Verapamil

Verapamil Information

Brand name: Calan, Isoptin

Generic Name: Verapamil

Other Common Names: Cronovera

Calan (verapamil HCl) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) used to treat angina (chest pain) or high blood pressure. It is also used to treat and prevent a rapid heart rate. It may also be used to treat other conditions as determined by your doctor. It is available for oral administration in film-coated tablets containing 40 mg, 80 mg, or 120 mg of verapamil hydrochloride.

Angina and Arrhythmia

Verapamil is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). The mechanism of the antianginal and antiarrhythmic effects of verapamil is believed to be related to its specific cellular action of selectively inhibiting transmembrane influx of calcium in cardiac muscle, coronary and systemic arteries and in cells of the intracardiac conduction system. Verapamil blocks the transmembrane influx of calcium through the slow channel (calcium ion antagonism) without affecting, to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues.

Verapamil's antiarrhythmic effects are believed to be brought about largely by its action on the sinoatrial (SA) and atrioventricular (AV) nodes. Verapamil depresses AV nodal conduction and prolongs functional refractory periods. Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Through this action, it interrupts re-entrant pathways and slows the ventricular rate.

Verapamil may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see Warnings). Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis.

Verapamil is a potent smooth muscle relaxant with vasodilatory properties, as well as a depressant of myocardial contractility, and these effects are largely independent of autonomic influences. Its antianginal action in exertional angina seems to result from a decrease in resistance in the systemic vasculature, as well as from a direct effect on myocardial contraction. The net pharmacologic effect is a decrease in myocardial oxygen consumption. Verapamil's effectiveness in vasospastic angina is due to a decrease in coronary vascular tone.

Essential Hypertension

Verapamil exerts antihypertensive effects by inducing peripheral vasodilation and reducing peripheral vascular resistance usually without reflex tachycardia. These effects are mediated by inhibition of calcium ion influx into smooth muscle cells of the arteriolar wall. Verapamil does not blunt hemodynamic response to isometric or dynamic exercise.

Compared to baseline, verapamil administration did not affect electrolytes, glucose and creatinine. The hypotensive effect of verapamil is not blunted by an increase in sodium intake.

How Does Verapamil Work?

Verapamil is a calcium ion influx inhibitor (slowchannel blocker or calcium ion antagonist) that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Mechanism of action Angina: The precise mechanism of action of Verapamil as an antianginal agent remains to be fully determined, but includes the following two mechanisms:

Relaxation and prevention of coronary artery spasm: Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of Verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.

Reduction of oxygen utilization: Verapamil regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of Verapamil in chronic stable effort angina.

Arrhythmia: Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. This property accounts for the ability of Verapamil to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation.

Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, Verapamil may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see Warnings). Verapamil decreases the frequency of episodes of paroxysmal supraventricular tachycardia.

Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but in depressed atrial fibers it decreases amplitude, velocity of depolarization, and conduction velocity. Verapamil may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see Warnings).

Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.

Essential hypertension: Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise Verapamil does not alter systolic cardiac function in patients with normal ventricular function.

Verapamil does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of Verapamil.

Verapamil Structural Formula and Composition

Verapamil Side Effects

Contraindications to Verapamil

Verapamil HCl tablets are contraindicated in:

Severe left ventricular dysfunction (see Warnings)

Hypotension (systolic pressure less than 90mm Hg) or cardiogenic shock
Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)
Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (See Warnings.)
Patients with known hypersensitivity to verapamil hydrochloride.

Drug interactions

Alcohol

Verapamil may increase blood alcohol concentrations and prolong its effects.

Beta-blockers

Controlled studies in small numbers of patients suggest that the concomitant use of Calan and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractility.

In one study involving 15 patients treated with high doses of propranolol (median dose, 480 mg/day; range, 160 to 1,280 mg/day) for severe angina, with preserved left ventricular function (ejection fraction greater than 35%), the hemodynamic effects of additional therapy with verapamil HCl were assessed using invasive methods. The addition of verapamil to high-dose beta-blockers induced modest negative inotropic and chronotropic effects that were not severe enough to limit short-term (48 hours) combination therapy in this study. These modest cardiodepressant effects persisted for greater than 6 but less than 30 hours after abrupt withdrawal of beta-blockers and were closely related to plasma levels of propranolol.

The primary verapamil/beta-blocker interaction in this study appeared to be hemodynamic rather than electrophysiologic.

In other studies verapamil did not generally induce significant negative inotropic, chronotropic, or dromotropic effects in patients with preserved left ventricular function receiving low or moderate doses of propranolol (less than or equal to 320 mg/day); in some patients, however, combined therapy did produce such effects. Therefore, if combined therapy is used, close surveillance of clinical status should be carried out. Combined therapy should usually be avoided in patients with atrioventricular conduction abnormalities and those with depressed left ventricular function.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together.

Digitalis

Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted.

However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively.

Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be reassessed to avoid over- or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of Calan use, the patient should be reassessed to avoid underdigitalization.

Antihypertensive agents: Verapamil administered concomitantly with oral antihypertensive agents (eg, vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored.

Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Antiarrhythmic agents

Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.
Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

If you suspect a Verapamil Overdose

Symptoms Based on reports of intentional overdosage of verapamil, the following symptoms have been observed. Hypotension occurs, varying from transient to severe. Conduction disturbances seen included: prolongation of AV conduction time, AV dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole.

Treatment Supportive (see Table II). Gastric lavage should be undertaken, even later than 12 hours after ingestion, if no gastrointestinal motility is present. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion influx across the slow channel. These pharmacologic interventions have been effectively used in treatment of overdosage with verapamil. Clinically significant hypotensive reactions should be treated with vasopressor agents. AV block is treated with atropine and cardiac pacing. Asystole should be handled by the usual advanced cardiac life support measures including the use of vasopressor agents, e.g. isoproterenol HCl. Verapamil is not removed by hemodialysis.

Isoptin SR In case of overdosage with large amounts of Isoptin SR, it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Depending on the time of ingestion, incompletely dissolved tablets may be present along the entire length of the gastrointestinal tract which function as active drug depots. Extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage and high enemas.

Taking Verapamil during Pregnancy or Breast-feeding

Pregnancy Category C

Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams.

This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Labor and delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing mothers: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.