Cutaneous adverse reactions associated with calcium channel blockers

The calcium channel blockers, nifedipine, verapamil, and diltiazem, are widely used for the treatment of cardiovascular disease. In spite of their widespread use, little data about the frequency and spectrum of cutaneous reactions associated with these agents have been published. Based on reports provided to the FDA's Division of Epidemiology and Drug Surveillance, and the American Academy of Dermatology's Adverse Drug Reaction Reporting System, it appears that the frequency of adverse cutaneous events associated with these drugs is low, but that occasionally severe reactions are associated with the use of these drugs. Among the more serious reactions associated with the calcium channel blockers are toxic epidermal necrolysis with diltiazem, Stevens-Johnson syndrome and erythema multiforme, which have been associated with all three drugs in this class, and exfoliative dermatitis, which has also been reported with all three agents. Most serious reactions associated with these agents occur within two weeks of initiating drug therapy. These findings suggest that calcium channel blockers are occasional causes of a wide spectrum of cutaneous reactions and should be considered as possible causative factors in patients who develop adverse cutaneous reactions while using these drugs.     

Electrophysiologic effects of calcium channel blockers on supraventricular tachycardia in children

Calcium channel blockers (diltiazem or verapamil) were administered in 17 pediatric patients with supraventricular tachycardia to evaluate their drug effects on electrophysiologic properties and the tachycardia zone. Using electrophysiologic technique, 10 patients were diagnosed as having orthodromic reciprocating tachycardia (ORT), including three patients with concealed atrioventricular bypass tracts. Four patients were diagnosed as having atrioventricular nodal re-entrant tachycardia (AVNRT) of the slow-fast type and three patients were diagnosed as having intra-atrial re-entrant tachycardia (IART). Diltiazem was given to 10 patients; verapamil, to eight patients at doses of 0.15-0.2 mg/kg intravenously. Electrophysiologic properties and the tachycardia zone were then evaluated before and after the administration of calcium channel blockers. Diltiazem and verapamil produced no significant changes in the sinus node and atrial functions including basic sinus cycle length, sinoatrial conduction time, maximum sinus node recovery time and the effective atrial refractory period. Although sinus cycle length was shortened after verapamil in half the cases, it was due to increased sympathetic tone secondary to hypotension rather than to direct action of verapamil. Calcium channel blockers, however, prolonged the PR interval and significantly increased the effective refractory period of the atrioventricular node. Properties of the atrioventricular bypass tracts were not affected by calcium channel blockers. Diltiazem and verapamil were markedly effective in ORT and AVNRT. Their re-entrant circuits, including the atrioventricular node and the tachycardia zones, were shortened or resolved. However, IART showed no significant change in the tachycardia zone after the administration of calcium channel blockers, because the re-entrant circuit was not present within the atrioventricular node.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, verapamil and nitrendipine are reviewed. Although nifedipine stimulates plasma renin activity on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function; glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although diltiazem and nifedipine increase salt and water excretion on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are unchanged. Thus, calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.     

Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms

The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropic state) when evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine greater than diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil greater than nifedipine greater than diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine greater than verapamil greater than diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.     

Calcium antagonists and myocardial infarction

In vitro and in vivo studies have demonstrated many similarities between the three calcium antagonists verapamil, nifedipine, and diltiazem in relation to protection of the myocardium during hypoxia. Important clinical differences exist between the three drugs when they are used during or after an acute myocardial infarction with the purpose of preventing death and reinfarction. The balance between the negative inotropic and the vasodilator properties and concomitant treatment with beta blockers may explain the results of clinical trials with the three calcium antagonists. Patients not treated with beta blockers. Nifedipine has been demonstrated to be no better than placebo both during and after an acute myocardial infarction. No placebo-controlled studies exist with diltiazem. Verapamil had no effect during the acute phase of a myocardial infarction. After a myocardial infarction, verapamil improved survival and reduced the reinfarction rate, an effect primarily found in patients without heart failure in the coronary care unit. Patients also treated with beta blockers. Nifedipine prevents the development of myocardial infarcts in patients with unstable angina. Diltiazem probably prevents reinfarction in the first two weeks after non-Q-wave infarction. Secondary prevention with diltiazem after an acute myocardial infarction had no overall effect on death or cardiac events (i.e., reinfarction or cardiac death). Subgroup analysis demonstrated in diltiazem-treated patients, compared with placebo-treated patients, a significant reduction of cardiac events in patients without and a significant increase of cardiac events in patients with heart failure. At present no indications exist for nifedipine during or after a myocardial infarction; further studies are needed with diltiazem, and verapamil may be used in secondary prevention of death and reinfarction.     

