Verapamil (verapamil HCl)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Verapamil hydrochloride is a nondihydropyridine calcium-channel blocking agent (calcium-channel blocker).
Verapamil hydrochloride is a phenylalkylamine-derivative calcium-channel blocker. Because most currently available calcium-channel blockers are dihydropyridines (e.g., amlodipine, nicardipine), verapamil, like diltiazem, has been referred to as a nondihydropyridine calcium-channel blocker. Verapamil hydrochloride is commercially available as a racemic mixture; available dosage forms include tablets, extended-release tablets, extended-release and controlled extended-release capsules (containing pellets), and injection for IV use.
Verapamil has pharmacologic actions similar to those of other calcium-channel blockers (e.g., diltiazem, nifedipine), however vascular-cardiac selectivity ratios differ. The principal physiologic action of verapamil is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells. By inhibiting calcium influx, verapamil inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries.
In patients with Prinzmetal variant angina (vasospastic angina), inhibition of spontaneous and ergonovine-induced coronary artery spasm by verapamil results in increased myocardial oxygen delivery. Dilation of systemic arteries by verapamil results in a decrease in total peripheral resistance, systemic blood pressure, and afterload of the heart. Decreases in peripheral vascular resistance usually occur without orthostatic decreases in blood pressure or reflex tachycardia.
The reduction in afterload, seen at rest and with exercise, and its resultant decrease in oxygen consumption are thought to be responsible for the effects of verapamil in patients with unstable and chronic stable angina. Verapamil has substantial inhibitory effects on the cardiac conduction system and is considered a Vaughan Williams class IV antiarrhythmic agent. Verapamil also slows conduction and prolongs refractoriness in the atrioventricular (AV) node; this usually also results in PR-interval prolongation on ECG, which is correlated with plasma verapamil concentrations (especially during initial titration of verapamil therapy), and may rarely cause second- or third-degree AV block (even in patients without preexisting conduction defects).
Although verapamil rarely produces clinically important changes in the rate of sinoatrial (SA) node discharge or recovery time, the drug may reduce the resting heart rate and produce sinus arrest or SA block in patients with SA node disease (e.g., sick sinus syndrome). Verapamil reduces afterload and myocardial contractility.
The hypotensive effect of verapamil is usually evident within the first week of therapy. Maximum antiarrhythmic effects are generally apparent within 48 hours after initiating a given verapamil dosage. After a single IV injection of verapamil, hemodynamic effects peak within 3-5 minutes and usually persist for 30-60 minutes, but may persist for as long as 6 hours.
Conversion to sinus rhythm is achieved with IV verapamil usually within 10 minutes after administration. Slowing of the ventricular rate in patients with atrial fibrillation or flutter generally persists for 30-60 minutes following a single IV injection.
Cardiac disease, the negative inotropic effect of verapamil is offset by reduced afterload, and cardiac index usually is not reduced except in patients with severe left ventricular dysfunction.
Approximately 90% of an oral dose of verapamil hydrochloride is absorbed from the GI tract following oral administration of conventional tablets of the drug. Only about 20-35% of an oral dose reaches systemic circulation as unchanged drug following administration of conventional tablets since verapamil is rapidly metabolized on first pass through the liver. The manufacturers state that oral bioavailability of extended-release capsules or tablets of the drug is similar to that of the conventional tablets when the drug is administered under fasting conditions.
Oral bioavailability of the drug may be substantially increased in patients with hepatic dysfunction (e.g., in those with hepatic cirrhosis).
In healthy adults, peak plasma concentrations are reached within 1-2 hours after oral administration of conventional tablets of the drug and within 7-9 or 5-8 hours after extended-release capsules or tablets, respectively. Following oral administration of a single 240-mg extended-release capsule or tablet under fasting conditions, mean peak plasma verapamil concentrations of about 77, or 150-165 ng/mL, respectively, were achieved. Food decreases the rate and extent of absorption of extended-release verapamil tablets but produces smaller differences between peak and trough plasma concentrations of the drug; food does not appear to substantially affect the absorption of conventional tablets, extended-release capsules, or controlled-onset, extended-release capsules of the drug.
