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Drugs

, Volume 33, Issue 4, pp 296–345 | Cite as

Nicardipine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy, in the Treatment of Angina Pectoris, Hypertension and Related Cardiovascular Disorders
  • Eugene M. Sorkin
  • Stephen P. Clissold
Drug Evaluation

Summary

Synopsis

Nicardipine1 is an antagonist of calcium influx through the slow channel of the cell membrane and has been shown to be an effective and relatively well-tolerated treatment for stable effort angina and rest angina due to coronary artery spasm, and mild to moderate hypertension. Although its exact mechanism of action in these disease states has not been precisely defined, the potent coronary and peripheral arterial dilator properties of nicardipine, with concomitant improvements in oxygen supply/demand and reductions in systemic vascular resistance, are of major importance.

Clinical studies have shown that nicardipine appears to be effective in the treatment of chronic stable exercise-induced angina pectoris and possibly in angina at rest due to coronary artery spasm. In the treatment of stable angina, nicardipine has proved to be equally as effective as nifedipine. However, haemodynamic and clinical studies indicate that nicardipine may have a further advantage of not depressing cardiac conduction or left ventricular function, even in patients with compromised cardiac pumping ability. Nicardipine also appears to be useful as initial monotherapy or in combination with other antihypertensive drugs when used in the treatment of mild to moderate hypertension, and may have some advantages over other vasodilators in this regard in that it may not be as frequently associated with fluid retention or weight gain as other similar drugs. In the treatment of hypertension nicardipine has been shown to be as effective as drugs such as hydrochlorothiazide, cyclopenthiazide, propranolol and verapamil in short term studies although confirmation of its long term usefulness in well-designed clinical trials is still required. Similarly, although the use of nicardipine in other disorders such as congestive heart failure and cerebrovascular disease has provided encouraging preliminary results, more studies are needed to clarify its place in their treatment.

Side effects appear to be dose related and more frequent within the first few weeks of therapy. Most of these effects are minor and transient in nature and include headache, flushing and peripheral oedema.

Thus, there is no doubt that nicardipine provides a suitable alternative to other drugs available for the treatment of angina and hypertension. However, further well-designed comparative clinical trials are needed to clarify its relative place in the long term management of these disorders.

Pharmacodynamic Properties

Nicardipine, in common with other calcium antagonists, inhibits the slow inward current of calcium in normal cardiac tissues. In humans, nicardipine has either significantly shortened or had no effect on sinus nodal recovery time. In clinically practical doses nicardipine has had few untoward effects on sinoatrial and atrioventricular nodal function, and because it has not shown any major antiarrhythmic effects it may be safe for patients with some cardiac conduction disturbances.

Intravenous and oral doses of nicardipine may produce dose-related decreases in mean arterial blood pressure and increases in heart rate of up to 30% and 8 to 26%, respectively, and the duration of these effects — which may be as long as 3 hours — have generally been greater in patients at rest than in those at exercise. Although reductions in blood pressure have been effectively maintained for several months without evidence of tachyphylaxis, increases in heart rate occasionally seen after acute administration are not observed after long term (greater than 2 months) oral treatment.

The primary haemodynamic effect of nicardipine is peripheral vasodilatation leading to a reflex increase in cardiac pumping activity. Thus, cardiac index is increased while systemic vascular resistance is decreased, and these effects are maintained during long term therapy. The magnitude of the blood pressure reduction induced by nicardipine has been shown to be directly related to the concurrent decreases in systemic vascular resistance. Cardiac pumping ability is probably improved due to a reduction in afterload.

Although nicardipine has been shown to cause similar haemodynamic responses to nifedipine when given orally to healthy subjects, intracoronary injections of nifedipine in patients with coronary artery disease resulted in decreases in left ventricular contractility and relaxation, while intracoronary nicardipine produced no such effects. In patients at rest, nicardipine appears to increase cardiac index to a greater extent than verapamil, while pulmonary artery occluded pressure is increased after verapamil but not after nicardipine administration. Additionally, although verapamil and nicardipine produced similar haemodynamic effects during exercise, verapamil achieved these results at the expense of a significantly increased left ventricular filling pressure, while nicardipine did not.

