Dilzem Mechanism of Action

Pharmacological Category: Calcium Channel Blocker (Benzothiazepine derivatives).
Pharmacology: Pharmacodynamics: The therapeutic benefits achieved with diltiazem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.
Mechanism of Action: Although precise mechanisms of its antianginal actions are still being delineated, diltiazem is believed to act in the following ways: Angina Due to Coronary Artery Spasm: Diltiazem has been shown to be a potent dilator of both epicardial and subendocardial coronary arteries. Spontaneous and ergonovine-induced coronary artery spasm are inhibited.
Exertional 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 exercise workloads.
Hypertension: The antihypertensive effect of diltiazem is achieved 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 normotensive individuals.
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 non-ischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.
Hemodynamic and Electrophysiologic Effects: Like other calcium antagonists, diltiazem decreases sinoatrial and AV 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 and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate/blood pressure product for any given workload. Studies to date, 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. Resting heart rate is usually unchanged or slightly reduced by diltiazem.
Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. 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 in doses of up to 360 mg/day has resulted in small increases in PR interval, but has not usually produced abnormal prolongation.
Diltiazem produces antihypertensive effects in both the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with chronic antihypertensive effects. Diltiazem decreases 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. Heart rate at maximum exercise does not change or is slightly reduced. Chronic therapy produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed.
Pharmacokinetics: Absorption: Diltiazem is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to IV dosing) of about 40%. Single oral doses of 30 mg to 120 mg result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 3 hours after drug administration. There is a departure from dose linearity when single doses of diltiazem above 60 mg are given; a 120 mg dose gave plasma levels three times that of the 60 mg dose.
Distribution: In vitro studies have shown that 70% to 80% of diltiazem is bound to plasma proteins. Competitive ligand-binding studies also have shown that binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. Therapeutic plasma levels of diltiazem appear to be in the range of 50 ng/mL to 200 ng/mL.
Metabolism: Diltiazem undergoes extensive hepatic metabolism and undergoes biotransformation by cytochrome P-450 (CYP) 3A4; therefore, only 2% to 4% of the unchanged drug appears in the urine. In cases of serious liver damage, delayed biotransformation may be anticipated. Desacetyldiltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent a coronary vasodilatory as diltiazem.
Excretion: The plasma elimination half-life following single- or multiple-drug administration is approximately 3.5 hours.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.