What is Nicorandil?

What is Nicorandil?

Nicorandil is a unique antianginal medication that combines two distinct mechanisms of action: nitrate-like vasodilation and ATP-sensitive potassium channel activation, making it a balanced arterial and venous vasodilator used primarily as a second-line agent for chronic stable angina. 1

Mechanism of Action

Nicorandil has a dual pharmacological profile that distinguishes it from other antianginal agents:

• Nitrate component: Contains a nitrate moiety in its chemical structure that activates nitric oxide (NO) signaling pathways, causing venodilation and reducing preload 2, 3
• Potassium channel activation: Opens ATP-sensitive potassium channels (K+ ATP) in arterial smooth muscle, producing arterial vasodilation and reducing afterload 2, 4
• Balanced vasodilation: Unlike pure nitrates, nicorandil dilates both arterial resistance vessels and venous capacitance vessels, resulting in reductions in both preload and afterload without significantly impairing myocardial contractility or atrioventricular conduction 5, 6

Clinical Indications and Place in Therapy

The European Society of Cardiology recommends nicorandil as a Class IIb (may be considered) second-line option for angina management, not as first-line therapy. 1

• Beta-blockers remain the preferred first-line treatment for angina due to proven mortality and heart failure hospitalization benefits 1
• When beta-blockers cannot be tolerated, alternative first-line options include ivabradine (Class IIa, Level A), oral/transcutaneous nitrates (Class IIa, Level A), and amlodipine (Class IIa, Level A), all of which have stronger recommendations than nicorandil 1
• Nicorandil may be considered when angina persists despite beta-blocker therapy or as an alternative when beta-blockers are contraindicated 1
• The 2024 ESC guidelines downgraded nicorandil to Class IIb as add-on therapy for inadequate symptom control 1

Dosing and Administration

• Usual therapeutic dose: 20 mg twice daily for prevention of angina 1
• Starting dose: 5-10 mg twice daily to minimize headache, with gradual titration 2
• Dose range: 10-40 mg daily in divided doses 5, 6
• The twice-daily regimen provides sustained efficacy with good tolerability 5

Clinical Efficacy

• Comparative studies demonstrate equivalent efficacy to isosorbide dinitrate, propranolol, atenolol, nifedipine, and diltiazem in stable angina 2, 5
• Controls 69-80% of patients with stable chronic angina when used as monotherapy 5
• The IONA outcome study showed reduction in the composite endpoint of cardiovascular death, nonfatal MI, or unplanned hospitalization for chest pain, though benefits were primarily driven by reduced hospitalizations for unstable angina rather than mortality reduction 1
• Sustained efficacy has been demonstrated for up to 1 year without evidence of tolerance development 2, 5

Potential Cardioprotective Effects

• The K+ ATP channel activation mechanism may provide direct cytoprotective effects by augmenting physiological processes that protect the heart during ischemic events 1, 2
• Studies in patients undergoing PTCA show nicorandil reduces ST-segment elevation during ischemia 4
• A propensity-matched cohort showed beneficial effects when followed for 7 years 1

Adverse Effects

Common side effects (occur frequently but are generally mild):

• Headache: Most common adverse effect, occurring in approximately one-third of patients receiving 10-20 mg twice daily 7, 2
  • Usually occurs early in treatment and declines with continued use 2
  • Was the primary reason for withdrawal in 39% of patients in the IONA study 7
  • Can be minimized by starting at lower doses (5 mg twice daily) 2
• Facial flushing and hypotension: Result from vasodilatory properties 7
• Tachycardia: Develops as compensatory response to vasodilation 7
• Reflux: Recognized common adverse effect 7

Serious but rare side effects:

• Skin, mucosal, and eye ulceration: Rare but serious complications have been reported 1, 7
• Gastrointestinal complications: Concomitant use with aspirin may increase risk of GI ulcers, perforations, and hemorrhage 1, 7

Important Contraindications and Drug Interactions

The following combinations should be avoided:

• Do not combine with nitrates: Lacks additional efficacy and is not recommended by ESC 1
• Do not combine with ivabradine or ranolazine: Unknown safety profile for these combinations 1
• Use caution in heart failure: Safety remains uncertain in this population 1

Clinical Context

Nicorandil represents a unique pharmacological approach to angina management with its dual mechanism of action, but it has been relegated to second-line status in current guidelines due to limited mortality benefit and the availability of better-studied alternatives. Its role is primarily in patients who have inadequate symptom control with first-line agents or cannot tolerate standard therapies.