The addition of nicardipine to patients receiving β-blockers has further reduced blood pressure and decreased left ventricular systolic pressure and systemic vascular resistance from values obtained with β-blockers alone. Moreover, heart rate, cardiac output and ventricular relaxation, which are decreased after β-blocker therapy, are normalised after the introduction of nicardipine to the treatment regimen. Thus, cardiac pump function and inotropic activity appear to be improved after nicardipine is added to β-blocker therapy. In contrast, nifedipine may produce a small but definitely negative inotropic effect when added to β-blocker therapy. Since beneficial haemodynamic and cardiac pumping effects result from the addition of nicardipine to patients previously treated with β-blockers, even in patients with impaired left ventricular function, nicardipine may present no additional hazard to patients already receiving β-blockers.

The administration of nicardipine to patients with coronary artery disease results in an increase in coronary blood flow due to coronary vasodilatation and decreases in coronary vascular resistance. Nicardipine may have a relatively greater affinity for coronary vessels than those in other vascular beds since it apparently reduces coronary vascular resistance to a greater extent than systemic vascular resistance. In patients receiving β-blockers, the addition of nicardipine has further increased coronary blood flow and decreased coronary vascular resistance by as much as 21 and 32%, respectively.

By virtue of its ability to decrease systemic vascular resistance (afterload), nicardipine may improve blood distribution in ischaemic myocardial tissue thus imparting to the drug cardioprotective properties. Since it has also been shown to reduce left ventricular lactate production in patients with angina pectoris, it may be that nicardipine improves perfusion and aerobic metabolism in chronically ischaemic areas, leading to improvements in ventricular function.

Other pharmacological effects of nicardipine include increased peripheral blood flow and decreased peripheral vascular resistance, as well as a potent dose-related cerebral vasodilating effect. Nicardipine may also increase renal blood flow and glomerular filtration rate and decrease renovascular resistance, whereas plasma renin activity may be slightly or markedly increased. Interestingly, although plasma aldosterone concentrations do not appear to be significantly affected, nicardipine administration has resulted in modest and short-acting natriuretic effects due to an effect on the renal tubule.

Pharmacokinetic Properties

Although more well-designed investigations involving larger numbers of volunteers and patients are required for a better understanding of the pharmacokinetic properties of nicardipine, studies have shown that after oral administration nicardipine is rapidly and completely absorbed, with peak plasma concentrations occurring between 20 minutes and 2 hours. Despite the fact that nicardipine is well absorbed, it has a low systemic bioavailability due to extensive presystemic metabolism. Non-linear increases in peak plasma concentrations, areas under the plasma concentration-time curves (AUCs) and systemic bioavailability occur after both intravenous and oral doses of nicardipine, suggesting that liver drug metabolising enzymes become saturated with nicardipine or its metabolites at higher doses of the drug. The administration of nicardipine to elderly patients may result in higher minimum and maximum plasma concentrations, possibly due to a decreased first-pass effect in this patient population. Conversely, food has been found to decrease both the maximum plasma concentrations and AUCs obtained after oral administration of the drug. Plasma concentrations of nicardipine exhibit no tendency to increase during prolonged periods of administration.

In vitro studies using human plasma have shown that over 90% of nicardipine is plasma protein bound at concentrations of 100 μg/L, and volumes of distribution in healthy volunteers have ranged from 0.6 L/kg to 63L.

Nicardipine is rapidly and extensively removed by hepatic first-pass extraction during its entrance into the systemic circulation and is metabolised to inactive metabolites. Less than 0.03% of parent drug is recovered from the urine of humans. The plasma elimination half-life of nicardipine has ranged from 44 to 107 minutes in most studies with clearance of the drug due mainly to hepatic mechanisms. In healthy volunteers, intravenous nicardipine clearance values were 0.4 to 0.9 L/h/kg to 72 L/h, while progressive decreases in clearance values with increasing oral doses of the drug indicate a saturation of the hepatic removal mechanisms. Nicardipine is excreted mainly through the bile and faeces and the drug may be used in patients with severe renal failure; slightly higher values for Cmax and AUC in this class of patient indicate that a dosage at the lower end of the recommended range is appropriate. Pharmacokinetic data from patients with liver disease is not available and nicardipine should be used with caution in such patients.