When the extended-release or the controlled-onset, extended-release pellet filled capsules were administered by opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule; similar results were observed with norverapamil, the active metabolite.
The commercially available controlled-onset, extended-release capsules of verapamil hydrochloride (e.g., Verelan(R) PM) contain the drug in an oral diffusion delivery system formulation that also is designed to initiate delivery of the drug 4-5 hours after ingestion. The diffusion delivery system consists of controlled-release coated pellets enclosed in a hard gelatin capsule. The nonenteric controlled-release coating contains water-soluble and water-insoluble polymers.
When exposed to water in the GI tract, the soluble polymer on individual pellets slowly dissolves, allowing the drug to diffuse through the resultant pores, while the insoluble polymer continues to act as a barrier maintaining controlled release of the drug into the GI tract. The rate of verapamil delivery in the GI tract is independent of posture, pH, and presence of food in the GI tract. The peak plasma concentration is reached within about 11 hours after administration of controlled-onset, extended-release pellet filled capsules.
However, administration of the extended-release capsules in the morning, instead of at bedtime, increased the extent of absorption of verapamil and/or decreased the metabolism to norverapamil.
The commercially available fixed combination preparation containing trandolapril and verapamil hydrochloride extended-release tablets (verapamil/trandolapril) is formulated such that trandolapril is released immediately and the verapamil component is extended-release. Peak plasma concentrations of trandolapril and verapamil are reached in 0.5-2 and 4-15 hours, respectively. Verapamil bioavailability following administration of verapamil/trandolapril fixed-combination tablets with a high-fat meal is reduced; time to peak verapamil and norverapamil concentrations are delayed by approximately 7 hours.
Approximately 90% of verapamil is bound to plasma proteins. Verapamil and norverapamil distribute into cerebrospinal fluid. Verapamil crosses the placenta and is present in umbilical vein blood at delivery.
The drug is distributed into milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01-0.1% of the mother's verapamil dose.
Plasma concentrations of verapamil appear to decline in a biphasic or triphasic manner following IV administration of the drug. After IV infusion or administration of a single oral dose, verapamil has a plasma half-life of 2-8 hours. After 1-2 days of oral administration of the drug, plasma half-life may increase to 4.5-12 hours.
Clearance is decreased 30% and plasma half-life of the drug also is increased to 14-16 hours in patients with hepatic cirrhosis. Plasma elimination half-life also appears to be increased and clearance is decreased in geriatric patients.
Verapamil is rapidly and almost completely metabolized in the liver to at least 13 metabolites. Only norverapamil is present in plasma in more than trace amounts. Norverapamil, an active (approximately 20% of the cardiovascular activity of verapamil) metabolite, achieves plasma concentrations approximately equal to those of verapamil within 4-6 hours of administration.
Food decreases the rate and extent of drug reaching systemic circulation as norverapamil following oral administration of extended-release verapamil tablets. Approximately 70 and 16% of an oral or IV dose are excreted as metabolites in urine and feces, respectively, within 5 days. Only 3-4% of a dose is excreted in urine as unchanged drug.
Neither verapamil nor norverapamil appear to be removed appreciably by hemodialysis.
USES: This medication is used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Verapamil belongs to a class of drugs known as calcium channel blockers.
It works by relaxing blood vessels so blood can flow more easily. It may also lower your heart rate.
Generic name: verapamil HCl
Pronunciation: (ver-AP-a-mil)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Verapamil
Indications
The following indications are listed for Verapamil:
- Hypertension
Also known as: Elevated Blood Pressure, Essential Hypertension, Hyperpiesia, Hyperpiesis, Hypertensive Disorder, Systemic Arterial Hypertension.
Dosing
Dosage of verapamil hydrochloride is expressed in terms of the hydrochloride salt.
Verapamil hydrochloride is administered orally or by direct IV injection depending on the indication. The drug has also been administered by IV infusion+ and by intra-arterial injection+, but safety and efficacy of these methods of administration have not been established.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
In vitro studies indicate that verapamil is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4, 1A2, 2C8, 2C9, and 2C18. Verapamil also inhibits CYP3A4.
When used in fixed combination with trandolapril, the drug interactions associated with each drug must be considered.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Severe left ventricular dysfunction.
