A 6-week double-blind comparison of amlodipine and placebo in patients with stable exertional angina pectoris receiving concomitant beta-blocker therapy

This study was a multicenter, double-blind comparison of the antianginal efficacy and safety of amlodipine and placebo as adjunctive therapy with constant recommended maintenance doses of beta-blockers. Patients with stable exertional angina pectoris were randomized to placebo or amlodipine at a starting dose of 5 mg once daily. The amlodipine dose was adjusted to 10 mg daily after 2 weeks if angina attacks were not abolished. Antianginal efficacy was assessed throughout the study with angina diaries, investigators' and patients' global evaluations, and with bicycle exercise tests during a placebo run-in period (baseline) and after 2 and 6 weeks of double-blind treatment. On baseline-final analysis, the exercise time to angina onset increased by 13% with amlodipine compared to 6% with placebo (p < 0.05). The total exercise time increased by 11% on amlodipine compared with 2% on placebo, though this difference did not reach statistical significance. Angina attack frequency and nitroglycerin consumption were both reduced by adding amlodipine to beta-blocker treatment. Amlodipine in combination with beta-blocker therapy was well tolerated, with a low incidence of side effects and laboratory test abnormalities. The study showed clearly that addition of amlodipine to beta-blocker therapy in patients with stable angina pectoris was well tolerated and gave improved antianginal efficacy.     

Open comparative study to assess the efficacy and safety of two calcium antagonists: amlodipine and diltiazem in the treatment of symptomatic myocardial ischemia

The efficacy and safety of amlodipine (5-10 mg once daily) and diltiazem (30-60 mg three times daily) were compared in 40 patients with symptomatic myocardial ischemia. A 2-week placebo run-in period was followed by 10 weeks of open treatment with amlodipine (n = 20) or diltiazem (n = 20). Concomitant treatment with other antianginal drugs (except other calcium antagonists) was permitted throughout the study. The baseline blood pressures were 166/93 and 160/91 mm Hg for the amlodipine group and diltiazem groups, respectively. Amlodipine (mean final daily dose of 9.25 mg) reduced blood pressure by - 27/-11 mm Hg compared with a reduction of - 17/-8 mm Hg for diltiazem (mean final daily dose of 180 mg), with no significant effects on heart rate. A significantly greater reduction in the mean rate-pressure product was observed after amlodipine (-20.8%) when compared with diltiazem (-13.1%) (p < 0.05). Amlodipine reduced the mean weekly angina attacks to zero after 6 weeks of treatment (baseline of 3.4 attacks/week) compared with a reduction from 3.3 to 0.35 attacks/week after 10 weeks of treatment with diltiazem. The amlodipine group had a reduction in mean nitroglycerin consumption from baseline of 1.1 mg/week to zero by week 6, whereas the diltiazem group had reduced mean weekly intake from 0.9 to 0.1 mg at the end of the study. The overall assessment of clinical efficacy was excellent for 100% of amlodipine patients compared with 40% of diltiazem patients. The high-density lipoprotein cholesterol/total cholesterol ratio increased by 15.8% with amlodipine compared to diltiazem, which produced a 4.5% decrease. Amlodipine decreased triglycerides by 7.1% compared to 4.5% with diltiazem. The incidence and severity of side effects was comparable for both treatments. Amlodipine once daily was effective and well tolerated in the treatment of patients with symptomatic myocardial ischemia and was comparable with diltiazem three times daily.     

Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial

BACKGROUND AND OBJECTIVE: Current medical therapies for the symptoms of angina pectoris aim to improve oxygen supply and reduce oxygen demand in the myocardium. Not all patients respond to current antianginal monotherapy, or even combination therapy, and a new class of antianginal drug that complements existing therapies would be useful. This study was undertaken to compare the antianginal and anti-ischaemic effects of the novel heart-rate-lowering agent ivabradine and of the calcium channel antagonist amlodipine. PATIENTS AND METHODS: Patients with a >/=3-month history of chronic, stable effort-induced angina were randomised to receive ivabradine 7.5mg (n = 400) or 10mg (n = 391) twice daily or amlodipine 10mg once daily (n = 404) for a 3-month, double-blind period. Bicycle exercise tolerance tests were performed at baseline and monthly intervals. The primary efficacy criterion was the change from baseline in total exercise duration after 3 months of treatment. Secondary efficacy criteria included changes in time to angina onset and time to 1mm ST-segment depression, rate-pressure product at trough drug activity, as well as short-acting nitrate use and anginal attack frequency (as recorded in patient diaries). RESULTS: At 3 months, total exercise duration was improved by 27.6 +/- 91.7, 21.7 +/- 94.5 and 31.2 +/- 92.0 seconds with ivabradine 7.5 and 10mg and amlodipine, respectively, both ivabradine groups were comparable to amlodipine (p-value for noninferiority < 0.001). Similar results were observed for time to angina onset and time to 1mm ST-segment depression. Heart rate decreased significantly by 11-13 beats/min at rest and by 12-15 beats/min at peak of exercise with ivabradine but not amlodipine, and rate-pressure product decreased more with ivabradine than amlodipine (p-value vs amlodipine <0.001, at rest and at peak of exercise). Anginal attack frequency and short-acting nitrate use decreased substantially in all treatment groups with no significant difference between treatment groups. The most frequent adverse events were visual symptoms and sinus bradycardia with ivabradine (0.8% and 0.4% withdrawals, respectively) and peripheral oedema with amlodipine (1.5% withdrawals). CONCLUSIONS: In patients with stable angina, ivabradine has comparable efficacy to amlodipine in improving exercise tolerance, a superior effect on the reduction of rate-pressure product (a surrogate marker of myocardial oxygen consumption) and similar safety.     

Bepridil. A review of its pharmacological properties and therapeutic use in stable angina pectoris.

Bepridil is a calcium antagonist with direct negative chronotropic, dromotropic, inotropic and vasodilatory actions which reduces myocardial oxygen consumption and increases coronary blood flow, leading to a significant anti-ischaemic and antianginal effect in the absence of reflex tachycardia. In contrast to other calcium channel blockers, bepridil produces only modest peripheral vasodilatation and displays weak antihypertensive activity. Its plasma elimination half-life of 1 to 2 days permits once daily administration. Results of short term clinical trials have shown bepridil to be of comparable efficacy to nifedipine, verapamil, diltiazem, propranolol and nadolol in decreasing the frequency of anginal attacks and consumption of nitroglycerin (glyceryl trinitrate) in patients with stable angina. Bepridil is more effective than nifedipine in improving exercise performance in patients with stable angina. Although bepridil proved superior to diltiazem in improving exercise performance in patients refractory to diltiazem, further studies are required to confirm the efficacy of bepridil in patients refractory to, or intolerant of, other antianginal agents. Bepridil in therapeutic doses is well tolerated, and appears to have a similar adverse effect profile to the established calcium antagonists. However, rate-dependent prolongation of the QTc interval and development of torsade de pointes have been associated with the use of bepridil. Therefore, bepridil is contraindicated in patients with hypokalaemia, those receiving other drugs that may prolong the QT interval, and those with congenital QT interval prolongation. Future clinical research will help to further define the position of bepridil as an antianginal treatment relative to the traditional calcium antagonists; in the interim, bepridil is indicated for the treatment of patients with angina refractory to or intolerant of other agents.     

