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VASCOR (bepridil hydrochloride) inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. This has been demonstrated in isolated myocardial and vascular smooth muscle preparations in which both the slope of the calcium dose response curve and the maximum calcium-induced inotropic response were significantly reduced by bepridil hydrochloride. In cardiac myocytes in vitro, bepridil hydrochloride was shown to be tightly bound to actin. A negative inotropic effect can be seen in the isolated guinea pig atria.
In in vitro studies, bepridil hydrochloride has also been demonstrated to inhibit the sodium inward current. Reductions in the maximal upstroke velocity and the amplitude of the action potential, as well as increases in the duration of the normal action potential, have been observed. Additionally, bepridil hydrochloride has been shown to possess local anesthetic activity in isolated myocardial preparations. It effects electrophysiological changes that are observed with several classes of anti-arrhythmic agents.
In controlled clinical studies with 200-400 mg of VASCOR (bepridil) , given as a once daily dose, exercise tolerance was improved and angina frequency and daily nitroglycerin use was reduced compared to placebo. Improvement in exercise performance was dose related. In one controlled clinical study, VASCOR (bepridil) was added to propranolol in daily doses of up to 240 mg. The 200-400 mg dose of VASCOR (bepridil) was well tolerated [patients entered were not allowed to be in NYHA Class III or IV heart failure] and there was an added effect of VASCOR (bepridil) on exercise tolerance.
In another controlled clinical study, VASCOR (bepridil) in doses of up to 400 mg/day, significantly improved exercise tolerance compared to diltiazem hydrochloride in patients refractory to diltiazem hydrochloride therapy.
Mechanism of Action: The precise mechanism of action for VASCOR (bepridil) as an anti-anginal agent remains to be fully determined, but is believed to include the following mechanisms:
VASCOR (bepridil) regularly reduces heart rate and arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing total peripheral resistance (afterload) against which the heart works. In exercise tolerance tests in patients with stable angina the heart rate/blood pressure product was reduced with VASCOR (bepridil) for a given work load.
Hemodynamic Effects: VASCOR (bepridil) produces dose dependent slowing of the heart, and reflex tachycardia is not seen. The mean decrease in heart rate in US clinical trials was 3 b.p.m. Orally administered VASCOR (bepridil) also produces modest decreases (less than 5 mm Hg) in systolic and diastolic blood pressure in normotensive patients and somewhat larger decreases in hypertensive patients.
Intravenous administration of VASCOR (bepridil) is associated with a modest reduction in left ventricular contractility (dP/dt), and increased filling pressure, but radionuclide cineangiography studies in angina patients demonstrated improvement in ejection fraction at rest and during exercise following oral VASCOR (bepridil) therapy. Patients with impaired cardiac function [overt heart failure] were not included in these studies.
Electrophysiological Effects: Intravenous administration of VASCOR (bepridil) in man prolongs the effective refractory periods of the atria and ventricles, and the functional refractory period of the AV node. There was a tendency for the AV node effective refractory period and A-H interval to be increased as well. Intravenous and oral administration of VASCOR (bepridil) slow heart rate, prolong the QT and QTc intervals, and alter the morphology of the T-wave (indentation). In clinical trials with angina patients, the mean percent prolongation of the QTc interval was approximately 8%, and of QT about 10%. The prolongation of QT is dose related, varying from about 0.030 sec at doses of 200 mg once a day to 0.055 sec at 400 mg once a day. Upon cessation of therapy, the ECG gradually normalizes. No instances of greater than first-degree heart block have been observed in US controlled or open clinical studies with VASCOR (bepridil) , and first-degree heart block occurred in 0.2% of patients in these studies.
Pulmonary Function: In healthy subjects and asthmatic patients, intravenous VASCOR (bepridil) did not cause bronchoconstriction. VASCOR (bepridil) has been safely used in asthmatic patients and in patients with chronic obstructive lung disease.
Pharmacokinetics and Metabolism: In studies with healthy volunteers, VASCOR (bepridil) is rapidly and completely absorbed after oral administration. The time to peak bepridil plasma concentration is about 2 to 3 hours. Over a ten day period, approximately 70% of a single dose of VASCOR (bepridil) is excreted in the urine and 22% in the feces, as metabolites of bepridil. Excretion of unmetabolized drug is negligible. In healthy male volunteers, the relationship between dose and steady-state blood levels of bepridil was linear over the range of 200 to 400 mg/day. Elimination of bepridil is biphasic, with a distribution half-life of about 2 hours. The terminal elimination half-life following the cessation of multiple dosing averaged 42 hours (range 26-64 hours). However, during a given dosing interval, decay from the peak concentration occurs relatively rapidly indicating a dosing interval half-life shorter than 24 hours. Following once-daily dosing with therapeutic doses, steady-state was reached in about 8 days in healthy volunteers. The clearance of bepridil decreases after multiple dosing.
Clearance of bepridil in angina patients was lower than that in healthy volunteers, resulting in higher average plasma bepridil concentrations. At steady state, maximum bepridil concentrations averaged 2332 ng/ml (range 1451 to 3609) and mean minimum concentrations were 1174 ng/ml (range 226 to 2639) in angina patients following 300 mg/day doses of VASCOR.
Bepridil is more than 99% bound to plasma proteins. Administration of VASCOR (bepridil) after a meal resulted in a clinically insignificant delay in time to peak concentration, but neither peak bepridil plasma levels nor the extent of absorption was changed.
Bepridil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug is greater in patients with impaired renal function. Peak plasma concentration of bepridil was increased 3-fold and t 1/2 was increased more than 2-fold in elderly (>74 years) receiving oral bepridil 100 mg twice daily for 3 weeks compared to younger volunteers (see PRECAUTIONS Geriatric Use ).
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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