Matzim LA(Diltiazem Hydrochloride) - America[美国药品]

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Matzim LA(Diltiazem Hydrochloride)

2013-11-07 00:19:42 来源: 作者: 【大中小】浏览:481次评论:0条

Diltiazem Extended Release TabletsPronunciation
Generic Name: diltiazem hydrochloride
Dosage Form: tablet, extended release
DILTIAZEM HYDROCHLORIDE EXTENDED- RELEASE TABLETS
Rx only
Once-a-day dosage
Diltiazem Extended Release Tablets Description
Diltiazem hydrochloride is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)one,3-(acetyloxy)- 5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-cis-. The chemical structure is:

Diltiazem Hydrochloride Structure

Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol and chloroform. It has a molecular weight of 450.99. Diltiazem hydrochloride extended-release tablets, for oral administration, are formulated as a once-a-day extended-release tablet containing 120 mg, 180 mg, 240 mg, 300 mg, 360 mg or 420 mg of diltiazem hydrochloride.

Also contains: candelilla wax powder, colloidal silicon dioxide, corn starch, ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, nonoxynol 100, polyacrylate dispersion, polyethylene oxide, polysorbate 80, povidone, sucrose, talc, titanium dioxide and triacetin.

Diltiazem Extended Release Tablets - Clinical Pharmacology

The therapeutic effects of diltiazem 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 produces 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 has 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 work loads. 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 which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and non-ischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.

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 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 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 tablets

A single 360 mg dose of diltiazem hydrochloride extended-release tablets results in detectable plasma levels within 3 to 4 hours and peak plasma levels between 11 and 18 hours; absorption occurs throughout the dosing interval. The apparent elimination half-life for diltiazem hydrochloride extended-release tablets after single or multiple dosing is 6 to 9 hours. When diltiazem hydrochloride extended-release tablets were coadministered with a high fat content breakfast, diltiazem peak and systemic exposures were not affected indicating that the tablet can be administered without regard to food. As the dose of diltiazem hydrochloride extended-release tablets is increased from 120 to 240 mg, area-under-the-curve increases 2.5-fold.

Pharmacodynamics and Clinical Studies

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 work load. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output,