Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Diltiazem is a calcium antagonist. It restricts the slow channel entry of calcium ions into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction in the amount of available intracellular calcium and consequently a (1) reduction of myocardial oxygen consumption, (2) dilation of small and large coronary arteries, (3) mild peripheral vasodilation, (4) negative dromotropic effects, (5) reflex positive chronotropic and inotropic effects due to reflex sympathetic activity are partially inhibited and result in a slight reduction or no change in heart rate.
The antihypertensive effect is due to the reduction in peripheral vascular resistance.
The antianginal effect is due to a reduction in the peripheral resistance, thereby decreasing the after-load, whilst a reduction in the vasomotor tone of the coronary circulation maintains the coronary blood flow. Cardiac contractility and ventricular ejection fraction are unchanged. Diltiazem increases exercise capacity and improves indices of myocardial ischaemia in the angina patient. Diltiazem relieves the spasm of vasospastic (Prinzmetal) angina.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
An oral dose of diltiazem is almost completely absorbed. Despite this, diltiazem has a low bioavailability owing to extensive first pass metabolism. This process is saturable at higher doses of the drug resulting in a non-linear accumulation and higher blood concentrations at steady state than would be anticipated from those following a single dose.


ADIZEM CD® capsules reduce the degree of saturation by presenting diltiazem in a retarded fashion therefore eliminating the high peak concentrations of the absorption phase. This allows the capsule to be administered once daily.
In pharmacokinetic studies in healthy volunteers, diltiazem was well absorbed. The controlled release capsules provided prolonged absorption of the drug, producing peak steady state plasma concentrations between 4 and 14 hours postdose. The availability of diltiazem from ADIZEM CD® capsules 120 mg (o.d.) relative to a prolonged release 60 mg diltiazem preparation (b.d.) was approximately 79% at steady state. Similarly, the availability of diltiazem from the 240 mg capsule (o.d.) relative to prolonged release 120 mg diltiazem preparation (b.d) was approximately 78%. The extent of absorption of diltiazem was not affected when ADIZEM CD® capsules were co-administered with a high-fat meal.

Distribution
Diltiazem has a high volume of distribution with typical study results in the range of 3-11 litres/kg. Protein binding is about 80% and is not concentration-dependent at levels likely to be found clinically. Protein binding does not appear to be influenced by phenylbutazone, warfarin, propranolol, salicylic acid or digoxin.
Biotransformation
Diltiazem is extensively metabolised by the liver. The desacetyl metabolite is considered to be approximately 25% to 50% as potent a coronary vasodilator as diltiazem and is present in plasma at concentrations of 10% to 20% of parent.
Elimination
The mean elimination half life of diltiazem is around 4 hours but this is extended from prolonged-release formulations. Mean plasma concentrations in elderly subjects and patients with renal and hepatic insufficiency are higher than in young subjects.