Patch tests for diagnosis of delayed hypersensitivity to cephalosporins

BackgroundFew studies have reported delayed hypersensitivity reactions to systemically administered cephalosporins. The diagnostic procedures and extracts for these reactions are not standardized, and little is known about the extent of cross reactivity among different cephalosporins.Cases reportWe report 2 cases of delayed hypersensitivity reactions due to cephalosporins presenting as erythrodermia.Case 1. An 80-year-old man developed generalized pruritus and erythema 2-3 days after starting treatment with cefuroxime. The drug was stopped and antihistamines and corticosteroids were administered. The patient improved 5-6 days later, and mild superficial desquamation was observed.Case 2. A 66-year-old woman experienced similar symptoms 4-5 days after beginning cefazolin. She reported a similar reaction with ceftazidime 8 years previously.Methods and resultsSkin prick tests and specific IgE against penicillin G and V, amoxicillin, ampicillin and cephalosporins were negative. Intradermal tests with ceftazidime and cefazolin were positive in case 2 at delayed reading. Patch tests using benzylpenicillin, ampicillin, amoxicillin, several cephalosporins, aztreonam and imipenem were positive to all the cephalosporins tested (at 48 and 96 hours) and were negative to the other betalactams. Controlled administration of amoxicillin, benzylpenicillin, aztreonam and imipenem was well tolerated by both patients.Conclusions1) We report 2 cases of delayed hypersensitivity reactions due to cephalosporins presenting as erythrodermia. 2) Epicutaneous tests were useful for diagnosis. 3) Both patients tested positive to all cephalosporins and negative to other betalactams.     

Short- and long-term effects of calcium entry blockers on the kidney

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, nitrendipine, nicardipine and verapamil are reviewed. Although nifedipine may acutely increase plasma renin activity, most of the calcium entry blockers have no sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function: Glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although all of the calcium entry blockers acutely increase salt and water excretion, most of the calcium entry blockers have no clinically sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are usually unchanged. Calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.     

The relative sensitization by acidosis of five calcium blockers in cat papillary muscles

We have previously reported that the negative inotropic effects of both verapamil and nifedipine on cat papillary muscles are enhanced as pH is lowered from 7.4 to 6.8 and 6.0. These studies have now been extended to compare the relative sensitization by acidosis of verapamil, nifedipine, lidoflazine, perhexilene and diltiazem. Developed tension was recorded in cat papillary muscles and the calcium concentration was adjusted over the range 2 to 10 mM. At pH 7.4, addition of all five drugs moved the dose response curve to the right with pA2 values from 4.82 (lidoflazine) to 9.94 (nifedipine). At pH 6.0, there was eight-fold sensitization by acidosis for verapamil, but four, three, and two-fold sensitization for nifedipine, lidoflazine and perhexilene. Diltiazem, however, was not sensitized by acidosis. The differential effects of acidosis on the negative inotropic properties of the five drugs may reflect their ancillary properties opposite gating of the calcium channel, local anaesthesia, intracellular calcium movement or Na+/Ca2+ exchange, but also suggest that diltiazem may have the property of inhibiting the effects of low pH on cell membranes.     

Hepatotoxicity of ethanol: protective effect of calcium channel blockers in isolated hepatocytes

Abstract: This study examines the effects of three calcium channel blockers (verapamil, nifedipine and diltiazem) on isolated rat hepatocytes exposed to ethanol. In the first part of our study, hepatocytes were incubated with increasing concentrations of ethanol (100, 300, 500, 1000 mM) for varying times. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) release were measured to evaluate the cytotoxic effects of ethanol. The concentration of 300 mM and time of incubation of 45 min were chosen for cytoprotection experiments in which calcium channel blockers, at two different concentrations, were added to the medium 30 min prior to the addition of ethanol. ALT, AST and LDH release as well as lipid peroxidation and cellular reduced gluthatione (GSH) were measured. Nifedipine and verapamil (25 μM) reduced ALT, AST and LDH activities. The highest dose of diltiazem (50 μM) was more effective than the lowest one (25 μM). Ethanol caused a significant depletion of cellular GSH content as well as a moderate enhancement of lipid peroxidation. While none of the three calcium channel blockers was able to restore the decrease in GSH levels, diltiazem (25 μM) and nifedipine (50 μM) showed the greatest effect, significantly reducing lipid peroxidation.     

