Nicardipine Hydrochloride

Introduction Overview

Generic Name

nicardipine hydrochloride

Brand Name

Cardene, Cardene IV

Dosage Form

capsule

Drug Class

Calcium channel blockers (dihydropyridine class)

Pharmacokinetics

Absorption:
Nicardipine hydrochloride capsules are completely absorbed following oral administration. Plasma concentrations are detectable as early as 20 minutes post-dose, with maximal plasma levels (Cmax) observed between 30 minutes and 2 hours, averaging a Tmax of around 1 hour. Although completely absorbed, nicardipine undergoes saturable first-pass hepatic metabolism, resulting in a systemic bioavailability of about 35% after a 30 mg oral dose at steady state. The presence of a high-fat meal reduces both the Cmax and area under the concentration curve (AUC) by 20–30%, though clinical trials were conducted without regard to meal timing, indicating some meal-related variability but retained efficacy.

Distribution:
Nicardipine is highly protein-bound (>95%) in human plasma across a range of concentrations, primarily to albumin. This extensive binding limits the free drug available for distribution but ensures a consistent pharmacokinetic profile. Nicardipine’s volume of distribution is moderate, reflecting its affinity for vascular smooth muscle tissues. In patients with mild renal impairment, plasma concentrations are increased approximately twofold due to altered elimination, but there is no evidence that nicardipine impairs renal function. The drug crosses biological membranes readily but has no reported significant accumulation outside plasma and vascular tissues.

Metabolism:
Nicardipine is extensively metabolized by liver cytochrome P450 enzymes, including CYP3A4, CYP2D6, and CYP2C8. The metabolism is characterized by saturable first-pass effect, which produces nonlinear pharmacokinetics where increases in dose lead to disproportionately higher plasma concentrations. Nicardipine does not induce its own metabolism but inhibits several CYP enzymes (CYP3A4, CYP2D6, CYP2C8, and CYP2C19), which may increase plasma levels of concomitant drugs such as cyclosporine and tacrolimus. Less than 1% of the unchanged drug is excreted in urine.

Elimination:
The terminal elimination half-life of nicardipine averages 8.6 hours at steady state following repeated dosing. However, the early elimination phase within 8 hours post-dose is faster, with a half-life of 2 to 4 hours. Steady-state plasma concentrations are achieved within 2 to 3 days when given three times daily dosing. In patients with severe liver impairment, plasma levels and half-life are substantially increased (half-life prolonged to 19 hours), necessitating cautious dosing adjustments. The drug’s metabolites are primarily excreted via urine (60%) and feces (35%), with over 90% recovered within 48 hours of dosing.

Dosage Forms

Available Dosage Forms:
Nicardipine hydrochloride is supplied as hard gelatin capsules for oral administration, containing either 20 mg or 30 mg of nicardipine hydrochloride. The 20 mg capsules are white opaque body with light blue opaque cap, imprinted "NIC 1" in black ink and filled with yellow granular powder. The 30 mg capsules have a light blue opaque body and blue opaque cap, imprinted "NIC 2" in black ink, also filled with yellow granular powder. Capsules are supplied in plastic bottles of 90.

Dosages for Adults and Adolescents:
For chronic stable angina, dosing begins at 20 mg three times daily with titration up to 40 mg three times daily as tolerated and clinically indicated. At least 3 days should be allowed between dose adjustments to ensure steady-state plasma concentrations are reached. For hypertension, dosing similarly starts at 20 mg three times daily, with the dose adjusted individually based on blood pressure response. Peak effect occurs 1-2 hours post-dose, and blood pressure should be monitored at peak and trough (8 hours post-dose) to assess adequacy of response and avoid hypotension.

Specific Patient Populations:
In patients with renal insufficiency, although nicardipine does not impair renal function, plasma levels are increased approximately twofold; cautious dose titration is advised starting at 20 mg thrice daily. In patients with severe hepatic insufficiency, plasma levels are greatly elevated with prolonged half-life; it is recommended to start with 20 mg twice daily and titrate carefully using clinical parameters while maintaining a twice daily schedule. Caution is warranted in patients with congestive heart failure due to potential negative inotropic effects.

Clinical Guidelines:
Nicardipine capsules are to be administered orally; sublingual nitrates may be used concurrently for acute anginal attacks. The drug may be safely combined with beta-blockers and thiazide diuretics. Close monitoring of blood pressure, especially during initial titration and at peak plasma levels, is critical to avoid symptomatic hypotension. Dose adjustments should be made gradually and with consideration of hepatic and renal function.

