Diltiazem

CLINICAL PHARMACOLOGY The therapeutic effects of diltiazem hydrochloride extended-release capsules are believed to be related to its ability to inhibit the cellular influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle. Mechanisms of Action Hypertension : Diltiazem hydrochloride extended-release capsules produce its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives. Angina : Diltiazem hydrochloride extended-release capsules have been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal workloads. Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasms are inhibited by diltiazem. In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels that cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose- dependent decreases in systemic blood pressure and decreases in peripheral resistance. Hemodynamic and Electrophysiologic Effects Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses. In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem. In hypertensive patients, diltiazem hydrochloride extended-release capsules produce antihypertensive effects both in the supine and standing positions. In a double-blind, parallel, dose-response study utilizing doses ranging from 90 to 540 mg once daily, diltiazem hydrochloride extended-release capsules lowered supine diastolic blood pressure in an apparent linear manner over the entire dose range studied. The changes in diastolic blood pressure, measured at trough, for placebo, 90 mg, 180 mg, 360 mg, and 540 mg were -2.9, -4.5, -6.1, -9.5, and -10.5 mm Hg, respectively. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects. Diltiazem hydrochloride extended-release capsules decrease vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem hydrochloride extended-release capsules produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem hydrochloride extended-release capsules reduce the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio. In a double-blind, parallel dose-response study of doses from 60 mg to 480 mg once daily, diltiazem hydrochloride extended-release capsules increased time to termination of exercise in a linear manner over the entire dose range studied. The improvement in time to termination of exercise utilizing a Bruce exercise protocol, measured at trough, for placebo, 60 mg, 120 mg, 240 mg, 360 mg, and 480 mg was 29, 40, 56, 51, 69, and 68 seconds, respectively. As doses of diltiazem hydrochloride extended-release capsules were increased, overall angina frequency was decreased. Diltiazem hydrochloride extended-release capsules, 180 mg once daily, or placebo was administered in a double-blind study to patients receiving concomitant treatment with long-acting nitrates and/or beta-blockers. A significant increase in time to termination of exercise and a significant decrease in overall angina frequency was observed. In this trial the overall frequency of adverse events in the diltiazem hydrochloride extended-release capsule treatment group was the same as the placebo group. Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of diltiazem hydrochloride in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases). Chronic oral administration of diltiazem hydrochloride to patients in doses of up to 540 mg/day has resulted in small increases in PR interval and on occasion produces abnormal prolongation (see WARNINGS ). Pharmacokinetics and Metabolism Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%. Diltiazem hydrochloride undergoes extensive metabolism in which only 2% to 4% of the unchanged drug appears in the urine. Drugs which induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition. Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites, which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2 to 5 hours for diltiazem. In vitro binding studies show diltiazem hydrochloride is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown diltiazem hydrochloride binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as diltiazem. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single study in nine patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function. Diltiazem hydrochloride extended-release capsules : When compared to a regimen of diltiazem hydrochloride tablets at steady- state, more than 95% of drug is absorbed from the diltiazem hydrochloride extended-release capsules formulation. A single 360 mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours; absorption occurs throughout the dosing interval. When diltiazem hydrochloride extended-release capsules were coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected. Dose-dumping does not occur. The apparent elimination half-life after single or multiple dosing is 5 to 8 hours. A departure from linearity similar to that seen with diltiazem hydrochloride tablets and diltiazem hydrochloride sustained-release capsules is observed. As the dose of diltiazem hydrochloride extended-release capsules is increased from a daily dose of 120 mg to 240 mg, there is an increase in the area under the curve of 2.7 times. When the dose is increased from 240 mg to 360 mg, there is an increase in the area under the curve of 1.6 times. In an in vitro dissolution study, the release rate of diltiazem from diltiazem hydrochloride extended-release capsules increased significantly as the alcohol percentage in the dissolution medium increased. The effect of alcohol on the release rate may lead to a change in the pharmacokinetics of diltiazem, such as a more rapid absorption and/or an increase in the systemic exposure of diltiazem (see PRECAUTIONS , Drug Interactions ).