Diltiazem

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Abstract
Diltiazem is a calcium antagonist effective in the treatment of stable, variant and unstable angina pectoris and mild to moderate systemic hypertension, with a generally favourable adverse effect profile. It is also effective in terminating supraventricular tachycardia and in controlling the ventricular response to atrial fibrillation/flutter. Atrioventricular block, the risk of which may be exacerbated by concomitant β-adrenoceptor antagonist therapy, occurs rarely as an adverse effect of diltiazem treatment. Diltiazem appears to exert complex cardioprotective effects which have been of benefit after intracoronary administration to patients undergoing coronary angiography and bypass procedures. In addition, long term diltiazem treatment has produced a significant reduction in subsequent cardiac events in patients with non-Q wave myocardial infarction. Thus, diltiazem is an effective and well-tolerated first-line or alternative treatment of patients with ischaemic heart disease, systemic hypertension, and supraventricular arrhythmias, with possible potential in limiting ischaemia-induced myocardial damage. Although diltiazem is a potent vasodilator, the reduction in blood pressure that accompanies its use is usually accomplished without reflex tachycardia, probably because the drug suppresses sinoatrial node stimulation. As a result, the double product (an indirect measure of myocardial oxygen demand) is reduced. In hypertensive patients, the fall in blood pressure, with regular administration, is sustained over 24 hours relative to natural circadian variation. Diltiazem has mild negative inotropic effects at clinically useful dosages but may improve myocardial relaxation and diastolic function together with decreases in afterload to produce a net improvement in left ventricular performance. In addition to reducing peripheral vascular resistance, diltiazem decreases coronary resistance. Total coronary flow is generally unchanged but there is evidence in some instances of improved patency of stenotic lesions during exertion and improved perfusion of myocardium supplied by occluded vessels. However, in some patients with complete occlusion of the left anterior descending coronary artery and distal collaterals, diltiazem may worsen flow dynamics. In common with other calcium antagonists, it is effective in preventing coronary artery spasm in patients susceptible to ergometrine (ergonovine). Work in animal heart preparations indicates that the presence of diltiazem prior to occlusion and reperfusion conserves high energy phosphates within the cell and reduces myocardial damage. Cardioprotective activity in intact animals may also involve improving the coronary vasodilatory response to ischaemia and stabilising cardiac conduction in the early phase. The response of vascular smooth muscle to diltiazem varies somewhat according to the anatomical origin of the tissue. In humans, increased blood flow has been demonstrated in the fingers and forearm, and in the splanchnic circulation only when preconstricted by digoxin. Diltiazem neither reduces renal blood flow nor alters glomerular filtration rate despite significant reductions in mean arterial pressure and systemic vascular resistance. Renal function may improve in patients with dysfunction related to hypertension. In the short term, urine flow rate and sodium excretion may increase but no effect on serum electrolyte levels or fluid retention has been observed long term. Evaluation of glucose and lipid homeostasis in diabetic and nondiabetic subjects treated with calcium antagonists indicates that diltiazem does not affect energy metabolism in the majority of individuals. After oral administration, peak plasma diltiazem concentrations are achieved within 1.5 hours for the fast release formulation and 3 to 4 hours for the slow release formulation. 90% of the administered dose is absorbed but extensive first-pass metabolism limits the absolute bioavailability to 30 to 40%. Absolute bioavailability is dose related but does not depend on dose formulation. Peak plasma concentrations of diltiazem are approximately 0.04 to 0.07 mg/L after 60mg, 0.09 to 0.12 mg/L after 90mg and 0.06 to 0.15 mg/L after 120mg. A minimum plasma diltiazem concentration of 0.10 mg/L is associated with haemodynamic change and clinical improvement. Marked individual variation occurs in plasma concentrations, particularly for the slow release formulation of diltiazem, and accumulation occurs after multiple doses. Steady-state plasma concentrations are achieved after 3 to 5 days. The mean volume of distribution is 5 L/kg. The drug is highly lipophilic and appears in cerebrospinal fluid (as studied in rabbits) and breast milk. Diltiazem is highly protein bound (80 to 90%) and binding is unaffected by its most active metabolite, deacetyl diltiazem, which is itself 60 to 75% protein bound. Diltiazem is metabolised to several metabolites, the most important being N-monodemethyl diltiazem with 20% of the potency of diltiazem, deacetyl diltiazem with 50% of the potency of the parent drug, and jV-demethyl deacetyl diltiazem. These metabolites are detectable in plasma within 30 minutes, reaching concentrations of 30 to 50%, 10 to 30% and 10 to 20% of the parent drug, respectively. The elimination half-life of orally administered diltiazem averages about 4.5 hours, with a range of 2 to 5 hours reported for intravenously administered drug. The half-lives of the N-monodemethyl and deacetyl diltiazem metabolites are approximately 7 and 8 hours, respectively. Elderly subjects demonstrate a prolonged half-life although peak plasma