Mechanism Of Action

Nicardipine hydrochloride is a dihydropyridine calcium channel blocker that selectively inhibits the influx of extracellular calcium ions through L-type voltage-gated calcium channels into vascular smooth muscle and cardiac muscle cells. By blocking these slow calcium channels, nicardipine prevents calcium-mediated contraction of vascular smooth muscle, leading to vasodilation primarily in the arterial coronary and peripheral vasculature. This action reduces systemic vascular resistance and arterial blood pressure, improving myocardial oxygen supply-demand balance.

At the molecular level, nicardipine binds to the α1 subunit of the L-type calcium channels, altering the channel conformation and preventing calcium influx during depolarization phases of the cell membrane. This inhibition decreases intracellular calcium concentration, which is critical for excitation-contraction coupling. Nicardipine's vascular selectivity minimizes direct cardiac effects, allowing for coronary and systemic vasodilation without significant negative inotropic impact at therapeutic doses.

Cellular pathways influenced include vasodilation of coronary arteries, leading to increased coronary blood flow, and reduction of afterload on the heart through peripheral arterial dilation. Nicardipine also improves left ventricular diastolic function by enhancing myocardial relaxation and reducing ischemia. Unlike non-dihydropyridine calcium channel blockers, nicardipine has little effect on cardiac conduction and does not significantly depress myocardial contractility in patients without severe left ventricular dysfunction.

Clinical implications include its use as an effective antihypertensive and antianginal agent. It improves exercise tolerance and decreases frequency of anginal attacks by reducing myocardial oxygen consumption and increasing oxygen delivery. Its mechanism compares to other dihydropyridines like nifedipine but has a longer half-life and more sustained vasodilatory effects. Research studies validate its efficacy in reducing blood pressure and treating stable angina with a favorable tolerability profile, with noted exceptions in patients with advanced aortic stenosis or significant heart failure.

Pharmacological Actions

Selective inhibition of L-type calcium channels in vascular smooth muscle.
Potent arterial vasodilation leading to decreased systemic vascular resistance.
Reduction of myocardial afterload, improving cardiac efficiency.
Coronary artery dilation, enhancing myocardial oxygen supply.
Increased exercise tolerance and delayed onset of angina symptoms.
Negative inotropic effects minimal at therapeutic doses, but possible in severe left ventricular dysfunction.
Non-linear pharmacokinetics due to saturable first-pass hepatic metabolism.
Marked reduction in blood pressure with peak effects within 1-2 hours post-dose.
Mild increase in heart rate secondary to vasodilation-induced reflex tachycardia.
No significant direct impact on cardiac conduction system or QT interval.
Inhibition of multiple cytochrome P450 enzymes, affecting metabolism of concurrent drugs.
Does not cause generalized fluid retention; however, pedal edema is a frequent vasodilator side effect.
Improves left ventricular diastolic distensibility by enhancing myocardial relaxation in ischemic areas.

Therapeutic Or Clinical Uses

Management of chronic stable angina, either as monotherapy or in combination with beta-blockers.
Treatment of mild to moderate hypertension alone or in combination with other antihypertensive agents.
Reduction of blood pressure to prevent cardiovascular complications related to hypertension.
Improvement of exercise tolerance and reduction in frequency and severity of anginal attacks.
Adjunct therapy to nitrates and beta-blockers for angina prophylaxis.
Use in hypertensive patients with concomitant coronary artery disease to reduce myocardial oxygen demand.
Therapeutic option in patients intolerant of other antihypertensive agents.
Off-label use considerations include managing hypertension in elderly patients with preserved efficacy.
Management of afterload reduction in certain cases of congestive heart failure, with caution.
Alternative to other calcium channel blockers with different pharmacokinetic profiles.

Side Or Adverse Effects

Pedal edema, reported in approximately 7-8% of patients; dose-related.
Flushing and facial warmth, occurring in up to 10% of hypertensive patients.
Headache, seen in 6-8% of clinical trial subjects.
Dizziness, especially upon initiation or dose escalation.
Asthenia and fatigue, mild and transient.
Palpitations and tachycardia due to reflex sympathetic activation.
Increased frequency, duration, or severity of angina attacks in approximately 5-7% of patients.
Nausea, dyspepsia, and dry mouth at low frequencies.
Somnolence and mild central nervous system effects.
Rash and pruritus in some patients.
Syncope and hypotension, mainly at peak plasma concentrations or overdose.
Rare cardiovascular events including postural hypotension, ventricular extrasystoles, or atypical chest pain.
Rare allergic reactions or infections.
Musculoskeletal complaints such as arthralgia and myalgia.
Gastrointestinal disturbances including constipation and abnormal liver chemistries.

