Nicardipine

Summary

Synopsis

Nicardipine is a second generation dihydropyridine calcium antagonist which selectively inhibits vascular smooth muscle contraction.

In elderly patients, the drug Has demonstrated clinical efficacy in the management of hypertension, angina pectoris and ischaemia-related cerebrovascular disease. In particular, nicardipine effectively controls blood pressure in elderly hypertensive patients with or without coexistent disease. In noncomparative trials, a regimen containing nicardipine has been associated with an improvement of symptoms in hypertensive patients with concurrent coronary artery, cerebrovascular or peripheral vascular disease, while in essentially ‘healthy’ elderly hypertensive patients, nicardipine monotherapy has resulted in improved indices of mobility and cognitive function. As yet, however, there is no evidence that nicardipine (and/or other calcium channel antagonists) decreases cardiovascular morbidity and mortality in elderly patients, as has been demonstrated for more established antihypertensive therapies, namely diuretics and/or β-blockers.

The pharmacokinetic properties of nicardipine in elderly hypertensive patients appear to be similar to those in younger patients.

The main adverse events associated with nicardipine in the elderly are related to the vasodilator properties of the drug and include pedal oedema, headache and flushing. However, the drug does not exacerbate spontaneous postural hypotension in the elderly, nor does it adversely affect the coronary artery disease risk profile, even in patients with type II diabetes mellitus.

In summary, widespread clinical experience in the elderly indicates that nicardipine monotherapy or a regimen containing nicardipine is useful for the treatment of hypertension, particularly in patients with coexistent coronary artery, cerebrovascular or peripheral vascular disease. Nicardipine monotherapy has also demonstrated efficacy in angina pectoris and shown promise in the management of ischaemia-related cerebrovascular diseases, notably subarachnoid haemorrhage.

Pharmacology

Nicardipine is a potent arterial vasodilator which decreases systemic and peripheral vascular resistances, thereby lowering mean blood pressure in hypertensive subjects. Importantly, long term nicardipine therapy appears to regress the structural and/or functional change in peripheral arterial compliance observed in hypertensive patients, although it has yet to be established whether this effect is permanent. Nicardipine also decreases renovascular resistance and increases renal blood flow and glomerular filtration rate. Overall, therefore, the drug should produce a favourable pharmacodynamic effect in elderly normotensive and hypertensive patients, who are each character ised by an age-related increase in peripheral vascular resistance and decrease in arterial compliance, as well as a steady decline in glomerular filtration rate.

Due to a reduction in afterload, nicardipine improves indices of left ventricular filling function in patients with coronary artery disease, as well as ejection fraction and cardiac output in elderly hypertensive patients and patients with moderate to severe congestive heart failure.

The acute reflex increase in heart rate which accompanies nicardipine-induced peripheral vasodilation is small, probably reflecting an age-related decrease in baroreceptor sensitivity in the elderly. Moreover, the increase in heart rate is transient and resolves during continuous administration of the drug due to a resetting of baroreceptor sensitivity.

Intravenous administration of nicardipine decreases coronary and cerebral vascular resistances, thereby increasing the blood supply to ischaemic myocardial and cerebral tissue in patients with coronary artery and cerebrovascular disease, respectively.

Nicardipine does not adversely affect metabolic or hormonal parameters in patients with mild to moderate hypertension, including those with coexistent type II diabetes mellitus. Moreover, in this type of patient, short term antihypertensive therapy with nicardipine is associated with a reduction in urinary albumin excretion which is equivalent to that observed with a range of angiotensin converting enzyme (ACE) inhibitors.

The steady-state pharmacokinetics of nicardipine appear to be similar in young and elderly hypertensive patients, although plasma nicardipine concentrations were slightly elevated in the latter, probably reflecting a reduced first-pass effect. There was, however, no evidence of accumutation following chronic administration of a low therapeutic dosage of nicardipine (60 mg/day). Plasma concentrations of nicardipine are also elevated in patients with hepatic failure, and to a lesser extent, patients with renal failure.

Clinical Efficacy

In the elderly, nicardipine has primarily been investigated in the management of chronic mild to moderate (stage I–II) hypertension in patients with or without coexistent disease. The efficacy of nicardipine has also been evaluated in the management of perioperative hypertension, and ischaemia-related cardiovascular and cerebrovascular disease.

The antihypertensive efficacy of nicardipine does not appear to vary with age and the tendency for a slightly greater reduction of systolic blood pressure in older patients probably reflects higher pretreatment values in this age group.

