Parkinsn's List Drug DataBase verapamil / Calan,Isoptin,Verelan,Anpec,Cordilox,Verecaps

The P-I-E-N-O Parkinsn's List Drug Database

verapamil / Calan^TM ,Isoptin^TM ,Verelan^TM ,Anpec^TM ,Cordilox^TM , Verecaps^TM

BLOOD PRESSURE:

Description: Verapamil is an oral and parenteral calcium-channel blocking (CCB) agent. It is useful for the treatment of angina, hypertension, and for supraventricular tachyarrhythmias. Verapamil is considered a class IV antiarrhythmic agent. In atrial fibrillation, verapamil is more effective than digoxin for controlling ventricular rate. Verapamil can be effective in decreasing left ventricular hypertrophy, presumably due to its afterload-reducing effects, and has been shown to decrease reinfarction in patients with uncompromised left ventricular function, although no reduction in mortality was observed. Verapamil may provide beneficial hemodynamic effects in selected patients with hypertrophic cardiomyopathy. Verapamil was synthesized in 1962 and, in 1981, became the first CCB to be approved by the FDA. Verapamil is marketed in several oral dosage forms that are not completely interchangeable. Verapamil is currently under investigation for the treatment of ocular hypertension and glaucoma as an ophthalmic preparation and for the treatment of atherosclerosis. Verapamil has also been used in the treatment of mania.

Mechanism of Action: Verapamil inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. It exerts its activity at the membrane surface of arterial smooth muscle cells and within conductile and contractile tissue in the myocardium. Serum calcium levels remain unchanged. Calcium channels in myocardial and vascular smooth muscle cell membranes are selective and allow a slow inward flow of calcium, which contributes to excitation- contraction coupling and electrical discharge of conduction cells (plateau phase of the action potential) in the heart and vasculature. Verapamil inhibits this influx, possibly by deforming the channel, or inhibiting ion-control gating mechanisms. Intracellularly, it also may interfere with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. These actions increase oxygen delivery to the myocardial tissue and decrease total peripheral resistance, systemic blood pressure, and afterload. This reduction in myocardial oxygen demand, cardiac workload, and vascular tone is believed to be responsible for the drug's beneficial effects in angina and its antihypertensive activities. Inhibition of calcium-mediated smooth muscle contraction is thought to also be the explanation of verapamil's action in the prevention and treatment of migraine, asthma, and premature labor. Verapamil exerts equipotent effects on calcium channels in SA and AV nodes, and on the peripheral vasculature, however, verapamil is less potent as a peripheral vasodilator than nifedipine and related dihydropyridine analogs.

The electrophysiologic effects of verapamil make it a favorable agent for controlling and/or converting certain supraventricular arrhythmias. In the myocardium, membrane "pores" are termed "slow channels" if they are selective for calcium influx and "fast channels" if they are selective for sodium influx. Nodal tissue (e.g., sinus node and AV node) possesses only calcium channels, which explains why verapamil is effective in treating arrhythmias dependent on nodal conduction. The inherent rhythm of nodal tissue is a function of the "slow" inward flow of calcium through gated channels in the membrane. By slowing conduction through the AV node, verapamil affects the ventricular response rate in tachyarrhythmias that originate above the AV node. Verapamil is ineffective for treating ventricular arrhythmias since ectopic foci arising in this region of the myocardium are primarily dependent on alterations of sodium influx and are more readily suppressed with sodium influx-inhibiting drugs such as lidocaine and related analogs. Verapamil's inhibitory effects on conduction through the atrioventricular (AV) node is stronger than nifedipine's and similar to diltiazem's, which is reflected on the ECG as a prolonged PR interval. Second- or third-degree heart block is possible, especially if verapamil is given to patients receiving œ-blockers. Verapamil may decrease resting heart rate, particularly in patients with sick sinus syndrome. Clinical arrhythmias for which verapamil is effective include paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation/flutter, and other atrial-based tachycardias. Verapamil is more effective than digoxin for controlling ventricular rate in atrial fibrillation since the effects of verapamil on the AV node persist during sympathetic stimulation.

Finally, animal data has shown that CCBs including verapamil may interfere with the atherogenic process. Interestingly, human data have also shown a beneficial effect but clinical studies are limited. The mechanism of this effect may be related to prevention of accumulation of intracellular calcium in vascular smooth muscle cells.

