CLINICAL PHARMACOLOGY
Verapamil hydrochloride is a calcium ion influx inhibitor (slow-channel 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 hydrochloride as an antianginal agent
remains to be fully determined, but includes the following two mechanisms:
1. 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.
2. 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.
Pharmacokinetics and metabolism
More than 90% of the orally administered dose of verapamil
hydrochloride is absorbed. Because of rapid biotransformation of verapamil
during its first pass through the portal circulation, bioavailability ranges
from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours
after oral administration. Chronic oral administration of 120 mg of verapamil
hydrochloride every 6 hours resulted in plasma levels of verapamil ranging from
125 to 400 ng/mL, with higher values reported occasionally. A nonlinear
correlation between the verapamil dose administered and verapamil plasma levels
does exist. No relationship has been established between the plasma
concentration of verapamil and a reduction in blood pressure. In early dose
titration with verapamil a relationship exists between verapamil plasma
concentration and prolongation of the PR interval. However, during chronic
administration this relationship may disappear. The mean elimination half-life
in single-dose studies ranged from 2.8 to 7.4 hours. In these same studies,
after repetitive dosing, the half-life increased to a range from 4.5 to 12 hours
(after less than 10 consecutive doses given 6 hours apart). Half-life of
verapamil may increase during titration. Aging may affect the pharmacokinetics
of verapamil. Elimination half-life may be prolonged in the elderly. In healthy
men, orally administered verapamil hydrochloride undergoes extensive metabolism
in the liver. Twelve metabolites have been identified in plasma; all except
norverapamil are present in trace amounts only. Norverapamil can reach
steady-state plasma concentrations approximately equal to those of verapamil
itself. The cardiovascular activity of norverapamil appears to be approximately
20% that of verapamil. Approximately 70% of an administered dose is excreted as
metabolites in the urine and 16% or more in the feces within 5 days. About 3% to
4% is excreted in the urine as unchanged drug. Approximately 90% is bound to
plasma proteins. In patients with hepatic insufficiency, metabolism is delayed
and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS); the volume
of distribution is increased and plasma clearance reduced to about 30% of
normal. Verapamil clearance values suggest that patients with liver dysfunction
may attain therapeutic verapamil plasma concentrations with one third of the
oral daily dose required for patients with normal liver functions.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil
levels were noted in the cerebrospinal fluid with estimated partition
coefficient of 0.06 for verapamil and 0.04 for norverapamil.
Hemodynamics and myocardial metabolism
Verapamil reduces afterload and myocardial contractility.
Improved left ventricular diastolic function in patients with IHSS and those
with coronary heart disease has also been observed with verapamil hydrochloride
therapy. 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. However, in patients with severe left
ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mm Hg or
ejection fraction less than 30%), or in patients taking beta-adrenergic blocking
agents or other cardiodepressant drugs, deterioration of ventricular function
may occur (see Drug
interactions).
Pulmonary function
Verapamil does not induce bronchoconstriction and, hence, does
not impair ventilatory function.
ANIMAL PHARMACOLOGY & OR TOXICOLOGY
In chronic animal toxicology studies verapamil caused lenticular and/or suture
line changes at 30 mg/kg/day or greater, and frank cataracts at 62.5 mg/kg/day
or greater in the beagle dog but not in the rat. Development of cataracts due to
verapamil has not been reported in man.
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