Diltiazem

Publisher Website
Google Scholar
Abstract
Synopsis: Diltiazem1 is an orally and intravenously active calcium channel blocking agent shown to be an effective and well- tolerated treatment for stable angina and angina due to coronary artery spasm. Its efficacy in these diseases has generally been similar to that of nifedipine or verapamil — alternative calcium channel blockers with which diltiazem has many electrophysiological, haemodynamic, and antiarrhythmic similarities. The antianginal mechanism of diltiazem cannot be precisely described; however, it appears to increase myocardial oxygen supply and decrease myocardial oxygen demand, mainly by coronary artery dilatation and/or via both direct and indirect haemodynamic alterations. Diltiazem has also shown substantial efficacy in the treatment of unstable angina, hypertension, and supraventricular tachyarrhythmias, but further study is necessary before its place in the treatment of these diseases may be clearly established. Although headache due to peripheral vasodilatation and depression of atrioventricular nodal conduction may be troublesome, side effects occur in only 2 to 10% of patients receiving diltiazem and are generally minor in nature. Thus, diltiazem offers a worthwhile alternative to other agents currently available for the treatment of angina pectoris. Although the infrequency of serious side effects may offer an advantage, its relative place in therapy compared with that of other calcium channel blockers remains to be clarified. Pharmacodynamic Studies: Like other calcium channel blocking agents, diltiazem caused a dose-dependent inhibition of the slow inward calcium current in normal cardiac tissue. This usually resulted in lengthening of the intranodal (A-H interval) conduction time, prolongation of the effective and functional refractory periods of the atrioventricular node, and increasing of Wenckebach cycle lengths. With the exception of a decrease in heart rate (especially after moderate to long term treatment), diltiazem usually did not induce measurable changes in the surface electrocardiogram. In concentrations ranging from 0.1 to 10 µmol/L, diltiazem usually inhibited spontaneous contractile activity and contractions induced by depolarisation or agonist substances in isolated coronary artery smooth muscle from laboratory animals or man, although it generally has been less potent in this regard than nifedipine or verapamil. In in vivo studies in laboratory animals and man, diltiazem usually increased coronary sinus blood flow, and these increases were associated with decreases in myocardial oxygen extraction in some cases. In vitro, diltiazem decreased myocardial contractility, but in vivo its potent vasodilatory activity often led to decreases in peripheral resistance and blood pressure, with a resultant increase in cardiac output due to the decreased afterload. The baroreceptormediated increase in β-adrenergic tone, which may occur indirectly following diltiazem administration, can exert positive chronotropic and positive inotropic effects which may further modify haemodynamic response to the drug. In laboratory animals and man, partial or complete autonomic blockade has significantly altered these reflexive haemodynamic responses to diltiazem. Single-dose oral or intravenous administration of diltiazem increased exercise tolerance in patients with stable angina as assessed by increases in exercise time and by decreases in the magnitude or the time to onset of ST segment depression, usually while causing only minor haemodynamic alterations. In dogs, diltiazem demonstrated a general cardioprotective effect following laboratory-induced myocardial ischaemia (with subsequent reperfusion) as evidenced by decreased transmembrane calcium flux and damage in heart mitochondria, decreases in myocardial tissue concentrations of lactic acid and free fatty acids, increased concentrations of myocardial ATP, decreased platelet aggregation, increased regional and collateral blood flow in ischaemic myocardium (with an increased subendocardial to subepicardial ratio of flow), and decreased incidence of arrhythmias (usually ventricular tachycardia or fibrillation) associated with coronary occlusion/myocardial ischaemia. As with other calcium channel blocking agents, diltiazem has inhibited spontaneous and agonist-induced contractile activity in a wide range of vascular smooth muscle preparations from laboratory animals including the renal artery or vein, aorta, pulmonary artery, portal vein, mesenteric artery, femoral artery or vein and cerebral artery. However, as with coronary artery smooth muscle, comparative studies have generally shown diltiazem to exert less inhibition of contractile activity than nifedipine or verapamil in equimolar concentrations. The exact mechanism of diltiazem