Pharmacokinetics: Verapamil is administered orally and intravenously. Verapamil is marketed in several oral dosage forms that are not completely interchangeable. It is rapidly and well absorbed (90%) following an oral dose, but it undergoes extensive first-pass metabolism, resulting in a bioavailability of 20-35%. Oral verapamil is a racemic mixture. Food reduces the bioavailability of extended-release verapamil tablets but not other dosage forms of the drug. The administration of food with SR tablets does, however, decrease the peak-to-trough variability in serum concentrations. Hepatic enzyme-inducing drugs, such as rifampin, or hepatic disease can significantly affect the bioavailability of verapamil. The first-pass effect explains the large discrepancy between oral and parenteral doses.

The onset of action occurs within 1-2 hours following oral administration and within 1-5 minutes following intravenous dosing. Peak pharmacodynamic effects are observed in 1-2 hours and 5 hours for the immediate- and sustained-release oral preparations of the drug, respectively. After intravenous administration, the hemodynamic effects of verapamil peak within 5 minutes and persist for 10-20 minutes, although they can be much longer in some patients. The effects of IV verapamil on AV nodal conduction occur within 1-2 minutes, peak within 10-15 minutes, and persist for 30-60 minutes, although prolonged effects on conduction have been reported. The duration of activity for verapamil averages 8-10 hours for standard-release preparations and 24 hours for extended-release formulations.

Verapamil and its active and primary metabolite norverapamil are well distributed throughout the body including the CNS. The drug is excreted into breast milk, reaching concentrations approaching those in maternal serum and posing potential problems for infants of nursing mothers. Verapamil also readily crosses the placenta. Approximately 90% of the drug is bound to plasma proteins.

Although verapamil is extensively metabolized in the liver to more than 10 metabolites, only norverapamil is detectable in the serum to any great extent. Norverapamil possesses approximately 20% of the pharmacologic activity of the parent compound. The first-pass metabolism of verapamil is stereoselective, with preferential metabolism of the l-isomer. The elimination half- life of verapamil averages 2-5 hours following single doses of the drug and increases with chronic dosing to 5-12 hours. The half-life of verapamil is also prolonged to approximately 14 hours in patients with hepatic impairment. The half-life of norverapamil ranges 4-10 hours.

Elimination of verapamil occurs primarily via renal pathways (70%), and 16% of the drug is eliminated in the feces within 5 days. Less than 5% of the drug is excreted in the urine as the parent compound.

CONTRAINDICATIONS/PRECAUTIONS: Verapamil should be used cautiously in patients with ventricular dysfunction, severe bradycardia, cardiogenic shock, or congestive heart failure and/or in patients taking œ-adrenergic blocking agents because verapamil can precipitate or exacerbate heart failure in these patients, or cause excessive bradycardia or cardiac conduction abnormalities. Verapamil can be used for ventricular dysfunction due to a supraventricular tachyarrhythmia, which is amenable to verapamil therapy. It should be noted that verapamil's afterload-reducing effects can be beneficial in these patients and can counteract the drug's negative inotropic effects. If these patients are receiving digitalis, however, verapamil may further depress AV node conduction, possibly leading to varying degrees of conduction block (see Drug Interactions). Heart failure associated with an acute myocardial infarction may be worsened by administration of verapamil.

Verapamil decreases peripheral resistance and can worsen hypotension. Verapamil should not be used in patients with systolic blood pressures of less than 90 mm Hg (i.e., severe hypotension). Verapamil should be used with caution in patients with mild to moderate hypotension. Blood pressure should be monitored carefully in all patients receiving verapamil. If moderate hypotension is a result of SVT, then verapamil may be used because correction of the arrhythmia can improve the hypotension.

Verapamil should not be used in patients with sick sinus syndrome or advanced heart block (second- or third-degree AV block) who do not have a functioning artificial pacemaker in place. Use of verapamil in patients with these conditions may lead to severe hypotension, bradycardia, or asystole.