Nicardipine monotherapy achieved satisfactory control of blood pressure in 63 to 76% of essentially ‘healthy’ elderly patients, compared with 13 to 55% of patients who received double-blind placebo treatment. In comparisons with other active treatments, the efficacy of nicardipine 60 to 100 mg/day was equivalent to that of nifedipine 40 mg/day, as well as enalapril 10 to 20 mg/day or captopril 37.5 to 150 mg/day, although nicardipine provided more sustained control of systolic blood pressure than captopril. Importantly, nicardipine did not adversely affect quality of life in these patients, rather the drug has been associated with improved physical mobility and mental cognition.

In large scale uncontrolled trials, a regimen containing nicardipine has proven effective in the management of hypertension in older patients with coexistent disease, including coronary heart disease, diabetes mellitus (types I and II), peripheral vascular disease, renal insufficiency, obstructive lung disease and ischaemia-related cerebrovascular disease. Notably, an improvement in symptoms was seen in patients with coronary artery, peripheral vascular and cerebrovascular diseases. Overall, the antihypertensive efficacy of nicardipine was similar in elderly patients with or without coexistent disease.

Intravenous nicardipine has also demonstrated effective perioperative control of blood pressure in older patients, including those undergoing cataract or coronary artery bypass surgery.

Administration of nicardipine at a dosage of 90 mg/day or greater to patients with coronary artery disease results in a significant improvement in the symptoms of stable angina pectoris compared with placebo. In individual comparative trials with other active treatments, nicardipine has demonstrated similar antianginal efficacy to nifedipine and propranolol, but was slightly less effective than verapamil. Therapy based on nicardipine significantly retards the development of coronary atherosclerotic plaques in patients with minimal lesions, although, in common with other calcium antagonists tested, the drug does not significantly affect the developmental time course of advanced lesions.

Initial reports from a large scale, well designed trial appear to confirm the preliminary observation that nicardipine monotherapy alleviates angiographic and symptomatic vasospasm subsequent to subarachnoid haemorrhage. Moreover, in both the outpatient setting and during non-blind multicentre trials, nicardipine alone or in association with concomitant medication has demonstrated efficacy in relieving neurological deficits associated with a wide range of chronic ischaemia-related cerebrovascular diseases.

Tolerability

Most of the commonly reported adverse events associated with nicardipine monotherapy in the elderly are related to the vasodilator properties of the drug and include headache, pedal/ankle oedema, flushing, palpitations and tachycardia; the latter 2 effects reflecting reflex activation of the sympathetic nervous system. Common to all antihypertensive agents, however, nicardipine has also been associated with episodes of dizziness and asthenia. Adverse effects tend to occur during the initial 1 to 3 months of nicardipine therapy, after which their incidence steadily diminishes with time.

The incidence of adverse events (10%) and the withdrawal rate (11%) in elderly patients do not appear to vary significantly from those observed in other age groups. Compared with younger patients, nicardipine is generally associated with a higher incidence of peripheral and pedal oedema in the elderly, while the incidence of headache and flushing is lower. Pedal oedema, however, appears to be due to fluid redistribution rather than fluid retention.

Antihypertensive therapy involving nicardipine does not exacerbate postural hypotension in the elderly. Similarly, preliminary results suggest that nicardipine-induced hypotension does not cause any clinical problems in patients with subarachnoid haemorrhage, although patients with acute ischaemic stroke may be more sensitive to the hypotensive effects of the drug. Similarly, intravenous nicardipine should be administered with care to patients with sick sinus syndrome.

It remains to be established whether a possible ‘pro-ischaemic’ effect of nicardipine (and/or other dihydropyridines) is reduced in elderly patients with diminished sympathetic reflexes; further data specifically in elderly patients are required to clarify the potential risk in this population.

In hypertensive patients of all ages, nicardipine has been successfully combined with other established antihypertensive agents. In particular, nicardipine may be safely coadministered with β-blockers to treat essential hypertension and/or stable angina pectoris. However, in common with other dihydropyridines, nicardipine may aggravate the ‘β-blocker withdrawal syndrome’ and precipitate ischaemic events, particularly in patients with 3-vessel coronary artery disease.

In older patients receiving digoxin treatment for atrial fibrillation or congestive heart failure, coadministration of nicardipine does not significantly affect plasma digoxin concentrations.

Dosage and Administration

In elderly patients with essential hypertension, angina pectoris or related cardiovascular disorders, oral therapy with the immediate release formulation of nicardipine should be started at a dosage of 20mg 3 times daily. If the desired therapeutic response has not been achieved after 2 weeks of treatment, the dose may then be increased to 30 to 40mg, 3 times daily.

Sustained release nicardipine tablets (40 to 60mg) may be administered once or, more usually, twice daily to achieve the desired control of blood pressure.

Dosages at the lower end of the therapeutic range are appropriate for patients with renal dysfunction, while dose reduction is likely to be needed in patients with hepatic impairment.