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Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives. ATC-Code: C08DA01.
Pharmacology: Pharmacodynamics: Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odorless 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-(3,4-dimethoxyphenyl)ethyl}methylamino] propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride. It has a molecular weight of 491.07 and the molecular formula is C27H38N2O4 • HCl.
Mechanism of action and Pharmacodynamic effects: Verapamil inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of verapamil appears to be due to its effect on the slow channel in cells of the cardiac conductile system. Electrical activity through the sinoatrial (SA) and atrioventricular (AV) nodes depends, to a significant degree, upon calcium influx through the slow channel. By inhibiting this influx, verapamil slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response. By interrupting re-entry at the AV node, verapamil can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including Wolff-Parkinson-White (W-P-W) syndrome. Verapamil has no effect on conduction across accessory bypass tracts.
Clinical efficacy and safety: 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. In the isolated rabbit heart, concentrations of verapamil that markedly affect SA nodal fibers or fibers in the upper and middle regions of the AV node have very little effect on fibers in the lower AV node (NH region) and no effect on atrial action potentials or His bundle fibers. Verapamil does not induce peripheral arterial spasm nor does it alter total serum calcium levels. Verapamil reduces afterload and myocardial contractility.
In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload and cardiac index is usually not reduced, but in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mmHg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within three to five minutes after a bolus injection of verapamil. The commonly used intravenous doses of 5 to 10 mg verapamil hydrochloride produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased.
Pharmacokinetics: 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.
Absorption: 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 four to five hours after SR administration. The peak plasma concentration of norverapamil is attained approximately five hours after SR administration. The presence of food has no effect on the bioavailability of verapamil.
Distribution: 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.
Elimination: 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).
Special Populations: Pediatric: Limited information on the pharmacokinetics in the paediatric population is available. Steady-state plasma concentrations appear to be somewhat lower in the pediatric population after oral dosing compared to those observed in adults.
Geriatric: 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.
Renal insufficiency: 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.
Hepatic insufficiency: The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.
Toxicology: Preclinical safety data: Reproduction studies have been performed in rabbits and rats at oral verapamil 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, however, no adequate and well-controlled studies in pregnant women.