Verapamil should not be used in patients with conditions associated with an accessory bypass tract such as Wolff- Parkinson-White syndrome, some atrial fibrillation and/or flutter problems, or Lown-Ganong-Levine syndrome. In these patients, verapamil can paradoxically increase ventricular rate due to uninhibited antegrade conduction through the accessory bypass tract, resulting in potentially life-threatening conditions (ventricular fibrillation or cardiac arrest). Patients with these reentrant arrhythmias with a functioning artificial ventricular pacemaker may use still use a calcium channel blocker. Proper differentiation between supraventricular tachycardia and ventricular tachycardia is crucial when administering verapamil. Although verapamil may be effective in treating the former, administration to patients with ventricular tachycardia can cause ventricular fibrillation, severe hemodynamic deterioration, or death.

The elderly, patients with renal impairment, or patients with hepatic disease, such as cirrhosis or hepatic failure, can experience a delayed clearance of verapamil and can be at greater risk for accumulation and toxicity. The half-life of verapamil may be increased up to 14-16 hours in patients with hepatic impairment and plasma clearance may be reduced by 30%. Dosage adjustments may be necessary with hepatic impairment.

Verapamil should be used extremely cautiously in patients with hypertrophic cardiomyopathy because severe and sometimes fatal adverse reactions can occur such as pulmonary edema, hypotension, sinus arrest, and second-degree AV block.

Verapamil is contraindicated in patients with advanced aortic stenosis because it can worsen the abnormal pressure gradient associated with this condition.

Verapamil should be used with caution in patients with neuromuscular disease. Verapamil has been reported to decrease neuromuscular transmission in patients with Duchenne's muscular dystrophy. Verapamil has also prolonged recovery from the neuromuscular blockade from vecuronium. (see Drug Interactions)

Verapamil is a pregnancy category C drug. Verapamil crosses the placenta. Although verapamil has been shown to have deleterious effects on fetal growth and development, it is not known if verapamil is teratogenic. No adequate or well-controlled studies have been performed in humans: use of verapamil during pregnancy should be restricted to cases where therapeutic benefits outweigh the potential risk to the fetus.

Verapamil is contraindicated in patients with a known hypersensitivity to the drug or any of its excipients.

Verapamil is frequently causes constipation. Verapamill should be used cautiously in patients with GI obstruction, fecal impaction, or pre-existing constipation.

DRUG INTERACTIONS:

Significant hypotension has been reported during concomitant administration of quinidine and verapamil. In addition, verapamil inhibits quinidine clearance and significantly prolongs its half-life. If these two agents are used together, quinidine doses may need to be reduced.

Disopyramide and verapamil should not be used concomitantly due to additive negative inotropic effects and possible left ventricular impairment.

Concomitant administration of œ-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. œ-blockers should not be given to patients receiving verapamil. Verapamil can inhibit the metabolism of some œ- blockers, causing additive effects on slowing of AV conduction and depression of blood pressure. In addition, this combination should be avoided in patients with poor ventricular function due to increased negative inotropic effects.

Digoxin and verapamil interact pharmacokinetically and pharmacodynamically. Verapamil reduces the renal and nonrenal clearance of digoxin; serum levels of digoxin increase by 50-75% after verapamil is added. In addition, both drugs slow conduction through the AV node and for this reason, these drugs are sometimes used together for ventricular control in patients with atrial fibrillation or flutter. Dosages should be adjusted according to clinical response since digoxin serum concentrations may not accurately reflect response.

Verapamil is an antihypertensive agent, so its effects are additive with other antihypertensive agents. This interaction may be desirable, but dosages of concomitantly used agents should be adjusted carefully. Use of ›-blockers with verapamil can lead to excessive hypotension. The combination of clonidine and verapamil has been reported to cause AV block in some patients.

Verapamil, if administered to patients receiving carbamazepine, can cause carbamazepine toxicity within 36-96 hours in some patients. Verapamil appears to decrease the clearance of carbamazepine. Carbamazepine doses should be reduced if verapamil is added.

Rifampin, a potent hepatic enzyme inducer, significantly reduces the oral bioavailability of verapamil, presumably by increasing first-pass metabolism. Phenobarbital and phenytoin also have this effect on verapamil serum concentrations. Patients receiving verapamil should be monitored for loss of therapeutic effect if any of these hepatic enzyme inducing drugs are added.