*Hypotension (SBP <90 mm Hg) or cardiogenic shock.
*Sick sinus syndrome (unless a functioning artificial ventricular pacemaker is present).
*Second- or third-degree AV block (unless a functioning artificial ventricular pacemaker is present).
*Atrial flutter or fibrillation associated with an accessory bypass tract (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome).
*Severe congestive heart failure (unless the heart failure is caused by a supraventricular tachycardia amenable to verapamil therapy).
*Patients currently receiving, or having recently received (i.e., within a few hours of IV verapamil therapy), IV beta-adrenergic blocker therapy.
*Use of IV verapamil in patients with wide-complex ventricular tachycardia (QRS >=0.12 seconds).
*Known hypersensitivity to verapamil or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects reported with oral verapamil are constipation, dizziness, nausea, hypotension, headache, and edema.
The most common adverse effects reported with IV verapamil include symptomatic hypotension, bradycardia, severe tachycardia, dizziness, headache, nausea, and abdominal discomfort.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Controlled studies with verapamil in children have not been performed to date, but experience using IV verapamil in more than 250 children (about 50% were younger than 12 months of age and 25% were neonates) indicates that the drug produces effects similar to those in adults. However, severe hemodynamic effects, some of them fatal, have occurred rarely following IV administration of verapamil in neonates and infants. Therefore, the manufacturer states that IV verapamil should be used with caution in neonates and infants. Safety and efficacy of oral verapamil in children younger than 18 years of age have not been established.
There are no adequate and controlled studies to date using verapamil in pregnant women, and the drug should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus Verapamil crosses the placenta and is present in umbilical vein blood at delivery. Although the effects of verapamil on the mother and fetus during labor and delivery have not been fully determined, the drug has been used short-term without prolonging the duration of labor or increasing the need for forceps delivery or other obstetric intervention and without apparent adverse fetal effect in women who received verapamil as therapy for adverse cardiac effects induced by beta-adrenergic agonists that were used in the management of premature labor.
Reproduction studies in rabbits and rats using oral verapamil dosages up to 1.5 (15 mg/kg daily) and 6 (60 mg/kg daily) times the usual human oral dosage, respectively, have not revealed evidence of teratogenicity. However, in rats, this dosage has been shown to be embryocidal and was associated with retarded fetal growth and development, probably as a result of adverse maternal effects as evidenced by reduced maternal weight gain; this dosage has been shown to cause hypotension in rats.
Verapamil is distributed into milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01-0.1% of the mother's verapamil dose; this exposure should be considered when verapamil is administered to a nursing woman. Because of the potential for serious adverse effects of verapamil in nursing infants, the manufacturers recommend that nursing be discontinued during therapy with the drug.
In general, dose selection for an geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Hypertension: The manufacturer of the verapamil hydrochloride controlled-onset extended-release capsules states that an initial dosage of 100 mg daily at bedtime rarely may be necessary in elderly patients. The manufacturers of the extended-release pellet filled capsules and the extended-release tablets suggest an initial dosage of 120 mg once daily in the morning in patients who may have an increased response (e.g., elderly). The manufacturers of conventional verapamil hydrochloride tablets suggest an initial dosage of 40 mg 3 times daily in patients who may have an increased response (e.g., elderly).
Angina: The manufacturers of verapamil hydrochloride conventional tablets suggest an initial dosage of 40 mg 3 times daily in patients who may have an increased response (e.g., elderly).
Supraventricular arrhythmias: Slower injection rates (over at least 3 minutes) should be used in geriatric patients in order to minimize the risk of adverse effects.
While clinical experience to date has not revealed age-related differences in response to verapamil, clinical studies evaluating verapamil have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults; greater sensitivity cannot be ruled out. Aging may affect the pharmacokinetics of verapamil given to patients with hypertension; the elimination half-life may be prolonged, and an increased response to the drug may occur. The manufacturers of verapamil state that dosage for geriatric patients should be selected carefully, usually starting at the low end of the dosing range, because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. To minimize the risk of adverse effects, IV verapamil should be administered over at least 3 minutes in older patients.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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