil (120 mg) were evaluated in 8 patients with symptomatic sick sinus syndrome. Ninety min. after verapamil, calcium gluconate (1375 mg) was infused in an attempt to reverse the depressor actions of the drug. Verapamil significantly increased sinus node recovery time (P less than 0.05) and atrioventricular conduction time (P less than 0.01), and decreased both systolic (P less than 0.01) and diastolic blood pressure (P less than 0.05) and spontaneous heart rate (P less than 0.01). Intravenous calcium significantly reversed blood pressure reduction (P less than 0.001) and further lowered heart rate (P less than 0.05) without affecting sinus node recovery time and atrioventricular conduction significantly. There was no significant correlation between plasma verapamil concentrations and any of the cardiovascular parameters. These data confirm that verapamil is principly contraindicated in patients with sinus node dysfunction and demonstrate that the actual calcium dose, although partly reversing blood pressure reduction, cannot reverse the depressant action of the drug on the sinus and atrioventricular node in such patients.     

Comparison of the haemodynamic profiles of elgodipine and nicardipine in the anaesthetized dog.

1. The haemodynamic profile of elgodipine (1-30 micrograms kg-1, i.v.), a new dihydropyridine calcium antagonist, has been compared directly with that of nicardipine (1-30 micrograms kg-1, i.v.) in chloralose-anaesthetized dogs. 2. Nicardipine produced dose-related systemic, pulmonary and coronary vasodilatation accompanied by reflex tachycardia, inotropy and increases in cardiac output and myocardial oxygen consumption (MVO2). Elgodipine had similar vasodilator and hypotensive properties to nicardipine but produced less reflex inotropy, little or no reflex tachycardia and did not increase MVO2. 3. Both calcium antagonists were retested in a separate group of anaesthetized dogs pretreated with propranolol (1 mg kg-1, i.v.) and atropine (0.3 mg kg-1, i.v.) to abolish reflex autonomic tone to the heart and thus reveal the direct cardiac effects of each compound. Under these conditions both elgodipine and nicardipine decreased heart rate and cardiac contractility and slowed atrio-ventricular conduction. Elgodipine was approximately ten times more potent than nicardipine as a decelerator agent and slightly more potent in depressing cardiac contractility and increasing PR interval duration. Elgodipine, unlike nicardipine, slightly reduced the QTc interval of the electrocardiogram. Therefore, the potent decelerator effect of elgodipine, which was present throughout the dose-range, appears to be largely responsible for the suppression of reflex tachycardia observed when the baroreflex is functional. 4. Elgodipine is a potent systemic and coronary vasodilator with more marked direct cardiac effects than nicardipine, particularly with respect to slowing of heart rate. The ability of elgodipine to increase coronary blood flow without significant reflex tachycardia or increases in MVO2 suggests that this compound will have a more favourable effect on myocardial oxygen supply/demand balance than nicardipine. The haemodynamic profile of elgodipine may be suitable for the treatment of angina.     

Profile of coronary vasodilator and cardiac actions of bepridil revealed by use of isolated, blood-perfused heart preparations of the dog

We investigated the coronary vasodilator and cardiac actions of bepridil in various isolated, blood-perfused dog heart preparations. Intra-arterial bepridil increased blood flow in all preparations. In sinoatrial (SA) node preparations bepridil decreased sinus rate and produced atrial standstill in large doses. In paced atrioventricular (AV) node preparations, bepridil injected into the posterior septal artery (which supplies the AV node) increased AV conduction time (i.e., AV nodal conduction time) and in large doses produced second- or third-degree AV block. In the same preparations, bepridil in large doses injected into the anterior septal artery (which supplies the His-Purkinje ventricular system) prolonged AV conduction time (i.e., intraventricular conduction time). In paced papillary muscle preparations, bepridil reduced force of contraction only in large doses. In spontaneously beating papillary muscle preparations, bepridil decreased the rate of automaticity and the force of contraction as well. The order of effectiveness of bepridil on the above cardiovascular variables is as follows: coronary blood flow greater than AV nodal conduction greater than SA nodal automaticity much greater than ventricular automaticity ventricular muscle contraction much greater than intraventricular conduction. The results indicate bepridil to have a pharmacological profile different from that of verapamil, diltiazem, nifedipine, nicardipine, or KB-944.     

