Nicorandil

Introduction

Nicorandil is a vasodilatory agent used primarily in the management of angina pectoris. It is unique in that it combines two pharmacological properties: it acts as a nitrate-like donor of nitric oxide and as an opener of ATP-sensitive potassium (KATP) channels. This dual mechanism provides both arterial and venous dilation, improving coronary blood flow while reducing cardiac workload.

First introduced in Japan in the 1980s, nicorandil is now widely used in Europe, Asia, and other regions as an antianginal agent. It is recommended in patients with stable angina who are inadequately controlled with, or intolerant to, first-line agents such as beta-blockers or calcium channel blockers.

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Pharmacological Classification

• Class: Vasodilator with nitrate and potassium channel–activating properties

• ATC code: C01DX16

• Formulations:

  • Oral tablets (5 mg, 10 mg, 20 mg)

  • Modified-release tablets (available in some countries)

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Mechanism of Action

Nicorandil has a dual mechanism:

1. Nitrate-like action (NO donor)

   • The nitrate moiety releases nitric oxide (NO) in vascular smooth muscle.

   • NO activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP).

   • Elevated cGMP levels cause relaxation of vascular smooth muscle, leading to venodilation and reduced preload.

2. Potassium channel opening (KATP channel opener)

   • Nicorandil activates ATP-sensitive potassium channels in vascular smooth muscle.

   • This hyperpolarizes the cell membrane, closing voltage-dependent calcium channels.

   • Reduced intracellular calcium leads to arterial vasodilation, reducing afterload and increasing coronary blood flow.

The combined effect is reduced myocardial oxygen demand and increased myocardial oxygen supply.

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Pharmacokinetics

• Absorption: Rapidly absorbed after oral administration.

• Bioavailability: Approximately 75% (subject to first-pass metabolism).

• Distribution: Widely distributed, low protein binding.

• Metabolism: Metabolized in the liver mainly by denitration.

• Elimination: Excreted in urine, mainly as inactive metabolites.

• Half-life: 1–2 hours (allowing twice-daily dosing).

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Clinical Indications

1. Stable angina pectoris

   • Symptomatic treatment in patients not adequately controlled with beta-blockers or calcium channel blockers.

   • Used as add-on therapy or as monotherapy when first-line drugs are contraindicated or not tolerated.

2. Alternative antianginal option

   • Particularly beneficial in patients with intolerance to other vasodilators or those with refractory angina.

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Contraindications

• Hypersensitivity to nicorandil or excipients

• Hypotension (systolic BP <90 mmHg)

• Left ventricular failure with low filling pressures

• Cardiogenic shock

• Use with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) due to risk of severe hypotension

• Acute pulmonary edema

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Precautions

• Gastrointestinal ulceration: Nicorandil has been linked to gastrointestinal, skin, and mucosal ulcerations. Monitor for symptoms of ulceration, and discontinue if present.

• Hypotension: Risk of dizziness and syncope; use caution in elderly patients or those with volume depletion.

• Hepatic or renal impairment: Use cautiously, as data are limited.

• Combination therapy: When used with other vasodilators or antihypertensives, monitor closely for additive hypotension.

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Adverse Effects

Common

• Headache (often transient, related to vasodilation)

• Flushing

• Dizziness

• Palpitations

• Nausea

Less Common

• Hypotension, syncope

• Fatigue

• Rash or pruritus

Rare but Serious

• Gastrointestinal ulceration (oral, anal, gastric, intestinal)

• Skin ulceration

• Ocular ulceration

• Severe hypotension leading to ischemia

• Angioedema (rare hypersensitivity reaction)

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Drug Interactions

• Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil): Contraindicated due to profound risk of hypotension.

• Other nitrates (glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate): Additive vasodilatory effect, risk of severe hypotension.

• Antihypertensive agents (beta-blockers, calcium channel blockers, ACE inhibitors, diuretics): Enhanced hypotensive effect.

• Alcohol: May increase vasodilation and dizziness.

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Dosage

Adults (Oral)

• Initial dose: 5 mg twice daily (especially in patients prone to headaches).

• Typical maintenance dose: 10–20 mg twice daily.

• Maximum dose: Up to 40 mg twice daily (depending on patient response and tolerability).

Elderly Patients

• Start at the lower end of the dosage range due to increased sensitivity to hypotension.

Children

• Safety and efficacy not established; not recommended in pediatric population.

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Clinical Efficacy

• Randomized controlled trials and observational studies show that nicorandil significantly improves angina frequency, exercise tolerance, and quality of life in patients with stable angina.

• Long-term outcome studies (e.g., the IONA trial) demonstrated that nicorandil reduces major coronary events in high-risk patients with stable angina, supporting its use beyond symptom control.

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Patient Counseling Points

• Take regularly, usually twice daily.

• Headache may occur initially but often improves with continued use.

• Do not stop abruptly without medical advice; symptoms of angina may worsen.

• Avoid concomitant use with sildenafil or other erectile dysfunction medications.

• Report any unusual ulcers in the mouth, skin, or gastrointestinal tract promptly.

• Stand slowly from sitting or lying positions to reduce risk of dizziness.