in the treatment of angina pectoris is as yet unclear; however, its efficacy is probably dependent upon its coronary vasodilating properties (causing an increase in myocardial oxygen supply) and/or several of its haemodynamic effects (resulting in a decrease in myocardial work/oxygen demand). In laboratory animals, diltiazem has frequently induced renal artery dilatation, with resultant decreases in renal vascular resistance and increases in renal plasma flow. Data in man have varied, but dose-related increases in renal plasma flow have occurred, especially in patients with renovascular hypertension or in those with a family history of this disease. The increases in urine volume and rate of urinary sodium excretion seen after diltiazem are most likely due to its effect on renal plasma flow and its inhibition of sodium reabsorption in the proximal renal tubules. Diltiazem inhibited contractions in a wide variety of isolated gastrointestinal smooth muscle preparations from laboratory animals and has been administered to healthy volunteers and patients with oesophageal motor disorders, in whom it significantly lowered lower oesophageal sphincter pressure. In isolated bronchial or tracheal smooth muscle from guinea-pigs, diltiazem decreased basal tone and contractions due to various agonist agents. In in vivo studies, diltiazem inhibited antigen-induced bronchospasm in sensitised guinea-pigs, and decreased the bronchoconstrictive response to inhaled histamine or carbachol in man. Diltiazem decreased spontaneous electrical activity in isolated uterine smooth muscle derived from pregnant or postpartum mice, and delayed second pup deliveries similar to other calcium channel blockers, ritodrine, or salbutamol in a rat animal model of premature labour. Similarly, diltiazem decreased agonist-induced contractions in isolated rabbit urethra, and increased bladder volume and time to achieve maximum bladder emptying in laboratory animals, but single oral doses had only limited beneficial effects in children with neurogenic bladder dysfunction. As calcium plays an important role in platelet aggregation and release reactions, calcium channel blockade with diltiazem has decreased platelet aggregatory response to various substances [including ADP, adrenaline (epinephrine), and thrombin] in vitro and ex vivo, but haemostasis has not been significantly affected. In concentrations greater than those which are clinically desirable (1 to 100 µmol/L) diltiazem produced a dose-related and reversible suppression of glucose- or tolbutamide-induced insulin secretion in laboratory animals. In animals with experimental insulinoma and in 1 patient with insulinoma, diltiazem decreased serum immunoreactive insulin concentrations and decreased the frequency of hypoglycaemic attacks. However, studies to date in diabetic or non-diabetic patients have not revealed significant decreases in insulin secretion or increases in mean blood glucose concentrations. Plasma immunoreactive glucagon concentrations were not altered by the injection of diltiazem into the pancreatic artery of normal dogs, but were increased when diltiazem was injected into depancreatised dogs. This increase was accompanied by simultaneously increasing blood glucose concentrations. In a perfused rat liver, diltiazem (> 50 µmol/L) inhibited glycogenolysis. In man, lipid metabolism has not been altered by diltiazem 90 or 180mg daily for up to 3 months as evidenced by lack of change in plasma concentrations of total cholesterol, HDL-, LDL-, or VLDL-cholesterol, and triglycerides. In pregnant mice and rats, single or successive doses of diltiazem 12.5 to 600 mg/kg did not increase maternal mortality, but increased the number of early resorptions, decreased fetal weight and induced vertebral or skeletal malformations in some fetuses. Cleft palate and external malformations were present in some mice exposed to diltiazem in utero. Pharmacokinetic Studies: The absolute bioavailability of diltiazem is approximately 40% and may be affected by interindividual variability in first-pass metabolism, but not by patient age. The type of oral formulation (e.g. solution, slow release tablet, capsule) seems to affect the rate, but not the extent, of absorption with the relative bioavailability being greater than 90%. Diltiazem is 78 to 87% bound to plasma proteins, and this percentage is not affected by the presence of the active desacetyl metabolite. 