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Amlodipine

A Reappraisal of its Pharmacological Properties and Therapeutic Use in Cardiovascular Disease

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An Erratum to this article was published on 01 November 1995

Abstract

Synopsis

Amlodipine belongs to the dihydropyridine class of calcium channel blockers. Both short and long term studies indicate that amlodipine effectively lowers mild to moderately elevated blood pressure and relieves symptoms of angina pectoris. In comparative studies, its antihypertensive efficacy is similar to that of other established agents such as β-blockers, diuretics, ACE inhibitors and other calcium channel blockers (including the dihydropyridines); limited comparative data are, however, available in patients with angina pectoris. Amlodipine may offer potential in patients with congestive heart failure.

Vasodilator adverse events such as oedema, headaches, and flushing are commonly observed with amlodipine. The drug does not appear to cause postural hypotension, reflex tachycardia or cardiac conduction disturbances. Comparative studies suggest that amlodipine is at least as well tolerated as other standard agents.

Thus, amlodipine provides an attractive therapeutic option for the treatment of hypertension, and offers potential for patients with angina pectoris. Its beneficial effects in patients with congestive heart failure require confirmation in future studies.

Pharmacodynamic Properties

Amlodipine belongs to the dihydropyridine class of calcium channel blockers. Like other members of its class, amlodipine inhibits calcium influx into cardiac and vascular smooth muscle via L-type calcium channels. In patients with mild to moderate essential hypertension, the drug has a sustained and gradual onset of antihypertensive effects; observed reductions in mean systolic and diastolic blood pressures range from about 10 to 18% at dosages of 2.5 to 10 mg/day. These effects are achieved without accompanying postural hypotension. Amlodipine preserves circadian patterns of blood pressure changes and has favourable effects on cardiac output, systemic vascular resistance and left ventricular function, but has little effect on heart rate or cardiac conduction.

Amlodipine has demonstrated cardioprotective effects in animal studies. Reductions in atheroma formation and regression of myocardial hypertrophy have also been associated with amlodipine in animal models.

Preliminary data in humans show that amlodipine does not have deleterious effects on plasma lipids. Indeed, small reductions in plasma cholesterol, low density lipoprotein and triglyceride levels, and increases in high density lipoprotein levels have been observed in some individuals, but these were similar to those seen in placebo recipients. Statistically significant decreases in left ventricular mass have also been noted. Amlodipine has favourable effects on renal haemodynamics, and does not appear to adversely affect insulin sensitivity or circulating insulin or glucose levels. It has also shown antithrombotic potential.

Pharmacokinetic Properties

The pharmacokinetic properties of amlodipine have been investigated mainly in healthy volunteers. After oral administration, amlodipine is slowly absorbed; its relatively high oral bioavailability (≈64%) is unaffected by food. Peak plasma concentrations (Cmax) are observed 6 to 9 hours after oral administration. Amlodipine exhibits a linear pharmacokinetic profile, with strong positive correlations between oral dose and Cmax or area under the plasma concentration-time curve. Moreover, it has a large volume of distribution (21 L/kg) and is highly bound (>95%) to plasma proteins.

Amlodipine undergoes extensive but slow hepatic metabolism, with minimal first-pass or presystemic metabolism; none of its metabolites have clinically relevant pharmacological activity. Less than 10% of an orally administered dose is excreted unchanged; the remainder is recovered in urine (60%) and faeces (20 to 25%). Amlodipine is not dialysable. In contrast to other calcium channel blockers, amlodipine has a relatively long elimination half-life of 35 to 45 hours, which permits once daily administration.

Accumulation of amlodipine has been reported in patients with hepatic dysfunction and in the elderly. The disposition of amlodipine was not significantly altered in patients with renal insufficiency.