Electrophysiological and cardiovascular effects of pirmenol, a new class 1 antiarrhythmic drug

Pirmenol, a new antiarrhythmic agent, has been studied in the pithed rat and in the sinoatrial (SA) node, atrium, atrioventricular (AV) node, Purkinje cells, and ventricular muscle of the isolated rabbit heart. It resembles disopyramide chemically and in its electrophysiologic effects. Pirmenol decreased the maximum rate of depolarization (MRD) and overshoot potential in isolated rabbit atrium, Purkinje cells, and ventricle. Pirmenol caused bradycardia in pithed rats and isolated rabbit SA nodes. In the latter, repolarization was delayed, but there was little change in MRD or in the slope of the slow diastolic depolarization. Like disopyramide, but unlike lidocaine, pirmenol lengthened APD in all cardiac tissues studied. The above effects were dose-related and were reversed on washout. Pirmenol did not lengthen conduction time within the AV node. Unlike disopyramide, pirmenol had no negative inotropic action, and did not alter the relation between contractile force and extracellular calcium concentration. This suggests, as does the absence of effect on sinoatrial MRD or AV conduction, that pirmenol does not block calcium channels.     

Effects of verapamil and nifedipine on mechanisms of arrhythmia in an in vitro model of ischemia and reperfusion.

The effects of verapamil and nifedipine on cellular mechanisms of arrhythmia were examined in isolated canine Purkinje fiber-papillary muscles. Microelectrode recordings were made simultaneously from both tissues. Preparations were superfused with Tyrode's solution modified to mimic specific conditions of ischemia for 40 min with or without calcium channel blockers. Verapamil or nifedipine resulted in significantly greater depolarization of Purkinje tissue in response to ischemic conditions and increased the incidence of inexcitability or conduction block in Purkinje and muscle tissues. These calcium channel blockers caused only minor changes in ischemia-induced depolarization of muscle. In Purkinje tissue, return to nonischemic conditions in the absence of drugs caused, in sequence, oscillatory afterpotentials, temporary depolarization to inexcitability, and a phase of automaticity at low membrane potential. These events did not occur in muscle. Verapamil or nifedipine abolished oscillatory afterpotentials and low membrane potential automaticity in Purkinje tissue. However, reperfusion-induced depolarization and inexcitability of Purkinje tissue was delayed but not attenuated. This study demonstrates that verapamil or nifedipine exacerbate depolarization and depression of conduction in Purkinje tissue exposed to ischemic conditions. However, verapamil and nifedipine suppress some but not all potential mechanisms of arrhythmia induced by reperfusion.     

Calcium antagonists. Clinical use in the treatment of arrhythmias

Calcium antagonists have recently emerged as a class of drugs for the treatment of angina, hypertension and certain cardiac arrhythmias. Verapamil is the prototype calcium antagonist and has the most clearly defined antiarrhythmic properties. Other agents in the class include D-600 (gallopamil), tiapamil, nifedipine, and diltiazem. The antiarrhythmic effects of these compounds can be correlated with their electrophysiological properties which may differ significantly among different compounds and also between isolated tissues in intact animals and man. As a class they do not increase the effective refractory period of the atria, ventricle, His-Purkinje fibres or the accessory pathways in the heart. The dominant effect is slowing of conduction in the AV node with the prolongation of the AV nodal refractory period. The most marked changes are produced by verapamil, the least with nifedipine which is devoid of antiarrhythmic actions. Verapamil and its congeners as well as diltiazem terminate paroxysmal supraventricular tachycardia and slow the ventricular response in atrial flutter and fibrillation. They are also of prophylactic value in preventing recurrences of paroxysmal supraventricular tachycardia and controlling the ventricular response in atrial flutter and fibrillation during long term oral therapy. Their value in ventricular arrhythmias is uncertain but they are unlikely to be effective except in those complicating coronary artery spasms. The relative merits and potencies of various calcium antagonists in different arrhythmias need further studies.