Chemical formula: C₂₂H₂₆N₂O₄S Molecular mass: 414.518 g/mol PubChem compound: 39186
Diltiazem is a calcium antagonist. It restricts the slow channel entry of calcium into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction of the amount of available intracellular calcium reducing myocardial oxygen consumption. It increases exercise capacity and improves all indices of myocardial ischaemia in the angina patient.
Diltiazem relaxes large and small coronary arteries and relieves the spasm of vasospastic (prinzmetals) angina and the response to catecholamines but has little effect on the peripheral vasculature. There is therefore no possibility of reflex tachycardia. A small reduction in heart rate occurs which is accompanied by an increase in cardiac output, improved myocardial perfusion and reduction of ventricular work.
In animal studies, diltiazem protects the myocardium against the effects of ischaemia and reduces the damage produced by excessive entry of calcium into the myocardial cell during reperfusion.
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.
Diltiazem 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.
Diltiazem is effective in angina, protecting the heart against ischaemia, vasodilating coronary arteries and reducing myocardial oxygen requirements. It is well tolerated and does not generally give rise to side effects associated with peripheral vasodilators, nor cause significant myocardial depression.
Diltiazem is well absorbed (90%) in healthy volunteers following oral administration.
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.
Peak plasma concentrations occur 3 to 4 hours after dosing.
Due to a first pass effect, the bioavailability of the 60 mg tablet is about 40%. The mean apparent plasma half-life is 4-8 hours.
Diltiazem is 80 to 85% bound to plasma proteins. It 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.
Less than 5% of diltiazem is excreted unchanged in the urine.
There is a linear relationship between dose and plasma concentration. During long term administration to any one patient, plasma concentrations of diltiazem remain constant.
Mean plasma concentrations in elderly subjects and patients with renal and hepatic insufficiency are higher than in young subjects.
Diltiazem and its metabolites are poorly dialysed.
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.
Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg q.d. or 8 mg/kg q.d. for a 60-kg patient) resulted in embryo and fetal lethality. These studies revealed, in one species or another, a propensity to cause fetal abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights, pup survival, as well as prolonged delivery times and an increased incidence of stillbirths.
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