Interaction Of Verapamil Research Articles

Calcium antagonist affinity for adrenergic and cholinergic receptors in rabbit urinary bladder

AbstractCalcium antagonists have the ability to relax vesical smooth muscle in vitro and in vivo. The presumed mechanism of action is through the inhibition of calcium translocation, yet these agents have also been shown to bind to several different pharmacological receptors. By employing radioligand binding assays, the affinity of verapamil and diltiazem for several receptor populations in the rabbit detrusor was studied. Verapamil and diltiazem displayed binding affinities for receptor populations in the following order: alpha1‐ and alpha2‐ adrenergic > muscarinic cholinergic > beta‐adrenergic. In all instances verapamil affinity was greater than that of diltiazem. The relatively high Ic50's for both muscarinic and beta receptors indicate that the interactions of verapamil and diltiazem with these receptors are of little physiological significance.

Hemodynamic Interactions of Verapamil and Isoflurane

This elegant animal study clearly shows that verapamil enhances the direct myocardial depression of the volatile anesthetic isoflurane. This finding is not surprising because it was already known that similar enhancement of myocardial depression occurred between verapamil and halothane. Because of verapamil's disturbing tendency to produce an occasional AV block, this prototypic calcium entry blocker is not likely to find wide use in the intraoperative setting. As each new calcium entry blocker comes on the market, because they are so very different, it may well be that these kinds of studies will have to be repeated.

Combined Actions of Verapamil and Contrast Media on Atrioventricular Conduction

Peck WW, Slutsky RA, Mancini GBJ, Higgins CB. Combined actions of verapamil and contrast media on atrioventricular conduction: influence of osmolality of the media. Invest Radiol 1984;19:202-207. Since verapamil and contrast media both cause depression in the electrophysiologic function of the heart and both may exert these effects by actions on ionic calcium, the possible interaction of verapamil and intracoronary contrast media on atrioventricular conduction was studied in six dogs using surface electrocardiography and HIS bundle electrogram. The effects of intracoronary injection of standard ionic media (Renografin® 76) and low osmolal contrast media (Hexabrix and Hexabrix with calcium [8 mEq/L]) were compared. Each contrast media was assessed in the normal state and at four increasing doses of verapamil (0.125, 0.25, 0.5, and 1.0 mg/kg). The PR and AH intervals were substantially prolonged by intracoronary injection of Renografin 76 in the presence of a 1.0 mg/kg dose of verapamil (172 ± 41 msec to 724 ± 48 msec,P< 0.05 for PR interval, and 182 ± 41 msec to 734 ± 51 msec,P< 0.05 for AH interval), with most animals developing second degree heart block (Mobitz, type I). There was no change in the HV interval. Hexabrix and Hexabrix with calcium did not cause significant changes in PR or AH intervals at similar doses of verapamil. Thus, standard ionic contrast causes severe inhibition of atrioventricular conduction in the presence of verapamil, whereas low osmolal contrast media cause no significant negative dromotropic effects either in the presence or absence of verapamil. The osmolality of contrast media is an important mechanism responsible for the depression in atrioventricular conduction attending intracoronary contrast media in the presence of verapamil.

Combined Actions of Verapamil and Contrast Media on Atrioventricular Conduction

Since verapamil and contrast media both cause depression in the electrophysiologic function of the heart and both may exert these effects by actions on ionic calcium, the possible interaction of verapamil and intracoronary contrast media on atrioventricular conduction was studied in six dogs using surface electrocardiography and HIS bundle electrogram. The effects of intracoronary injection of standard ionic media (Renografin 76) and low osmolal contrast media (Hexabrix and Hexabrix with calcium [8 mEq/L]) were compared. Each contrast media was assessed in the normal state and at four increasing doses of verapamil (0.125, 0.25, 0.5, and 1.0 mg/kg). The PR and AH intervals were substantially prolonged by intracoronary injection of Renografin 76 in the presence of a 1.0 mg/kg dose of verapamil (172 +/- 41 msec to 724 +/- 48 msec, P less than 0.05 for PR interval, and 182 +/- 41 msec to 734 +/- 51 msec, P less than 0.05 for AH interval), with most animals developing second degree heart block (Mobitz, type I). There was no change in the HV interval. Hexabrix and Hexabrix with calcium did not cause significant changes in PR or AH intervals at similar doses of verapamil. Thus, standard ionic contrast causes severe inhibition of atrioventricular conduction in the presence of verapamil, whereas low osmolal contrast media cause no significant negative dromotropic effects either in the presence or absence of verapamil. The osmolality of contrast media is an important mechanism responsible for the depression in atrioventricular conduction attending intracoronary contrast media in the presence of verapamil.