Antianginal Response to Once-Daily Diltiazem CD in Patients Receiving Concomitant β-Blockers,Long-Acting Nitrates,or Both

Study Objective . To determine the safety and efficacy of diltiazem CD 180 mg administered once/day in patients with chronic stable angina inadequately controlled with β-blockers, long-acting nitrates, or both. Design . Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Setting . Medical clinics in the private and academic sectors. Patients . Of 172 patients, 170 completed the 2-week double-blind treatment period. Interventions . Patients received either diltiazem CD 180 mg or placebo once/day in combination with existing antianginal therapy. Measurements and Main Results . The time to termination of exercise tolerance testing, 24 hours after the dose increased significantly in the diltiazem CD group (37.2 sec) compared with the placebo group (21.3 sec, p=0.0438). Time to onset of angina during exercise testing also increased (57.6 vs 35.0 sec, respectively, p=0.0324), as did time to moderate angina (37.5 vs 20.6 sec, respectively, p=0.0354). The rates of total angina attacks and of angina attacks on exertion were significantly reduced in the diltiazem CD group versus placebo (p<0.05). Significant reductions in systolic and diastolic blood pressures and heart rate-blood pressure product measured at rest, submaximum exercise, and exercise termination were observed in diltiazem CD-treated patients compared with placebo (p<0.05). The frequency of treatment-related adverse events was identical in the two groups, 15.1%. Conclusion . Diltiazem CD 180 mg once/day is an effective, safe, and beneficial initial dosage when added to existing antianginal therapy.     

Diltiazem. A review of its pharmacological properties and therapeutic efficacy

Diltiazem 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.     

Efficacy and Tolerability of Nisoldipine Coat-Core vs Diltiazem Retard in Combination with a Beta-Blocker in Patients with Stable Exertional Angina Pectoris

A randomised, double-blind, placebo-controlled, parallel-group trial with forced titration study to investigate possible equivalence of efficacy and tolerability between nisoldipine coat-core (CC) 40mg once daily, and diltiazem retard 120mg twice daily, was carried out in 176 patients with stable angina pectoris who were already receiving beta-blocker therapy. A total of 164 patients were included in the tolerability analysis and 135 patients were evaluable for efficacy (nisoldipine CC, n = 69; diltiazem retard, n = 66). During bicycle exercise tolerance tests, time to 1mm ST-segment depression, total exercise time, and time to angina were assessed at baseline and at the end of the treatment period. The number of angina attacks and of consumed nitroglycerin tablets were recorded in weekly diaries. Time to onset of 1mm ST-segment depression increased by 69.4 +/- 100.0 seconds with nisoldipine CC and by 65.9 +/- 87.6 seconds with diltiazem retard. The two treatment regimens were equally effective in time to onset of 1mm ST-segment depression, time to angina pectoris, and in exercise duration. A beneficial effect on angina attacks and nitroglycerin consumption was achieved with both treatments. Patient compliance, as assessed by the number of returned tablets, was high, at over 80%. Six patients withdrew from the treatment because of adverse events. Mild and transient adverse events were reported by 24 patients during treatment. One patient experienced a severe circulatory shock on the combination of diltiazem retard and atenolol. Peripheral oedema and headache were more common on nisoldipine CC. We concluded that the two treatments were equally efficacious and tolerated in patients with stable angina pectoris.     

An open multicenter efficacy and safety evaluation of amlodipine in the treatment of symptomatic myocardial ischemia

The efficacy and safety of amlodipine (5-10 mg) once daily were studied in an open study in patients with symptomatic myocardial ischemia. The study is ongoing and this report is based on an interim analysis of data from 78 patients. A 2-week baseline period in which patients maintained their current antianginal therapy was followed by a 10-week treatment period with 5-10 mg of amlodipine/day. Both the median number of angina attacks per week and the median number of nitroglycerin (NTG) tablets consumed/week were significantly reduced after amlodipine (mean daily dose of 8.6 mg) when compared with baseline (p < 0.05). A total of 98.4% of patients (63/64) experienced a reduction in the frequency of angina attacks/week and 91% of patients (58/64) had angina attacks reduced to < or = 2/week. In self-assessments, 95% of patients (55/58) reported improved angina control and 91% (53/58) felt their ability to perform usual activities had improved. Twenty-seven patients experienced adverse events reported as drug related. The most common adverse event noted was edema. Amlodipine once daily significantly reduced the incidence of angina attacks and the concomitant need of nitroglycerin for relief of symptoms and thus improved the patients' ability to perform daily activities. Most adverse events reported were mild or moderate and the incidence is as would be expected in this patient population.     

