Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Napp Pharmaceuticals Ltd, Cambridge Science Park, Milton Road, Cambridge CB4 0GW
Pharmacotherapeutic group: Selective calcium channel blocker with direct cardiac effects
ATC Code: C08DB01
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.
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-XL 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 prolonged release capsules provided prolonged absorption of the drug, producing peak steady plasma concentrations between 4 and 14 hours post-dose. The availability of diltiazem from Adizem-XL 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 Adizem-SR tablets 120 mg (b.d.) was approximately 78%. The extent of absorption of diltiazem was not affected when Adizem-XL capsules were co-administered with a high-fat meal.
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.
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.
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.
Diltiazem was not genotoxic when tested in vitro in two bacterial mutation tests with and without metabolic activation, and in two clastogenicity assays.
Diltiazem was not carcinogenic in two long term carcinogenicity studies, in rats and mice.
Diltiazem was toxic to the developing embryo in studies in mice, rats and rabbits when dosed to the mother at critical stages during organ development. Skeletal malformations occurred in the limbs, tail and ribs of all three species.
Diltiazem had an adverse effect upon male fertility in rats, with decreases in sperm count, sperm motility and epididymal weight, although these effects were reversible on cessation of dosing.
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