Hyperkalemia and Cardiovascular Collapse after Verapamil and Dantrolene Administration in Swine

The cardiovascular and neuromuscular interactions of verapamil and dantrolene were evaluated in 20 chloralose-anesthetized swine. The animals were randomly divided into three groups. Group I, ten animals, received a bolus intravenous injection of 0.1 mg . kg-1 of verapamil followed by the continuous infusion of 5 micrograms . kg-1 . min-1. This group was then randomly divided into two equal subgroups. Five of these animals, Group Ia, continued to receive the verapamil infusion alone. The other five animals, Group Ib, received dantrolene in incremental doses of 1.0, 3.3, and 5.6 mg . kg-1 while the verapamil infusion was continued. An additional group of five animals, Group II, received the same incremental doses of dantrolene but did not receive verapamil. Five control animals, Group III, received the alpha-chloralose anesthetic without dantrolene or verapamil. Neuromuscular function, as measured by twitch height, was affected only by dantrolene, which produced a dose-dependent depression. Verapamil resulted in initial decreases in heart rate, arterial blood pressure, cardiac output, left ventricular dP/dt, and an increase in PR interval. Dantrolene alone produced a mild increase in arterial blood pressure. Dantrolene administration to verapamil-pretreated animals resulted in a profound depression in cardiac function, marked elevation in serum K+ (8.0 +/- 0.7 mEq . l-1), and no change in arterial pH (7.39 +/- 0.02). Cardiac arrest preceded by complete atrioventricular heart block occurred in one animal before and in four animals after the final dantrolene dose was given to animals pretreated with verapamil. Although we cannot extrapolate data from our porcine model to humans, further studies are indicated to help evaluate a possible fatal drug interaction before verapamil and dantrolene are used concomitantly in a clinical setting.

Hemodynamic interactions of verapamil and isoflurane.

The hemodynamic interactions of verapamil and isoflurane were studied in eight dogs. Left ventricular function was analyzed using a right heart bypass preparation to permit rigid hemodynamic control. Hemodynamic studies were performed at 0.7, 1.05, and 1.40% isoflurane before and during the maintenance of two stable levels of verapamil, administered intravenously by combining a bolus dose (0.2 mg X kg-1) with an infusion (3.0 and 6.0 micrograms X kg-1 X min-1). Isoflurane produced a concentration-dependent depression of left ventricular function as indicated by dP/dt max, per cent systolic shortening, and left ventricular function curves. This depression was enhanced in a dose-plasma concentration-dependent manner by verapamil and was reversed by calcium chloride. Isoflurane alone and the combination of verapamil and isoflurane decreased systemic vascular resistance in a dose-dependent fashion that was antagonized partially by calcium chloride. Therefore, verapamil can enhance the hemodynamic effects of isoflurane in a dose-related manner that needs to be considered when both drugs are administered together.

The interactions of verapamil, nifedipine and diltiazem with lignocaine on AV conduction in beating rabbit hearts: H.J. Smith, S.E. Halliday and W. Rouse. ICI (Pharmaceuticals Division), Alderley Park, Macclesfield, U.K.

The interactions of verapamil, nifedipine and diltiazem with lignocaine on AV conduction in beating rabbit hearts: H.J. Smith, S.E. Halliday and W. Rouse. ICI (Pharmaceuticals Division), Alderley Park, Macclesfield, U.K.

Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors.

To determine the specificity of the previously demonstrated competition of verapamil with radioligand binding to alpha-adrenergic receptors, we examined the interaction of calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors on several tissues. Verapamil competed for [3H] prazosin binding to alpha 1-adrenergic receptors and for [3H]yohimbine binding to alpha 2-adrenergic receptors in several tissues (human platelets, rat kidney and heart, and cultured muscle cells) with dissociation constants of 0.6-6 microM. The calcium channel blockers D600, D591, fendiline, and prenylamine--which are structural analogues of verapamil--also competed for [3H]yohimbine binding to human platelets. Two other calcium channel blockers, diltiazem and nifedipine, did not compete for [3H] yohimbine binding to human platelets or [3H]prazosin binding to membranes prepared from rat ventricles. We used [3H]nitrendipine binding to identify putative calcium channels on rat myocardial membranes. Nifedipine and verapamil blocked these [3H]nitrendipine-binding sites on ventricular membranes, but epinephrine and prazosin did not, indicating that the ventricular alpha 1 receptors and calcium channels are distinct. We found no specific [3H]nitrendipine binding to human platelets. We conclude that the interaction of verapamil with alpha-adrenergic receptors is not receptor subtype or tissue specific, that interaction with alpha-adrenergic receptors is not a property of all calcium channel blockers, and that the interaction of verapamil with alpha-adrenergic receptors and its interaction with calcium channels occur at at least two distinct sites.

Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atrial fibrillation.

SUMMARY The safety, efficacy, and pharmacologic effect of combined verapamil and digoxin were studied in 10 patients with chronic atrial fibrillation. Heart rate recordings, treadmill exercise tests, physical examinations and serum digoxin concentrations during chronic digoxin therapy were compared with those after the acute administration of verapamil and 1, 2, 4, 6 and 10 weeks after the addition of oral verapamil to digoxin therapy. After both i.v. and chronic oral verapamil administration, resting and exercise heart rates were significantly lower. Increasing serum concentrations of verapamil correlated with increasing suppression of heart rate at rest and during exercise. The mean resting heart rate by 24-hour ambulatory ECG decreased from 87 ± 9 beats/min to 72 6 beats/min. The mean treadmill exercise heart rate decreased more markedly, from a mean of 151 26 beats/min to 106 ± 22 beats/min (both p < 0.001). During chronic therapy, heart rate reductions were seen 1 week after the addition of verapamil and were maintained without change for the duration of the trial. Blood pressures at rest and during exercise were unchanged. Cardiomegaly was present on the entry chest x-ray in six patients; after verapamil, heart size decreased in three and was unchanged in one; two patients had transient congestive heart failure that responded to diuretics. Serum digoxin levels increased from a mean of 1.6 ± 0.4 ng/ml to 2.7 + 0.9 ng/ml (p < 0.001) during verapamil. The increase was observed in hine of 10 patients but was not related to clinical signs of digitalis excess and no episodes of asystole were seen on the serial 24-hour ECGs. Chronic oral administration of verapamil, 320 mg/ day, resulted ih mean verapamil concentrations of 130–280 ng/ml (mean interdose concentration 140 ± 41 ng/ml) with great intersubject and intrasubject variability. We conclude that verapamil is effective in further suppressing the ventricular response rate in atrial fibrillation when given in combination with digitalis and can serve as an adjunct to digitalis therapy in the chronic management of patients with atrial fibrillation.

Interaction of verapamil with human platelet alpha-adrenergic receptors.

Platelet aggregation induced by epinephrine is an alpha-adrenergic event and is inhibited in vitro by the calcium-channel blocker, verapamil. We wondered whether this inhibition might be mediated by an interaction of verapamil with platelet alpha-adrenergic receptors. Verapamil inhibited the specific binding of [3H]dihydroergocryptine ([3H]DHE), a nonselective alpha-adrenergic antagonist, to intact platelets in a concentration-dependent and competitive manner. At 10 microM verapamil caused a fivefold decrease in the affinity of binding of [3H]DHE to platelet alpha-adrenergic receptors (P less than 0.001) with no change in the number of receptors per platelet. The inhibition of binding was not reversed by excess calcium. Verapamil also inhibited the binding of a selective alpha 2-adrenergic antagonist, [3H]yohimbine, to intact platelets, and inhibited the binding of an alpha 2-partial agonist, [3H]clonidine, to platelet membranes. Moreover there was a strong correlation between verapamil's effect on [3H]DHE binding and its effect on epinephrine-induced aggregation (r = 0.98). Although verapamil is commonly used as an inhibitor of calcium flux across cell membranes, the present studies demonstrate that verapamil also inhibits epinephrine-induced aggregation at the level of the platelet alpha-adrenergic receptor.

Verapamil interaction see Digoxin

Verapamil interaction see Digoxin

Interactions of verapamil and prostaglandins (PG) in isolated heart and coronary preparations

Interactions of verapamil and prostaglandins (PG) in isolated heart and coronary preparations

Papaverine and verapamil interaction with prostaglandin E 2 and Δ 9-tetrahydrocannabinol in the eye

Papaverine and verapamil both produce vasodilation of efferent uveal vessels in the eye. Papaverine completely blocks the tetrahydrocannabinol-induced intraocular pressure fall, and partially inhibits prostaglandin effects; the antagonism of these effects is caused by the vasodilatory action. No effect is seen on the prostaglandin or tetrahydrocannabinol-induced rise in total outflow facility. Based upon the interactions between prostaglandin or tetrahydrocannabinol, and verapamil, the latter acts on afferent and efferent uveal vessels as well as affecting the loss of fluid from the eye by an α-adrenergic antagonist effect. Prostaglandin is known to act locally in the eye thus the effects of papaverine and verapamil must be local. THC, however, acts via a central pathway as well as a local effect in the eye but in view of the interaction of papaverine and verapamil with prostaglandin, it is concluded that both papaverine and verapamil act locally in the eye by different mechanisms to produce their effects.