35 to 40% of the bound fraction binds to albumin, whereas the remainder binds to α1-acid glycoprotein and various gammaglobulins. The mean volume of distribution following single doses of diltiazem has approximated 5.3 L/kg. The major route for diltiazem metabolism following oral administration is via deacetylation or N-demethylation, followed by O-demethylation or deacetylation. The metabolites are then converted to glucuronide and/or sulphate conjugates. Reported half-lives for the elimination phase of diltiazem in healthy volunteers have ranged from 2 to 7 hours (average about 4.5 hours). Mean total clearance estimations in healthy volunteers and patients undergoing cardiac catheterisation have ranged from 11.5 to 21.3 ml/kg/min. Renal dysfunction (creatinine clearance < 20 ml/min) did not appear to significantly affect the elimination kinetics of diltiazem in doses up to 180mg daily. To date, well designed studies to assess the effects of liver dysfunction on diltiazem clearance have not been reported. Several studies have shown a significant correlation between diltiazem plasma concentrations and antianginal efficacy following oral administration, but plasma concentrations may show significant interindividual variability with identical doses. Therapeutic Trials: Diltiazem has been shown to be effective in chronic stable angina as assessed objectively by increases in exercise time and/or the time to onset of ST segment depression during exercise, and subjectively by decreases in the frequency of anginal attacks or glyceryl trinitrate (nitroglycerin) usage. Only moderate haemodynamic alterations occurred in patients with stable angina treated for 1 to 2 weeks with up to 360mg of diltiazem daily. In comparative studies, diltiazem 180 or 360mg daily has exerted antianginal efficacy equal to or greater than that of propranolol 240mg daily or their combination; however, the combination of high dose diltiazem and high dose propranolol appeared to have a high potential for producing significant bradyarrhythmias. In well-controlled comparative studies, the efficacy of diltiazem 180 or 360mg daily in the treatment of stable angina was similar or superior to that of nifedipine 30 to 60mg daily or verapamil 360 to 480mg daily. A daily combination of diltiazem 240mg with propranolol 160mg decreased heart rate in patients with stable angina and normal or near-normal left ventricular function similar to the combination of verapamil 360mg daily with the same dose of propranolol, but the diltiazem/propranolol combination induced a lesser negative inotropic effect. In open studies and controlled efficacy evaluations, diltiazem 240 to 360mg daily demonstrated significant effectiveness in the treatment of variant angina as assessed by decreases in anginal frequency and glyceryl trinitrate use, and decreases in the number of cardiovascular ‘events’ (arrhythmias, acute myocardial infarction, sudden death, hospitalisation to ‘rule out’ myocardial infarction). The efficacy of diltiazem in variant angina was approximately equal to that of nifedipine or verapamil; however, fewer patients receiving a mean dose of diltiazem 240mg daily sustained side effects due to treatment compared with those taking nifedipine (mean dose 68mg daily) or verapamil (mean dose 419mg daily). Diltiazem 360mg daily was superior to propranolol (mean dose 225mg daily) in the treatment of patients with coronary artery spasm as assessed by 24-hour electrocardiographic monitoring and ergonovine provocation. The combination of these 2 drugs was not superior in efficacy to either agent used alone. The long term (16 month) response to diltiazem in patients with variant angina was similar to that during short term double-blind administration; thus, the short term clinical response obtained with diltiazem may be predictive of its long term efficacy in this disease. An open study in a small (n = 12) group of patients with unstable angina has shown diltiazem 120 to 360mg to have significant effectiveness in suppressing ischaemia when used alone or in combination with long acting nitrates. Comparative studies in patients with unstable angina have shown diltiazem to be similar in efficacy to bepridil, but also somewhat more prone to induce side effects. Diltiazem appeared to be more effective than propranolol in the treatment of unstable angina when coronary artery spasm was predominant, whereas propranolol appeared to be of equal or greater effectiveness in patients with anginal pain unaccompanied by ST segment elevation. In open studies in patients with mild to moderate essential hypertension, diltiazem 90 to 180mg daily for 1 to 6 months decreased systolic and diastolic blood pressures 11 to 14% and 12 to 17%, respectively. Decreases in systolic and diastolic blood pressure within the same ranges have been noted with diltiazem 180mg daily in similar groups of patients treated in placebo-controlled studies. In short term studies, diltiazem and nifedipine were similar in antihypertensive effectiveness, but nifedipine caused a greater reduction in pulmonary vascular resistance. The antihypertensive effect of diltiazem 180mg daily was somewhat less potent than that of propranolol 60mg daily, but