Therapeutic Use

Oral dosages of amlodipine 2.5 to 10 mg/day produce dose-proportional reductions in blood pressure (of about 10 to 20%) in patients with mild to moderate essential hypertension. In studies ranging from 6 weeks to 4 years, amlodipine appears to be as effective as β-blockers, other calcium channel blockers, ACE inhibitors and diuretics in lowering elevated blood pressure at therapeutic dosages. 61 to 91% of amlodipine-treated patients achieved blood pressure normalisation or showed marked improvement. Differences in efficacy were not observed between different racial groups (including Blacks, Whites, Asians or Hispanics) or between the young and the elderly. Concomitant therapy with agents such as β-blockers may further improve blood pressure control in patients unresponsive or only partially responsive to amlodipine monotherapy. Preliminary data suggest that amlodipine may be effective in hypertensive patients with concomitant renal dysfunction, diabetes mellitus or hyperlipidaemia.

In patients with chronic stable angina pectoris, amlodipine improves both subjective [anginal attack frequency and nitroglycerin (glyceryl trinitrate) use] and objective (exercise duration, time to angina onset, and ST-segment deviation) symptoms of ischaemia. Limited comparative data suggest that at therapeutic dosages the antianginal efficacy of amlodipine is generally similar to that of diltiazem, nadolol and nifedipine. Moreover, the drug may be beneficial in patients with vasospastic angina. However, these results require confirmation in larger patient groups.

Early findings indicate that amlodipine may offer potential in the treatment of patients with congestive heart failure or Raynaud’s phenomenon. Quality-of-life assessments suggest that amlodipine is unlikely to impair patients’ well-being.

Tolerability

In an analysis of 40 double-blind placebo-controlled studies, adverse events were reported by 30 and 22% of patients receiving amlodipine and placebo, respectively; treatment withdrawals were similar in both groups (1.1 vs 0.7%). Vasodilatory effects such as oedema, headaches, flushing and dizziness are commonly seen during amlodipine therapy; however, oedema is usually mild or moderate in severity and rarely requires treatment withdrawal. Oedema may occur more frequently in the elderly, but the overall incidence of adverse events and treatment withdrawals is otherwise comparable to that observed in younger patients. Clinically important abnormalities in laboratory tests have not been observed. In most comparative short term studies amlodipine was at least as well tolerated as other calcium channel blockers, β-blockers, ACE inhibitors and diuretics. Pooled postmarketing Prescription-Event Monitoring data from a total of 37 670 patients indicate that vasodilatory events occur more frequently with amlodipine, and other newer dihydropyridines, than with diltiazem.

Dosage and Administration

In patients with hypertension, stable angina pectoris or vasospastic angina, in the elderly and in patients with renal impairment, amlodipine should be initiated at oral dosages of 5mg once daily, and slowly titrated to a maximum of 10 mg/day, if required. Optimal antihypertensive efficacy at a given dosage may only be achieved after 6 to 8 weeks of therapy. Although dosage recommendations have not as yet been established for patients with hepatic dysfunction, these patients are likely to require reduced dosages.

Dosage adjustments are not required when amlodipine is given concurrently with thiazide diuretics, β-blockers or ACE inhibitors.

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    Malini Haria & Antona J. Wagstaff

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Various sections of the manuscript reviewed by: E.P. Cappuccio, Department of Public Health & Policy, Environmental Epidemiology Unit, London School of Hygiene & Tropical Medicine, University of London, London, England; H.L. Elliot, Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland; E. Faglia, Centra di Diabetologia, Ospedale Niguarda Ca’ Granda, Milan, Italy; F. Favales, Centra di Diabetologia, Ospedale Niguarda Ca’ Granda, Milan, Italy; R.M. Grimm Jr., Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota, USA; G. Lehmann, German Heart Centre, Department of Cardiology, Munich, Germany; P. Omvtk, Medical Department A, University of Bergen, Bergen, Norway; L.H. Opte, Heart Research Unit, University of Cape Town Medical School, Cape Town, South Africa; E.B. Raftery, Department of Cardiac Research, Northwick Park Hospital and Institute of Medical Research, Harrow, Middlesex, England; C.V.S. Ram, Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas, USA; T. Saruta, Department of Internal Medicine, School of Medicine Keio University, Tokyo, Japan.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259149.

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Haria, M., Wagstaff, A.J. Amlodipine. Drugs 50, 560–586 (1995). https://doi.org/10.2165/00003495-199550030-00009

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