Effects of calcium channel blockers on calcium uptake in rat aortic valve allografts.

BACKGROUND. The life span of human aortic valve allografts is finite, and many fail because of cusp rupture or calcification. Subcellular changes occurring in aortic valves in response to transplantation include the uptake of calcium. This study uses a heterotropic rat aortic valve transplant model to determine whether the calcium channel blockers diltiazem and verapamil might attenuate leaflet calcification. METHODS AND RESULTS. The 60 rats studied were divided into the following groups: 1) control: valves from normal, unoperated F1 generation of Lewis and Brown Norway cross (LBNF1) rats; 2) control: valves from syngeneic transplant combinations (Lewis/Lewis); 3) control: valves from allogeneic transplant combinations (LBNF1/Lewis, donor/recipient); 4) experimental: valves from allogeneic strain combinations treated with 30 mg/kg per day diltiazem; 5) experimental: valves from allogeneic strain combinations treated with 30 mg/kg per day verapamil. Drugs or saline (controls) were administered with osmotic pumps placed subcutaneously 2 days before transplantation. Animals were killed 3 weeks later, and the valves were harvested and prepared for calcium analysis. Energy-dispersive x-ray microanalysis was used to measure the calcium in a section of one leaflet from each valve studied. Paired t tests showed that allograft valves treated with diltiazem or verapamil contained significantly less calcium than allograft controls treated with saline (p < 0.001). When all five groups were subjected to one-way ANOVA, the valves in the allograft control group contained significantly more calcium than all other groups. All other groups were not different from each other. CONCLUSIONS. The calcium channel blockers verapamil and diltiazem were effective in preventing early calcification that occurs in aortic valves after transplantation. Thus, these agents might play a role in prolonging the life of human aortic valve allografts.     

Value of calcium inhibitors in stable effort angina. Diltiazem versus nifedipine

Few studies have been devoted to the role of calcium blockers in stable angina of effort. For this reason, we undertook, a double-blind, randomized study with placebo, to compare the effects of diltiazem (D) and nifedipine (N) on the ergometric parameters of 20 patients with angina of effort and with mono- or multivessel disease. The study protocol extended over 3 weeks and included a reference stress test, 8 days of placebo followed by a repeat yesy, an then 15 days during which each patient received 180 mg of D and/or 30 mg of N in cross-over. A stress test was performed at the end of each week. The calcium blockers appeared to improve the effort tolerance, the duration of the ergometric test and the amplitude of the maximal ST segment depression. Diltiazem showed itself to be superior to nifedipine by the absence of side effects and by an improved cardiac performance on effort.     

Modification of cardiac sarcolemmal Na+-Ca2+ exchange by diltiazem and verapamil

Cardiac sarcolemmal membranes were isolated from the rat heart and their ability for Na+-Ca2+ exchange in the absence or presence of diltiazem and verapamil was examined. Maximal Ca2+ influx activity of membranes due to Na+-dependent reaction occurred within 3 min and was about 5 nmol Ca2+/mg protein. Diltiazem (0.1 to 10 microM) depressed the Ca2+ influx activity significantly whereas verapamil (0.1 to 10 microM) had no effect at initial stages of the reaction (10 to 20 sec). The inhibitory effect of diltiazem on Ca2+ influx was found to be of an uncompetitive nature. Sodium was found to cause a rapid Ca2+ efflux from the calcium loaded membrane vesicles; about 70% of the Ca2+ efflux activity was increased by 0.1 to 10 microM of verapamil and 10 microM of diltiazem significantly. The stimulatory effect of these agents on Ca2+ efflux was associated with a change in Ka value from 16 to 5 mM Na+. Both diltiazem (0.1-3 microM) and verapamil (0.1-10 microM) did not affect the membrane Na+-K+ ATPase activity, but diltiazem in high concentrations (10-30 microM) had an inhibitory action. Specific calcium channel blocking agents, nitrendipine and nifedipine, depressed sodium-dependent Ca2+-efflux activity. A beta-adrenoreceptor antagonist, propranolol, unlike acebutolol, increased sodium-induced Ca2+-influx at high concentrations (10-100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative antioxidant activities of propranolol, nifedipine, verapamil, and diltiazem against sarcolemmal membrane lipid peroxidation

