Pharmacotherapeutic Group: Benzothiazepine derivatives. ATC Code: C08DB01.
Pharmacology: Pharmacodynamics: Diltiazem a benzothiazepine derivative that effectively blocks the slow calcium channels (L channels) of vascular smooth muscle and cardiac muscle cells. Slow calcium channels play an important role especially in the regulation of sinoatrial and atrioventricular node function in the cardiac muscle cells. Diltiazem possesses both peripheral and coronary vasodilator properties. However, diltiazem-induced fall in blood pressure is not commonly followed by reflectory tachycardia which is probably due to the depressive effect of the drug on the stimulation of sinoatrial node function. Diltiazem slows atrioventricular conduction. It also has a weak negative inotropic effect on the heart. Diltiazem improves relaxation of the cardiac muscle and diastolic function which together with decreased afterload improves the left ventricular function. In spite of coronary dilatation, the total flow in healthy coronary arteries does not usually change, but some improvement in the circulation of contracted arteries has been observed. Diltiazem relaxes smooth muscle also elsewhere in the body eg, the lower oesophageal sphincter muscle. Diltiazem has not been shown to have effect on electrolyte-, lipid- or glucose balance in healthy or diabetic persons.
Pharmacokinetics: Absorption: Diltiazem is completely absorbed after oral administration, but owing to its first-pass metabolism in the liver, the absolute bioavailability of diltiazem hydrochloride is only about 40% (with interindividual variability ranging from 24-74%).
Distribution: The bioavailability is independent of formulation or therapeutic dose. A diet rich in fat and protein slightly increases the bioavailability of a sustained-release capsule formulation, but this has no clinical significance.
The peak concentration in plasma is reached in about 3-4 hrs after administration of a conventional diltiazem tablet. The absorption is slower from a sustained-release tablet.
About 80% of diltiazem is bound to proteins, about 40% of this to plasma albumin. Diltiazem is widely distributed to various tissues. The apparent volume of distribution is 5 L/kg and the volume of central compartment is 0.9 L/kg. In the blood, diltiazem is evenly distributed to the plasma and blood cells. Steady state is reached within 3 days with the dosage of one 60 mg tablet 3 times daily.
Metabolism: Diltiazem is extensively metabolised and <4% is excreted unchanged in the urine. The total clearance of diltiazem is between 0.7 and 1.3 L/kg/hr. Five (5) unconjugated metabolites have been found in the urine, 2 of them also in conjugated forms. Diltiazem is metabolised through deacetylation, N-demethylation, and O-demethylation. Deacetyldiltiazem is an active metabolite (40-50% of the activity of diltiazem) with concentrations of about 15-35% of those of diltiazem. The pharmacodynamic significance of this metabolite is minor. Diltiazem is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Diltiazem and its N-demethylated metabolites also act as inhibitors of CYP3A4 enzyme.
Excretion: According to 3-compartment model, the half-life (t½) of diltiazem ranges from about 0.1 hrs in the first phase to 2.1 hrs in the middle and 9.8 hrs in the terminal phase. The elimination t½ varies between 4 and 7 hrs.
The pharmacokinetics of diltiazem has not been observed to change after repeated administrations. The drug is not accumulated and it does not induce its own metabolism. Studies with renal insufficiency and angina pectoris patients did not show difference in the pharmacokinetic profile of diltiazem as compared with studies on healthy volunteers.
Toxicology: Preclinical Safety Data: The acute toxicity of diltiazem was low (oral LD50 >500 mg/kg) in toxicity studies on rodents. The toxicity of diltiazem was mainly directed to the heart [transient electrocardiogram (ECG) changes]. In teratogenicity studies, diltiazem induced increased fetal mortality and malformations.