Combination of calcium channel blockers and β-adrenoceptor blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers

AIMS: The combination of calcium channel blockers and beta-adrenoceptor blockers is more effective for the treatment of exercise-induced angina pectoris than beta-adrenoceptor blocker monotherapy. As ischaemia in exercise-induced angina is preceded by increase in heart rate, calcium channel blockers with negative chronotropic properties may perform better for this purpose than nonchronotropic compounds. METHODS: A 335 patient double-blind parallel-group study comparing 14 day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and mibefradil 50 and 100 mg added to baseline beta-adrenoceptor blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. RESULTS: Although none of the calcium channel blockers improved duration of exercise or amount of workload, all significantly delayed onset of 1 mm ST-segment depression on ETT (P<0.001 for any treatment vs baseline). In addition, mibefradil, both low and high dose treatment, produced the longest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively, P<0. 003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly correlated with the reduction in rate pressure product (RPP). Serious symptoms of dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19 patients on mibefradil withdrew from trial. CONCLUSIONS: Calcium channel blockers with negative chronotropic properties provide greater delay of ischaemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness attenuates this benefit.     

A randomized, double-blind comparison of the efficacy and tolerability of once-daily modified-release diltiazem capsules with once-daily amlodipine tablets in patients with stable angina

A randomized, double-blind, parallel-group study comparing the efficacy and tolerability of once-daily diltiazem capsules with amlodipine tablets in patients with stable angina. After a run-in period of 1 to 3 weeks, 34 patients received once-daily diltiazem and 33 patients received amlodipine. Patients received either diltiazem, 240 mg/day, or amlodipine, 5 mg/day, for 2 weeks followed by diltiazem, 360 mg/day, or amlodipine, 10 mg/day, for 2 weeks. Standard treadmill exercise testing was the primary efficacy assessment. Patients also recorded incidence of angina attacks and use of glyceryl trinitrate spray. Both treatments gave significant improvement in time to onset of angina and time to maximal exercise. With the exception of amlodipine, 5 mg/day, both treatments gave significant increases in time to 1-mm ST segment depression. Diltiazem, 360 mg/day, gave a significant decrease in rate pressure product. There were no significant treatment differences in any of the exercise test parameters. Both treatments reduced incidence of angina attacks and use of glyceryl trinitrate spray. The incidence of edema was significantly less in patients receiving diltiazem. In conclusion, both treatments were effective in controlling patients' angina, but diltiazem was better tolerated, with a lower incidence of edema.     

Comparison of the antianginal efficacy of four calcium antagonists and propranolol in stable angina pectoris

Summary The antianginal effects of propranolol 160 mg/day, diltiazem 240 mg/day, nicardipine 80 mg/day, nifedipine 40 to 80 mg/day and verapamil 320 mg/day were compared in 12 patients with chronic stable angina pectoris using a symptom-limited exercise test.Compared to placebo propranolol and calcium antagonists similarly reduced (p<0.001) the frequency of antianginal attacks and nitroglycerin consumption, and increased exercise tolerance and time to 1 mm S-T segment depression. After propranolol the pressure-rate product at submaximal and maximal exercise was significantly decreased. The calcium antagonists produced a significant reduction in the submaximal pressure-rate product, but no significant change in the peak pressure-rate product. Maximum ST depression was significantly lower after propranolol and was unchanged after the calcium antagonists. None of the drugs caused significant adverse effects.The results indicate that in patients with stable effort angina pectoris, diltiazem, nicardipine, nifedipine and verapamil were as effective as propranolol in improving exercise tolerance and time to ischaemia, and they did not alter the peak pressurerate product. Different antianginal mechanisms may be operative for the various calcium antagonists.     