Therapeutic Trials

In many placebo-controlled trials for periods of up to 1 year, nicardipine has been shown to be effective in stable exercise-induced angina as assessed by decreases in anginal frequency and glyceryl trinitrate (nitroglycerin) consumption, and improvements in objective parameters such as work performance and time to onset and magnitude of ST-segment changes during exercise. Short term comparative trials have demonstrated that the antianginal efficacy of nicardipine is comparable to that of nifedipine, verapamil, diltiazem, propranolol and atenololol. Compared with nifedipine, nicardipine produced similar decreases in the number of anginal episodes per week and sublingual glyceryl trinitrate consumption, and increases in total exercise time, time to angina and 1mm ST-segment depression. Similarly, in vasospastic angina, nicardipine decreased both the frequency of symptomatic and asymptomatic episodes of angina and sublingual glyceryl trinitrate consumption by up to 81%.

In several open and placebo-controlled trials in patients with mild-to-moderate essential hypertension, the antihypertensive efficacy of nicardipine has been maintained for periods of up to 1 year. Nicardipine monotherapy decreased mean arterial blood pressure by more than 13mm Hg in 46 and 82% of newly diagnosed hypertensives in daily dosages of 30 and 60mg, respectively, indicating its potential usefulness in the initial treatment of the disease. In placebo-controlled trials, dose-related percentage decreases in supine and sitting systolic/diastolic blood pressures of 17/20 and 20/16mm Hg, respectively, have been recorded. Short term comparative studies demonstrated that nicardipine was at least as effective as drugs like hydrochlorothiazide, cyclopenthiazide, propranolol and verapamil in patients with mild to moderate hypertension. Limited studies have shown that nicardipine enhances the antihypertensive effects of other drug combinations. When added to antihypertensive regimens containing atenolol, nicardipine produced further significant reductions in blood pressure without causing increases in heart rate.

Despite encouraging results, the clinical evaluation of nicardipine in other therapeutic areas such as congestive heart failure and cerebrovascular disease has been of a preliminary nature. Firm conclusions regarding its relative efficacy in these areas await further research.

Side Effects

Side effects resulting from nicardipine administration, most of which are minor and transient in nature, appear to be dose related and more frequent during the first few weeks of therapy with the drug. Vasodilatation-related effects such as flushing, headache and peripheral oedema, which are extensions of the main pharmacodynamic properties of the drug, have occurred in as many as 37% of patients treated with nicardipine. However, placebo administration to these same patients yielded vasodilatation-related side effects in 23% of the group. Overall, vasodilatation-related side effects from nicardipine in clinical studies to date have necessitated withdrawal of approximately 11 to 14% of patients. Other cardiovascular side effects, including increased anginal symptoms, exercise-induced hypotension, palpitations, dyspnoea and myocardial infarction have been reported in as many as 27 and 14% of patients receiving nicardipine and placebo, respectively. Other side effects involving the central nervous, gastrointestinal, musculoskeletal or dermatological systems occur infrequently and with minor intensity. The abrupt withdrawal of nicardipine after 5 months of continuous therapy in patients with chronic stable angina pectoris has not resulted in increases in anginal symptoms compared to those reported prior to entry into the study.

Dosage and Administration

In adults with essential hypertension or angina pectoris, oral nicardipine should be initiated at a dosage of 20mg 3 times daily. If the desired therapeutic response has not been achieved after 2 weeks of treatment the dosage may be increased to 30 to 40mg 3 times a day.

Keywords

Verapamil Nifedipine Clinical Pharmacology Calcium Antagonist Systemic Vascular Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • Eugene M. Sorkin
    • 1
  • Stephen P. Clissold
    • 1
  1. 1.ADIS Drug Information ServicesMairangi Bay, Auckland 10New Zealand

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