The antiperoxidative activities of nifedipine, verapamil, and diltiazem were compared with that of propranolol by using an in vitro model of sarcolemmal membrane lipid peroxidation. Highly purified sarcolemmal membranes, isolated from canine ventricular myocytes, were peroxidized by a superoxide anion-producing and iron-catalyzed free radical-generating system (dihydroxy-fumarate plus FeCl3 and ADP). Lipid peroxidation after 20 minutes of incubation was monitored by malondialdehyde formation. Similar to propranolol, all three calcium blockers exhibited concentration-dependent (10-400 microM) inhibitory effects against sarcolemmal lipid peroxidation. The order of potency of these agents was nifedipine greater than propranolol greater than verapamil greater than diltiazem. Nifedipine, the most effective calcium blocker, was greater than twofold more potent than propranolol and achieved a significant effect at 10 microM. This study suggests that calcium blockers may provide antiperoxidative protection to cardiac membranes.     

Influence of a single dose of calcium channel blockers on platelet function

Calcium channel blockers are known to inhibit platelet aggregation in vitro and ex vivo. We studied the influence of a single oral dose of diltiazem (60 mg), nifedipine (10 mg) and verapamil (80 mg) on ADP-, collagen-, and epinephrine-induced platelet aggregation, malondialdehyde formation, serum thromboxane B(2) and platelet sensitivity to PGI(2) in 24 patients with coronary artery disease. Ninety minutes after drug intake most platelet function parameters were clearly decreased. Only collagen-stimulated platelet aggregation showed no significant drug effect. Malondialdehyde formation was more affected than ADP-induced platelet aggregation. Platelet sensitivity to PGI(2) was enhanced after nifedipine. These results suggest an alteration of the prostaglandin system as one of the underlying mechanisms. Diltiazem seems to be the most effective drug with a potent influence on platelet function ex vivo.     

Effect of calcium channel blocker diltiazem on cytoprotection and prostaglandin and sulfhydryl production by rat gastric epithelial cells

The calcium channel blockers verapamil and diltiazem protect gastric mucosa against exogenous injury in vivo. Whether this protection is mediated by systemic factors, such as blood flow, is due to inhibition of gastric acid secretion, or is associated with stimulation of endogenous protective agents such as prostaglandins or sulfhydryls, is unknown. We have evaluated whether diltiazem protects rat gastric epithelial cells in tissue culture (a model which excludes the influence of systemic factors) against damage induced by sodium taurocholate, indomethacin, or ethanol. Further we have assessed the effect of diltiazem on prostaglandin and sulfhydryl production. 51Chromium release assay and phase contrast microscopy have been used to assess cell damage. Sodium taurocholate, indomethacin, and ethanol-damaged cultured cells in a dose-dependent manner. Pretreatment with diltiazem did not prevent the drug-induced damage. Diltiazem did not increase PGE2 and 6-keto PGF1a production by cultured cells nor did it affect the cellular level of endogenous sulfhydryls. In conclusion, the calcium channel blocker diltiazem is not directly protective to rat gastric mucosal cells in vitro. Diltiazem does not stimulate prostaglandin production by gastric cells nor does it increase the cellular level of protective sulfhydryls.     

Effect of calcium channel blockers on hemodynamic responses to defibrillation

The hemodynamic response to sequences of ventricular fibrillation and defibrillation includes an adrenergic component that is important for the maintenance of blood pressure after successful defibrillation. Because calcium channel blocking drugs have antiadrenergic effects, we hypothesized that they might blunt the adrenergic response to defibrillation. Ventricular fibrillation was induced in 35 closed-chest dogs. Each received 4 to 7 direct current transthoracic shocks at three energy levels to determine defibrillation energy requirements. Heart rate and blood pressure were recorded. Energy sequences were repeated after 45 minutes of no intervention (control, n = 5) or after 45-minute infusions of diltiazem (0.1 mg/kg/min, n = 10), verapamil (0.1 mg/kg bolus plus 0.01 mg/kg/min, n = 10), or nifedipine (40 micrograms/min for 3 minutes plus 2 to 20 micrograms/min adjusted to maintain a 10 mm Hg drop in mean arterial pressure, n = 10). Our results show that the normal post-shock rise in mean arterial pressure was blunted by the calcium channel blockers diltiazem (systolic arterial pressure at 15 and 60 seconds post-shock, pre-drug versus post-drug: 102 +/- 9 versus 64 +/- 9 mm Hg and 113 +/- 10 versus 87 +/- 6 mm Hg; p less than 0.05) and verapamil (108 +/- 9 versus 78 +/- 12 mm Hg and 113 +/- 7 versus 90 +/- 10 mm Hg, p less than 0.05). There were no differences in blood pressure responses after nifedipine treatment or no drug. Heart rate responses were not altered by diltiazem or verapamil; after nifedipine administration, post-shock heart rates were slower.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium channel antagonists part II: Use and comparative properties of the three prototypical calcium antagonists in ischemic heart disease,including recommendations based on an analysis of 41 trials