In Process Citation

This double-blind dose-response crossover study was designed to compare the efficacy and tolerability of sustained-release (SR) and conventional diltiazem over 4 weeks in patients with stable angina pectoris. Following a 2-week placebo run-in period, 26 patients were randomised into 3 parallel groups to receive either diltiazem SR (180, 240 or 300mg once daily) or conventional diltiazem 60mg three times daily for 2 weeks. Treatments were then crossed over for a further 2-week study period. Antianginal efficacy was evaluated using submaximal treadmill exercise testing. At baseline, all 3 treatment groups were comparable for all parameters. Treatment with both conventional and SR formulations improved exercise time and reduced intensity of ischaemia, but the difference between groups at the end of each 2-week treatment phase was not statistically significant. The results did not suggest a dose-response relationship. Adverse reactions necessitated treatment discontinuation in two patients being treated with conventional diltiazem and in one patient receiving diltiazem SR 240mg. In conclusion, this study demonstrated that diltiazem SR 180, 240 and 300mg did not differ from the conventional formulation in terms of anti-ischaemic efficacy.     

Amlodipine in patients with angina uncontrolled by atenolol

Summary Dihydropyridine calcium antagonists are established second line treatment for angina uncontrolled by -adrenergic blockers. Amlodipine is a recently introduced, dihydropyridine with a long half life. In a double blind, placebo controlled, cross over trial we assessed the efficacy and safety of amlodipine in 20 patients with persistent angina despite treatment with atenolol. 17 male patients (mean age 58 y) completed the study. Two patients were withdrawn during placebo because of worsening angina and one withdrew whilst on amlodipine because of palpitations.Compared with baseline, amlodipine prolonged exercise time to S-T segment depression by a median of 12.5%; significantly more than was found with placebo (median 0%). The improvement in exercise time and time to angina also tended to be greater for amlodipine than placebo. GTN consumption, at a median of 1.3/week, was significantly less with amlodipine than placebo (2.8). Attacks of angina were also reduced.Standing systolic and diastolic blood pressures and sitting systolic blood pressure were lower with amlodipine than placebo. Heart rate did not change. There was no change in cardiac output (measured by doppler aortovelography) when amlodipine was added to atenolol. Holter monitor measurements of 24 h maximum and minimum heart rate, heart rate variation and extrasystole counts were the same for amlodipine and placebo.In conclusion, amlodipine is effective in patients with angina inadequately controlled by atenolol alone, and does not interfer with cardiac rhythm or function.     

地尔硫缓释片治疗稳定性心绞痛的临床疗效

目的 :观察地尔硫缓释片治疗稳定性心绞痛的疗效和安全性。方法 :72例稳定性心绞痛病人随机分为 2组 ,地尔硫组 37例 ,男性 2 0例 ,女性 17例 ,年龄 5 6a±s13a ,病程 6a± 4a ,给予地尔硫缓释片 90mg ,po ,qd ;氨氯地平组 35例 ,男性19例 ,女性 16例 ,年龄 5 5a± 13a ,病程 6a± 4a ,给予氨氯地平 5mg ,poqd。 2组服药 2wk后如不能控制心绞痛发作可剂量加倍 ,疗程均 6wk。结果 :对心绞痛症状的疗效地尔硫组显效 5 1% ,有效4 1% ,无效 8% ,总有效率 92 % ;氨氯地平组显效5 1% ,有效 4 0 % ,无效 9% ,总有效率 91% (P >0 .0 5 )。对心电图的疗效地尔硫组显效 2 7% ,改善 2 4 % ,无改变 4 9% ,总有效率 5 1% ;氨氯地平组显效 2 6% ,改善 2 6% ,无改变 4 8% ,总有效率5 2 % (P >0 .0 5 )。未发生严重不良反应。结论 :地尔硫缓释片治疗稳定性心绞痛是安全、有效的。     

Combination of calcium channel blockers and beta-blockers for patients with exercise-induced angina pectoris: beneficial effect of calcium channel blockers largely determined by their effect on heart rate.