The interaction between verapamil and lithium is variable and unpredictable. Verapamil administration has been associated with both decreased lithium concentrations and with lithium toxicity. Verapamil may substantially lower serum lithium concentrations when administered to patients stabilized on lithium therapy. This effect may be offset somewhat by the fact that calcium- channel blocking agents share some neuropharmacological actions with lithium; limited data suggest that oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Concurrent therapy, however, may lead to neurotoxicity, even without a measurable increase in lithium serum concentrations. Because verapamil has been associated with both decreased lithium concentrations and with lithium toxicity, verapamil should be avoided in patients receiving lithium.

Flecanide also possesses negative inotropic effects and inhibits AV node conduction. Use of flecanide in patients receiving verapamil therapy can produce additive effects on myocardial contractility and/or conduction.

Verapamil can inhibit cyclosporine metabolism and increase cyclosporine levels. Cyclosporine doses should be reduced if verapamil is added. Verapamil also inhibits the hepatic metabolism of carbamazepine, doxorubicin, midazolam, theophylline, and valproic acid. The interaction with midazolam occurred with oral midazolam.ID The significance of an interaction between verapamil and IV midazolam is uncertain but may be less significant due to absence of an effect on presystemic midazolam clearance.

Verapamil can potentiate the effects of neuromuscular blockers. Dosing of these agents may require adjustment in patients receiving verapamil.

Verapamil is highly protein-bound and theoretically could displace other highly protein-bound drugs from their binding sites. These drugs include warfarin or other oral anticoagulants, hydantoins, salicylates, sulfonylureas, or sulfonamides. Documented interactions, however, have not been reported.

Intravenous administration of calcium salts can antagonize some of the effects of calcium-channel blockers. Although the vascular effects (i.e., hypotension) may be reversed, in the case of verapamil the AV nodal effects do not seem to be affected by exogenously administered calcium salts.

Cimetidine can increase the plasma levels of verapamil. Cimetidine is believed to inhibit the hepatic metabolism of verapamil, although other mechanisms are possible.

ADVERSE REACTIONS: The most serious adverse effects associated with verapamil therapy represent extensions of its therapeutic effects on the AV node and the vasculature. These effects include sinus bradycardia; reflex sinus tachycardia; AV block of any degree, which may require atropine therapy when severe; and hypotension. The incidence of these adverse effects is greater in patients receiving the drug intravenously. Although verapamil is a negative inotrope, the risk of developing congestive heart failure or pulmonary edema is somewhat offset by verapamil's afterload-reducing actions. Nevertheless, predisposed patients should be monitored closely for signs and symptoms of worsening heart failure.

Tachycardia, including ventricular fibrillation, can occur in patients with accessory AV pathways who are given verapamil. Although verapamil is an effective drug for controlling ventricular rate in patients with atrial fibrillation or flutter, verapamil should not be used for this condition if an accessory bypass tract (Wolff-Parkinson-White syndrom or Lown- Ganong-Levine syndrome) is known or suspected.

The vasodilatory action of verapamil is responsible for some adverse effects such as dizziness and flushing. Lethargy, headache, and fatigue have also been reported.

Peripheral edema has been reported in a few patients receiving verapamil orally, and flushing also can occur.

Constipation is the most common adverse GI effect of verapamil therapy. This reaction appears to occur more frequently with verapamil than with other calcium-channel blockers. Other GI effects include nausea/vomiting, dyspepsia, and abdominal pain.

Temporary increases in hepatic enzymes can occur with verapamil therapy. The elevated hepatic enzymes may resolve despite continued therapy, but hepatotoxicity has been noted following rechallenge with the drug. In general, this has been a rare, idiosyncratic, hypersensitivity reaction.

PATIENT INFORMATION: The most serious adverse effects associated with verapamil therapy represent extensions of its therapeutic effects on the AV node and the vasculature. These effects include sinus bradycardia; reflex sinus tachycardia; AV block of any degree, which may require atropine therapy when severe; and hypotension. The incidence of these adverse effects is greater in patients receiving the drug intravenously. Although verapamil is a negative inotrope, the risk of developing congestive heart failure or pulmonary edema is somewhat offset by verapamil's afterload-reducing actions. Nevertheless, predisposed patients should be monitored closely for signs and symptoms of worsening heart failure.

The vasodilatory action of verapamil is responsible for some adverse effects such as dizziness and flushing. Lethargy, headache, and fatigue have also been reported.

Peripheral edema has been reported in a few patients receiving verapamil orally, and flushing also can occur.

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