Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives
ATC Code: C08DA01
Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odourless and has a bitter taste. It is soluble in water, freely soluble in chloroform, sparingly soluble in alcohol and practically insoluble in ether.
The chemical name of verapamil hydrochloride is benzeneacetonitrile, α‐[3‐[{2‐(3, 4dimethoxyphenyl) ethyl} methylaminol] propyl]‐3, 4‐dimethoxy‐α‐(1‐methylethyl) hydrochloride. It has a molecular weight of 491.07 and the molecular formula is C27H38N204 • HCl.
Verapamil inhibits the transmembrane influx of calcium ions into the heart and vascular smooth muscle cell. The myocardial oxygen demand is lowered directly as a result of the effect on the energy consuming metabolic processes of the myocardial cell and indirectly due to a reduction of the afterload.
Due to its effect on coronary vascular smooth muscle, Isoptin enhances myocardial blood flow, even in post‐stenotic areas, and relieves coronary spasms.
These properties contribute to the anti‐ischaemic and antianginal efficacy of Isoptin in all types of coronary artery disease. Isoptin has a marked antiarrhythmic effect, particularly in supraventricular arrhythmias. It delays impulse conduction in the AV node. Owing to this, sinus rhythm is restored and/or ventricular rate is normalised, depending on the type of arrhythmia. Normally, the rate is either not affected or only minimally lowered.
The antihypertensive effect of Isoptin stems from a decrease in peripheral vascular resistance, without an increase in heart rate as a reflex response. As early as day 1 of treatment, blood pressure falls; the effect is found to persist also in long‐term therapy.
Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R‐enantiomer and the S‐enantiomer. Verapamil is extensively metabolized. Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity of verapamil and accounts for 6% of excreted drug. The steady‐state plasma concentrations of norverapamil and verapamil are similar. Steady state after multiple once daily dosing is reached after three to four days.
Greater than 90% of verapamil is rapidly absorbed from the small intestine after oral administration. Mean systemic availability of the unchanged compound after a single dose of IR verapamil is 22% and that of SR verapamil approximately 33%, owing to an extensive hepatic first‐pass metabolism. Bioavailability is about two times higher with repeated administration. Peak verapamil plasma levels are reached one to two hours after IR administration, and four to five hours after SR administration. The peak plasma concentration of norverapamil is attained approximately one and five hours after IR or SR administration, respectively. The presence of food has no effect on the bioavailability of verapamil.
Half‐life values between 3 and 7 hours have been measured for the elimination of unchanged substance from the plasma after single intravenous and oral administration.
Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of verapamil is approximately 90%.
Metabolism Verapamil is extensively metabolized. In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N and O‐dealkylated products of verapamil. Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.
In coronary heart disease and hypertension, no correlation was found between the therapeutic effect and the plasma concentration; a definite correlation with the plasma level was determined only for the effect on the PR interval. The concentration curve of verapamil in the plasma is protracted after administration of the sustained‐release formulations, and is also flatter and more homogenous than after administration of the instant release formulations.
Following intravenous infusion, verapamil is eliminated bi‐exponentially, with a rapid early distribution phase (half‐life about four minutes) and a slower terminal elimination phase (half‐life two to five hours). Following oral administration, the elimination half‐life is three to seven hours. Approximately 50% of an administered dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7‐1.3 L/h/kg).
Limited information on the pharmacokinetics in the paediatric population is available. After intravenous dosing, the mean half‐life of verapamil was 9.17 hours and the mean clearance was 30 L/h, whereas it is around 70 L/h for a 70‐kg adult. Steady‐state plasma concentrations appear to be somewhat lower in the paediatric population after oral dosing compared to those observed in adults.
Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half‐life may be prolonged in the elderly. The antihypertensive effect of verapamil was found not to be age‐related.
Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end‐stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by hemodialysis.
The half‐life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution. Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolized.
Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 180 mg/m²/day and 360 mg/m²/day (compared to a maximum recommended human oral daily dose of 300 mg/m²) and have revealed no evidence of teratogenicity. In the rat, however, a dose similar to the clinical dose (360 mg/m²) was embryocidal and retarded foetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gain of dams). This oral dose has also been shown to cause hypotension in rats. There are, however, no adequate and well‐controlled studies in pregnant women.
The cardiovascular findings and the diffuse gingival hyperplasia seen in the chronic toxicity of verapamil hydrochloride are taken into account in Section 4.8 (Undesirable Effects).
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