concentrations and total clearance of diltiazem may not be altered in the aged. Renal dysfunction does not affect diltiazem pharmacokinetics. The effectiveness of diltiazem in patients with mild to moderate systemic hypertension (diastolic pressure 90 or 95mm Hg but 110 or 115mm Hg) has been proven in double-blind comparisons with placebo. Compared with other antihypertensive drugs [e.g. hydrochlorothiazide, β-adrenoceptor antagonists, other calcium antagonists, angiotensin converting enzyme (ACE) inhibitors] diltiazem was as effective when titrated according to diastolic blood pressure. Studies conducted over 12 to 20 months found no evidence of tolerance. When results of comparative trials were reanalysed by race and age, no trends strong enough to support the use of 1 agent over another were apparent although patient numbers were relatively small. Diltiazem was effective when given intravenously to patients with severe malignant hypertension and to patients with postoperative hypertension. In patients with stable exertional angina, short and long term diltiazem reduced the frequency of spontaneous anginal attacks and significantly improved exercise tolerance compared with placebo. The anti-ischaemic activity of diltiazem was equivalent to that of β-adrenoceptor antagonists and nifedipine or verapamil. In contrast to propranolol, diltiazem has been shown to improve left ventricular function in patients with ischaemic heart disease. When maximally tolerated propranolol (with and without long-acting nitrates) was not effective, the addition of diltiazem generally resulted in improvement. Diltiazem plus nifedipine was also an effective combination in patients unresponsive to either monotherapy. The use of diltiazem plus long acting nitrates is not extensively reported but does not appear to be particularly beneficial. Diltiazem has been shown to be effective in treating unstable angina — a condition with aspects of exertional and vasospasm-induced ischaemia. It compared favourably with intravenous nitroglycerin (glyceryl trinitrate) and oral propranolol in directly comparative trials. The potential of diltiazem in silent myocardial ischaemia remains to be clarified. Nonsignificant reductions in incidence of reinfarction have been described in patients with acute myocardial infarction treated with short term oral diltiazem; a significant protective effect was apparent in patients with angina associated with transient ST-T interval changes. In a further study among long term diltiazem recipients, there was a significantly higher rate of cardiac events in patients with pulmonary congestion, while those without pulmonary congestion had a lower rate. A similar but nonsignificant relationship was observed between ejection fraction (> 40%) and diltiazem treatment. In a cohort of patients with non-Q wave infarction, a significant reduction in cardiac events of 40% was observed. Diltiazem inhibits the slow inward calcium current, prolonging the effective and functional refractory periods of the atrioventricular node and intranodal (A-H) conduction. It was effective in terminating supraventricular tachycardia and in slowing the ventricular response to atrial fibrillation and flutter. A therapeutic role for diltiazem in the management of ventricular arrhythmias is unlikely. The role of diltiazem in treatment of Raynaud’s phenomenon, oesophageal motility disorders, migraine and cardiomyopathy, and its use as an adjunct to cardioplegia, requires further investigation. Diltiazem treatment appears to be associated with a low incidence of adverse effects. The principal adverse effects are predictable given the vasodilating properties of the drug and include oedema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%) and asthenia (1.2%). The most frequent serious adverse event is atrioventricular block, which occurs in approximately 0.2% of patients overall; patients receiving concurrent β- adrenoceptor antagonists may be at increased risk of developing conduction disturbances. Oral dosages recommended for the treatment of systemic hypertension and angina pectoris vary between countries and may reflect genetic differences as well as local medical practice. In patients with systemic hypertension, oral dosages of 120 to 360 mg/day are used in the United States, 180 to 360 mg/day in France and West Germany and 90 to 180 mg/day in Japan and Southeast Asia. The dosage in angina pectoris ranges between 120 to 360 mg/day in the United States, 120 to 180 mg/day in France, 90 to 180 mg/ day in Japan and is 90 mg/day in Southeast Asia. Intravenous diltiazem has been effective in unstable angina (0.3 mg/kg bolus followed by 0.2 mg/min infusion) and in controlling paroxysmal supraventricular tachycardia and atrial fibrillation/flutter (generally 0.1 to 0.3 mg/kg bolus injection). Diltiazem 1mg intracoronarily has been employed to prevent vasospasm during coronary angioplasty. Since diltiazem is metabolised, dosage reductions may be necessary in patients with hepatic impairment; however, no dosage adjustment is required in patients with renal dysfunction. Diltiazem is contraindicated in sick sinus syndrome or second or third degree atrioventricular block (except in the presence of a functioning ventricular pacemaker). It should be administered with caution in the presence of atrioventricular conduction delays or transient sinus pauses. It is contraindicated in hypotension and in patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission. Coadministration of diltiazem with cyclosporin increases plasma concentrations of cyclosporin; similarly, diltiazem increases digoxin concentrations.
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