Precautions

Careful blood pressure monitoring during initiation and dose titration, especially at peak plasma levels.
Use caution in patients with impaired hepatic function due to increased drug exposure and half-life extension.
Dose adjustment and close monitoring in patients with mild to moderate renal impairment.
Avoid use in patients with advanced aortic stenosis due to risk of worsening myocardial oxygen imbalance.
Exercise caution in congestive heart failure patients given potential negative inotropic effects.
Avoid abrupt discontinuation of concomitant beta-blocker therapy to prevent exacerbation of ischemic conditions.
Monitor for symptoms of excessive hypotension and tachycardia.
Evaluate serum digoxin levels when coadministered, as calcium channel blockers may alter digoxin pharmacokinetics.
Patients should be advised on possible vasodilator-related side effects such as flushing and edema.
Pregnant women should only receive nicardipine if benefits outweigh potential fetal risk; animal studies show embryocidal effects at high doses.
Breastfeeding is not recommended due to nicardipine secretion in milk.
Pediatric safety and efficacy not established; use not recommended for patients under 18 years.
Dosage should be cautiously initiated in elderly patients due to comorbidities and possible organ function decline.
Consider food effect on absorption but clinical efficacy is retained despite timing of meals.
Careful titration is advised to avoid transient hypotension, especially in cerebrovascular accident patients.

Warnings

Increased frequency, duration, or severity of angina reported in ~7% of patients starting or increasing dose.
May cause negative inotropic effects in some patients, especially those with severe left ventricular dysfunction; caution in heart failure.
Not a substitute for beta-blockers; abrupt withdrawal of beta-blockers during nicardipine therapy may be dangerous.
Symptomatic hypotension may occur due to vasodilation; blood pressure monitoring and dose adjustments are critical.
Use with caution in patients with impaired hepatic function as plasma levels and half-life are significantly increased.
Patients with aortic stenosis may experience worsened myocardial oxygen supply-demand balance.
Watch for reflex tachycardia which may complicate angina control.
Potential for increased plasma concentrations of certain drugs due to cytochrome P450 inhibition; monitor closely.
Use caution during anesthesia with fentanyl and beta-blockers due to risk of severe hypotension.
Prolonged QT interval observed minimally but clinical significance not established; monitor in patients with risk factors.

Contraindication

Known hypersensitivity to nicardipine or any component of the formulation.
Patients with advanced aortic stenosis due to risk of exacerbated myocardial oxygen imbalance and ischemia.
Contraindicated in patients with conditions where the vasodilatory effects could worsen clinical status without protective cardiac output support.
Not to be used in pediatric patients as safety and efficacy have not been established.
Use caution or avoid in patients with severe congestive heart failure without close monitoring.
Contraindicated in patients with documented hypersensitivity reactions to other calcium channel blockers of the dihydropyridine class.

Drug Interactions

Cimetidine increases nicardipine plasma levels; monitor patients carefully if coadministered.
Cyclosporine levels are elevated during concomitant use due to CYP3A4 inhibition by nicardipine; dosage adjustments recommended.
Tacrolimus plasma concentrations increase with nicardipine coadministration necessitating close monitoring and dose modification.
Beta-blockers are commonly used with nicardipine and the combination is generally well tolerated.
Serum digoxin levels may be influenced; measure digoxin concentrations after starting nicardipine therapy.
No alteration in nicardipine protein binding by furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen in vitro.
No significant effect of Maalox (antacid) on nicardipine absorption.
Potential for enhanced hypotensive effects when combined with other antihypertensives and vasodilators.
Severe hypotension reported during fentanyl anesthesia with concurrent beta-blocker and calcium channel blockers; volume expansion may be necessary.
Nicardipine inhibits multiple cytochrome P450 enzymes (CYP3A4, 2D6, 2C8, 2C19), potentially elevating plasma levels of various medications metabolized by these pathways.

Preparations Of The Drug

Nicardipine hydrochloride capsules 20 mg: white opaque body, light blue opaque cap, imprinted 'NIC 1', filled with yellow granular powder.
Nicardipine hydrochloride capsules 30 mg: light blue opaque body and cap, imprinted 'NIC 2', filled with yellow granular powder.
Inactive ingredients include silicon dioxide, lactose monohydrate, magnesium stearate, corn starch, sodium starch glycolate type A, FD&C blue no.1, gelatin, titanium dioxide, ferrosoferric oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac, and ammonia.
Supplied in bottles of 90 capsules with child-resistant closures.
Store at controlled room temperature 20° to 25°C (68° to 77°F), protect from light.
Capsule size approximately 17 mm (20 mg) and 19 mm (30 mg).
Manufactured and distributed by Bionpharma Inc., Princeton, NJ.
Available only by prescription for oral use.
Packaging designed to preserve stability and avoid moisture exposure.
Capsules contain black imprint ink made from black iron oxide and various alcohols and ammonia solutions.