blood pressure at rest or during exercise was decreased with lesser negative chronotropic and negative inotropic effects. Intravenous diltiazem (0.1 to 0.25 mg/kg) has been highly effective in the acute control of paroxysmal supraventricular tachycardia, with the most common response to treatment being conversion of the abnormality to sinus rhythm (usually within 1 to 2 minutes). Patients who do not respond with conversion almost always have a slowing of the ventricular response to the arrhythmia. The efficacy of diltiazem in paroxysmal supraventricular tachycardia is similar to that of verapamil and, like the latter agent, it appears to block the arrhythmia usually by decreasing anterograde conduction in the atrioventricular node. Orally administered diltiazem may be effective in the prevention of paroxysmal supraventricular tachycardia, and the acute response to intravenous diltiazem may be predictive of its efficacy in the long term prophylaxis of this arrhythmia. In patients with atrial fibrillation, diltiazem (0.1 to 0.3 mg/kg) usually inhibits atrioventricular conduction and decreases the ventricular response to this arrhythmia, although it may also ‘regularise’ the ventricular response or rarely convert the arrhythmia to sinus rhythm. Diltiazem has increased the ventricular response to paroxysmal atrial fibrillation associated with Wolff-Parkinson-White syndrome, and its use should probably be avoided in patients with this disease. Orally administered diltiazem (up to 480mg daily) alone or in combination with quinidine did not reliably convert the cardiac rhythm of patients with chronic atrial fibrillation to sinus rhythm, but did decrease the ventricular response to this arrhythmia. Similar to its effect in atrial fibrillation, diltiazem 0.15 to 0.30 mg/kg administered to patients with atrial flutter most frequently resulted in an increased atrioventricular block and a decrease in ventricular response. The data currently available suggests that diltiazem has little or no potential for widespread use in the treatment of ventricular arrhythmias. Although further study is required before conclusions regarding continued efficacy and safety may be reached, diltiazem has shown promising beneficial effects in vascular and non-vascular smooth muscle diseases including Raynaud’s phenomenon, migraine, and oesophageal motility disorders. Side Effects: The major, and potentially the most serious, side effects associated with diltiazem use occur secondary to 2 of its major actions: vasodilatation (resulting in headache or flushing, and occasional hypotension) and depression of atrioventricular nodal conduction (which may result in a sinus bradycardia or various degrees of atrioventricular block, especially in combination with other agents which also delay atrioventricular conduction). However, the total incidence of side effects with diltiazem is relatively infrequent (ranging from about 2 to 10% of patients, depending upon dosage). Abrupt withdrawal of diltiazem treatment in patients with stable angina has usually not been associated with a ‘rebound’ effect on anginal symptoms. Drug Interactions: Diltiazem may elevate plasma concentrations of digoxin 20 to 60% when these agents are coadministered orally. The mechanism of this interaction is as yet unclear. Diltiazem does not affect digoxin bioavailability, but it has been shown to decrease the renal clearance of digoxin in some studies. The pharmacokinetics of digitoxin do not appear to be affected by diltiazem. Strongly acidic drugs do not seem to interfere with the plasma protein binding of diltiazem, but diltiazem (150 and 300 µg/L) was capable of displacing propranolol from some plasma protein binding sites, thus elevating ‘free’ fractions of propranolol. The single-dose administration of diltiazem 120mg did not displace warfarin from its plasma protein binding sites. Dosage and Administration: In stable angina or angina due to coronary artery spasm, treatment with diltiazem is usually initiated with 30 to 60mg given 3 or 4 times daily, increasing to 120mg 3 times daily if needed; dosage may be titrated at 1- to 2-day intervals until the desired therapeutic response is obtained. The recommended maximum daily dose of diltiazem varies among countries, the highest being 480mg daily. Sublingual glyceryl trinitrate may be administered with diltiazem as needed for additional anginal relief. The coadministration of diltiazem and long acting nitrates appears safe, but the efficacy of this combination has not yet been thoroughly studied. Caution should be exercised when diltiazem is coadministered with digitalis glycosides and/or a β-adrenoceptor blocking agent, as these drugs may have additive depressant effects on the atrioventricular node, and drug interactions are a potential occurrence. Insufficient...