Amlodipine

Summary

Synopsis

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 thai should be advantageous in many patients

Pharmacodynamic Properties

Amlodipine, like other calcium entry blockers, inhibits the ‘slow’ channel influx of calcium into cardiac and vascular tissue. Its main site of action is the peripheral vasculature, although it also produces vasodilation in coronary vascular beds. Indeed, in patients with essential hypertension, intra-arterial infusions of amlodipine markedly increase forearm blood flow and reduce forearm vascular resistance, effects indicative of a peripheral arterial vasodilatory action. In vitro, amlodipine has been shown to inhibit potassium-induced contractions in human coronary artery preparations and, in several animal models, has dramatically increased coronary blood flow and reduced coronary vascular resistance. In humans, amlodipine has no significant effects on the sinoatrial or atrioventricular node

In patients with mild to moderate essential hypertension amlodipine has a sustained and gradual onset of antihypertensive effect. Medium term once-daily dosage regimens of 2.5 to 10mg produce reductions in mean systolic and diastolic blood pressures of about 10 to 18% in most studies. Moreover, in these patients amlodipine increases renal blood flow and glomerular filtration rate, and reduces renovascular resistance; plasma renin activity and aldosterone and cate-cholamine levels are not significantly affected. In addition, urine volume and urinary sodium excretion are unchanged, factors which suggest that amlodipine has no long term effect on sodium homeostasis

In animal models and in vitro studies using human cardiac tissue, high concentrations of amlodipine, which exceed clinically effective concentration ranges, have a weak negative inotropic effect. However, after short term administration to patients with coronary artery disease no significant cardiodepression occurs

As well as markedly reducing peripheral vascular resistance, and therefore afterload, amlodipine increases cardiac output and reduces stroke work. In addition to its ability to reduce afterload, amlodipine increases myocardial oxygen supply, reduces demand and improves exercise capacity in patients with symptomatic myocardial ischaemia

Animal studies have demonstrated a cardioprotective effect for amlodipine — in both in vivo and in vitro models of ischaemia-reperfusion; reductions in tissue calcium content and increases in shortening fraction have been noted after reperfusion

Amlodipine has demonstrated several other actions which warrant further study. These include antiatherosclerotic, antithrombotic and antihypertrophic actions. Indeed, amlodipine inhibits in vitro collagen synthesis in aortic strips from spontaneously hypertensive rats (SHRs), which may indicate antiatherosclerotic potential. It also stimulates LDL receptor binding in human fibroblasts in vitro, an effect which, if produced in vivo, may retard atherogenesis through intracellular accumulation of LDL and a reduced accumulation of cholesterol in arterial walls. With reference to an antithrombotic action, amlodipine has been shown to reduce platelet aggregation in patients with essential hypertension and, in terms of antihypertrophic effects, regression of myocardial hypertrophy has been noted in SHRs

Pharmacokinetic Properties

After oral administration amlodipine is slowly and almost completely absorbed; peak plasma concentrations are attained within 6 to 12 hours. Amlodipine has a relatively high oral bioavailability of 60 to 65%, which is not influenced by food. Moreover, amlodipine appears to have a linear pharmacokinetic profile, with strong positive correlations between oral dosage, and C_max and AUC_0–72. In healthy volunteers, steady-state plasma concentrations are achieved after 7 once-daily oral doses, without evidence of accumulation. Amlodipine has a large volume of distribution of 21 L/kg, and is more than 95% bound to plasma proteins

Unlike verapamil, diltiazem and nifedipine, amlodipine does not undergo extensive and variable presystemic metabolism, although it is extensively and slowly metabolised by the liver. The initial biotransformation is oxidation of the dihydropyridine ring to produce the pyridine analogue, usually followed by oxidative deamination of the basic 2-aminoethoxymethyl side chain. In fact, this metabolic pathway leads to the production of more than 75% of the urinary metabolites of amlodipine, none of which are conjugated. None of the amlodipine metabolites have significant pharmacological activity

In comparison with other calcium entry blockers amlodipine has a relatively long elimination half-life of 35 to 45 hours, which permits once-daily administration. Less than 10% of an orally administered dose of amlodipine is excreted unchanged; 60% of a dose is recovered in the urine and 20 to 25% in the faeces after either oral or intravenous administration. The latter indicates that amlodipine and its metabolites are excreted in the bile and/or across the gut wall

In patients with hepatic cirrhosis, and in the elderly, amlodipine elimination is significantly reduced and some degree of accumulation is noted; elimination half-life is prolonged and AUC is increased. Although in the elderly this may simply be a reflection of large intersubject variability, relevant dosage adjustments should be made in both patient groups. The pharmacokinetic profile of amlodipine does not appear to be significantly altered in patients with renal impairment

Therapeutic Efficacy

In patients with chronic stable angina pectoris amlodipine improves both subjective symptoms [i.e. nitroglycerin (glyceryl trinitrate) consumption and angina attack frequency] and objective symptoms (ST segment deviation, exercise duration and time to angina onset). A few small well designed comparative trials have shown the antianginal efficacy of amlodipine to be similar to that of diltiazem and nadolol, but its relative efficacy needs confirmation in larger comparative studies. Amlodipine also improves subjective symptoms in patients with vasospastic angina

Several short to medium term trials have shown amlodipine, in oral regimens of 2.5, 5 and 10mg once daily, to significantly reduce supine and standing systolic and diastolic blood pressures in a dose-dependent manner in patients with essential hypertension. Amlodipine 5 to 10mg once daily also significantly reduces mean ambulatory blood pressure throughout a 24-hour dose interval in hypertensive patients. These antihypertensive effects are achieved without accompanying reflex tachycardia or postural hypotension. In a few small but well designed medium term comparative trials the antihypertensive efficacy of amlodipine was slightly better than that of verapamil and similar to that of hydrochlorothiazide, captopril and atenolol. However, as is the case in angina pectoris, amlodipine’s relative efficacy in hypertension needs to be further assessed in larger comparative studies

Tolerability

Amlodipine is generally well tolerated during short term therapy (i.e. ⩽ 6 months) in patients with essential hypertension or angina pectoris. Pooled results from 40 double-blind placebo-controlled trials show that 529/1775 (29.8%) amlodipine vs 268/1213 (22.1%) placebo recipients experienced adverse effects; 1.1 vs 0.7% of patients withdrew from treatment. The main amlodipine-induced side effects (oedema and flushing) occur as a result of vasodilation and are thought to be dose-dependent. However, amlodipine-induced oedema is usually mild or moderate in severity and is rarely troublesome to patients. Again on the basis of pooled data from 40 studies, 9.8% of amlodipine vs 2.3% of placebo recipients had oedema, which was considered definitely related to treatment in 4.3 vs 0.4% of patients

Other adverse effects reported occasionally and considered to be possibly related to amlodipine therapy include muscle cramps, frequency of micturition/nocturia, coughing, impotence, asthma, epistaxis, nervousness and conjunctivitis. However, these reactions are infrequent and few have been severe enough to warrant stopping treatment

Comparative trials suggest that amlodipine is at least as well tolerated as atenolol, nadolol, verapamil, diltiazem and hydrochlorothiazide. However, pharmacodynamic data suggest that amlodipine may have a more favourable adverse effect profile than /5-blockers, thiazide diuretics and possibly some other calcium antagonists — for example, it does not appear to impair cardiac function or to cause postural hypotension, and reflex tachycardia occurs in only a small proportion of patients

Dosage and Administration

In patients with essential hypertension or angina pectoris, amlodipine should be initiated at a dosage of 5mg once daily orally and increased to 10mg once daily, if the desired therapeutic response has not been achieved after 2 weeks