The combination of calcium channel blockers and beta-blockers is more effective for the treatment of exercise-induced angina pectoris than beta-blocker monotherapy. As ischemia in exercise-induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with a negative chronotropic property may perform better for this purpose than nonchronotropic compounds. A 335-patient, 10-week, double-blind, parallel-group comparison of amlodipine 5 mg and 10 mg, diltiazem 200 mg and 300 mg, and mibefradil 50 mg and 100 mg treatment added to baseline beta-blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. All of the calcium channels blockers significantly delayed the onset of 1 mm ST-segment depression on ETT (p < 0.001 for any treatment vs. baseline). In addition, mibefradil, in both low- and high-dose treatments, produced the largest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 seconds, respectively, p < 0.003 and < 0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 seconds, respectively, p < 0.001 and < 0.001). A stepwise logistic regression analysis revealed that this beneficial effect of calcium channel blockers was largely dependent on their effect on heart rate. Serious symptoms of dizziness likewise occurred significantly more frequently on mibefradil (p < 0.05 vs. diltiazem) and urged no fewer than 19 patients on mibefradil to withdraw from the trial. The authors conclude that calcium channel blockers with a negative chronotropic property provide a better delay of ischemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness may reduce this benefit.     

Ranolazine in the management of chronic stable angina.

PURPOSE: A review of the pharmacology, pharmacokinetics, clinical trials, safety, and efficacy of ranolazine is presented. SUMMARY: Ranolazine has recently been approved as adjunctive treatment for chronic stable angina (CSA). Data suggest that ranolazine exerts its antiischemic effect through antagonism of the late sodium current and other cardiac ion channels. Peak plasma levels of ranolazine have been observed two to five hours following repeated dosing and are unaffected by food. In placebo-controlled and active-controlled clinical trials conducted with ranolazine, ranolazine has been effective in the treatment of patients with CSA. One trial demonstrated that monotherapy with extended-release ranolazine was effective against angina and ischemia in patients with CSA. Ranolazine improved exercise duration and time to onset of angina. In a trial in which ranolazine was given in combination with atenolol, diltiazem, or amlodipine, ranolazine produced clinically significant improvement in exercise duration and reduced the incidence of anginal attacks compared with placebo. Another trial demonstrated that extended-release ranolazine 1000 mg given twice daily reduced mean weekly angina episodes in patients with chronic angina. Ranolazine is generally well tolerated. In clinical trials, adverse effects were seen more in the ranolazine groups than in the placebo groups. CONCLUSION: Despite a lack of mortality data, ranolazine has demonstrated its efficacy and safety, either as monotherapy or in combination with other antianginal agents, in the management of CSA. Patients who fail optimal therapy with standard-of-care antianginal agents are the best candidates for treatment with ranolazine.     

Calcium Channel blockers: Spectrum of Side Effects and Drug Interactions

Abstract: Calcium antagonists are a chemically heterogenous group of agents with potent cardiovascular effects which are beneficial in the treatment of angina pectoris, arterial hypertension and cardiac arrhythmias. The main side effects for the group are dose-dependent and the result of the main action or actions of the calcium antagonists, i.e. vasodilatation, negative inotropic effects and antiarrhythmic effects. Pronounced hypotension is reported for the main calcium antagonist drugs; verapamil, diltiazem and nifedipine. While conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, tachycardia, headache and flush are more frequent after nifedipine. Constipation is relatively frequent after verapamil while nifedipine is reported to induce diarrhea in som patients. Idiosyncratic side effects are rare but have been reported from the skin, mouth, musculoskeletal system, the liver and the central nervous system. These side effects include urticarial rashes, gingival hyperplasia, arthralgia, hepathotoxicity and transistory mental confusion or akathisia. Verapamil, diltiazem and possibly also nifedipine have been reported to increase serum digoxin concentrations but the clinical relevance of these drug interactions are not clear. Furthermore, verapamil and diltiazem may potentiate the effects of β-adrenergic blocking drugs and verapamil may also potentiate the effects of neuromuscular blocking drugs. It is concluded that side effects after calcium antagonist drugs are mostly trivial and transient although they may sometimes be relatively common. Clinically relevant drug interactions are few. Judged from the point of efficacy and safety, calcium antagonists will have a major place in the future pharmacotherapy of several cardiovascular disorders.     

Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease.

Amlodipine, a basic dihydropyridine derivative, inhibits the calcium influx through 'slow' channels in peripheral vascular and coronary smooth muscle cells, thus producing marked vasodilation in peripheral and coronary vascular beds. Short to medium term clinical trials indicate that amlodipine is effective as both an antianginal agent in patients with stable angina pectoris and an antihypertensive agent in patients with mild to moderate hypertension. In small comparative studies amlodipine was at least as effective as 'standard' agents, including atenolol, verapamil, hydrochlorothiazide or captopril in hypertension, and diltiazem or nadolol in angina pectoris. Amlodipine is well tolerated, and does not appear to cause some of the undesirable effects often associated with other cardiovascular agents (e.g. adverse changes in serum lipid patterns, cardiac conduction disturbances, postural hypotension). The most common adverse effects associated with amlodipine therapy--oedema and flushing--are related to the vasodilatory action of the drug, and are generally mild to moderate in severity. Thus, amlodipine seems to provide a useful alternative to other agents currently available for the treatment of essential hypertension and chronic stable angina pectoris, with certain pharmacodynamic and tolerability properties that should be advantageous in many patients.     

A double-blind, placebo-controlled, parallel dose-response study of amlodipine in stable exertional angina pectoris

A placebo-controlled, double-blind, dose-response study of amlodipine (1.25, 2.5, 5, and 10 mg once daily) was carried out in 136 patients with stable exertional angina pectoris. Improvements in total exercise tolerance, time to onset of angina during exercise, ST-segment deviation at maximum common load, frequency of angina attacks, and nitroglycerin consumption were greater following amlodipine than placebo. The maximum improvement in exercise parameters occurred with the highest dose of amlodipine. All doses produced significant reductions in angina attack frequency and the rate of nitroglycerin consumption. Amlodipine was well tolerated and no patients were withdrawn due to adverse events or laboratory abnormalities.     

Telmisartan/Amlodipine

Telmisartan/amlodipine is a single-pill combination of telmisartan, an angiotensin II receptor antagonist, and amlodipine, a dihydropyridine calcium channel antagonist, which is taken orally once daily for the treatment of hypertension. In the US and the EU, single-pill telmisartan/amlodipine can be used as a replacement for separate telmisartan and amlodipine tablets, and by patients not achieving BP goals with amlodipine monotherapy. In addition, the US indication includes patients not achieving BP goals with telmisartan (or another angiotensin II receptor antagonist or calcium channel antagonist other than amlodipine) alone, and as initial therapy in patients considered likely to require multiple drugs to achieve their BP goals. In an 8-week, randomized, double-blind, factorial-design, placebo-controlled, multicenter study in adult patients with hypertension (n =1461), mean DBP was reduced from baseline to a significantly greater extent in recipients of telmisartan 40 or 80mg/day plus amlodipine 5 or 10mg/day than in those receiving equivalent dosages of telmisartan or amlodipine monotherapy. Single-pill telmisartan/amlodipine recipients had significantly greater reductions in BP than telmisartan or amlodipine monotherapy recipients in an 8-week, randomized, double-blind, multicenter study in adult patients with severe hypertension (n = 858), and in four 8-week, randomized, double-blind, multicenter trials in patients who had not responded to amlodipine (n = 1097, 947, and 531) or telmisartan (n = 314) monotherapy. Telmisartan/amlodipine was generally well tolerated in clinical trials, including two 36-week follow-up studies.