Summary An analysis of 41 trials of angina of all varieties confirms that calcium antagonists are an important advance and are now established therapy for these syndromes. In effort angina, verapamil in a dose of 360–480 mg daily is better than propranolol in standard doses. Although nifedipine is highly effective against vasospastic angina, its use in threatened myocardial infarction is not supported by recent studies, unless combined with a beta-blocker. Diltiazem has recently been tested with apparent benefit in non-Q-wave myocardial infarction. Otherwise, these calcium antagonist agents will all seem to have approximate equipotency in clinical ischemic syndromes including effort and vasospastic angina. Subjective side effects seem most troublesome in the case of nifedipine. All three calcium antagonists, especially nifedipine, have been successfully combined with beta-blocker therapy, yet occasional additive negative inotropic or chronotropic or dromotropic interactions may occur when verapamil or diltiazem is added to beta-blockade, and occasionally the direct negative inotropic potential of nifedipine may may become evident. The choice between the calcium antagonists is determined not only by the clinical picture but also by the anticipated side effects in a given patient and by the overall cardiovascular status. In patients with supraventricular tachycardias or sinus tachycardia, verapamil or diltiazem is preferred, whereas in patients with a resting bradycardia or borderline heart failure nifedipine is likely to be chosen.[This article appeared in Cardiovascular Drugs & Therapy, 1: 461–491, 1988]     

Comparison of the effects of calcium channel blockers and antiarrhythmic drugs on digitalis-induced oscillatory afterpotentials on canine Purkinje fiber

We studied the effects of Ca channel blockers and 3 antiarrhythmic drugs on the digitalis-induced oscillatory afterpotential (OAP). The OAP was observed in Purkinje fibers stimulated by pulse trains, with cycle lengths ranging from 1,000 to 300 msec. The Ca channel blockers verapamil, diltiazem and nifedipine (2.0 x 10(-6) M) depressed OAP significantly and abolished triggered activity. Verapamil was more effective than diltiazem. However, nicardipine and nitrendipine (2.0 x 10(-6) M) had no depressant effects on OAP or triggered activity. The antiarrhythmic drugs procainamide (1.0 x 10(-4) M), mexiletine (1.0 x 10(-5) M) and propranolol (1.0 x 10(-4) M) depressed both OAP and triggered activity. There were no significant differences in the depressant effects between the Ca2+ antagonists (except for nitrendipine and nicardipine) and the other antiarrhythmic drugs. The OAP coupling interval was prolonged by verapamil, diltiazem, propranolol, procainamide and mexiletine. Although the APD50 was shortened by verapamil, diltiazem and nifedipine, it was prolonged by propranolol. It is concluded that nifedipine, verapamil, diltiazem, procainamide, mexiletine and propranolol may be effective for digitalis-related arrhythmia.     

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.     

Calcium channel antagonists and inhibition of human sphincter of Oddi contractions

Objective. Nifedipine has been used in the treatment of sphincter of Oddi dyskinesia, a biliary disease characterized by upper abdominal pains and increased pressure in the sphincter. The effects of other calcium channel antagonists on sphincter of Oddi have not been elucidated. Material and Methods. We compared the effects of three calcium blockers with differing smooth muscle selectivity (verapamil, nifedipine and felodipine) on human sphincter of Oddi contractions. Transverse sections of the sphincter obtained from five patients undergoing Whipple resection were studied in an organ bath chamber in vitro. Results. All three calcium blockers significantly (>50%) inhibited the acetylcholine-induced and KCl-induced sphincter contractions in a dose-dependent manner. Both nifedipine and felodipine were more potent than verapamil in inhibiting the acetylcholine-induced contractions, whereas only nifedipine, but not felodipine, reduced the KCl-elicited contractions more than verapamil. Conclusions. The smooth muscle selective calcium channel antagonists are potent inhibitors of human sphincter of Oddi contractions. Although nifedipine is, to date, the only agent studied in clinical settings, other dihydropyridines are also likely to be useful in sphincter of Oddi dyskinesia.