Nicorandil
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Here is a comprehensive overview of Nicorandil:
Nicorandil
Classification & Availability
Nicorandil is a nicotinamide nitrate ester used as an antianginal agent. It is approved in Europe, Japan, and many Asian countries for stable angina pectoris but is not available in the United States.
Mechanism of Action
Nicorandil has a dual mechanism — a combination not seen with other antianginal drugs:
- Nitrate-like (cGMP-mediated) action: Releases nitric oxide → activates soluble guanylyl cyclase → ↑ cGMP → smooth muscle relaxation and vasodilation.
- K_ATP channel opener: Acts as an agonist at ATP-sensitive potassium channels → membrane hyperpolarization → vasodilation.
Its vasodilating action is potentiated by PDE5 inhibitors (e.g., sildenafil) and only partially blocked by K_ATP channel inhibitors like glibenclamide, confirming that both mechanisms are active.
Additionally, studies in isolated myocytes show it activates the Na⁺/Ca²⁺ exchanger, reducing intracellular Ca²⁺ overload.
Hemodynamic Effects
- Dilates both arterial and venous vascular beds → reduces afterload and preload
- No direct effect on myocardial contractility
- Decreased afterload increases cardiac output (stronger than nitrovasodilators alone)
- May cause reflex tachycardia
- Hemodynamic profile lies between nitrovasodilators and dihydropyridine CCBs
Cardioprotective Effects (Preconditioning)
Nicorandil mimics ischemic preconditioning — short ischemic episodes before sustained ischemia reduce subsequent myocardial injury. The mechanism involves mitochondrial K_ATP channel opening. Retrospective studies suggest a survival benefit in patients with stable CAD, though large prospective data are lacking.
One large clinical trial (IONA trial) showed a significant reduction in fatal and non-fatal coronary events.
Pharmacokinetics (ADME)
| Parameter | Detail |
|---|---|
| Absorption | Rapid after sublingual or oral dosing |
| Half-life (t½) | ~1 hour |
| Usual dosing | 20 mg twice daily |
| Note | Short t½ means clinically significant trough levels may not be achieved at standard dosing |
Adverse Effects
| Effect | Notes |
|---|---|
| Headache | Nitrate-like, common |
| Hypotension | Nitrate-like |
| Ulcerations | First reported 1997; can affect oral mucosa, skin, perianal/gastrointestinal sites — potentially serious |
| Tachycardia | Reflex, due to vasodilation |
Tolerance: Early studies reported a clear decrease or loss of antianginal effect after ~2 weeks of oral treatment.
Drug Interactions
- PDE5 inhibitors (sildenafil, tadalafil): Contraindicated — potentiate hypotension (same as with organic nitrates)
- Glibenclamide (sulfonylurea): Partially antagonizes the K_ATP opening action
Clinical Use
| Indication | Status |
|---|---|
| Stable angina pectoris | Approved (Europe, Japan, Asia) |
| Vasospastic angina | Used (often alongside nitrates) |
| Heart failure | Investigated — recent meta-analysis (PMID 40491110, 2025) |
| Contrast-induced nephropathy prevention | Under investigation — meta-analysis (PMID 40340567, 2025) |
| STEMI (intracoronary adjunct) | Studied in network meta-analysis (PMID 41364063, 2026) |
Role in Angina Guidelines
Nicorandil is a second-line antianginal agent (in countries where it is approved):
- First-line: β-blockers, rate-limiting CCBs (diltiazem, verapamil)
- Second-line: Long-acting nitrates, ranolazine; and in non-US countries — nicorandil, ivabradine, trimetazidine
Summary Comparison with Other Antianginals
| Drug | Mechanism | Preconditioning | Available in US |
|---|---|---|---|
| Nicorandil | NO release + K_ATP opener | Yes | No |
| Nitrates | NO release only | No | Yes |
| CCBs | Ca²⁺ channel blockade | No | Yes |
| Ranolazine | Late INa blockade | No | Yes |
| Ivabradine | HCN (If) blockade | No | Yes (HF only) |
Sources:
- Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 31 (Nicorandil section)
- Katzung's Basic and Clinical Pharmacology, 16th ed., Chapter 12
Recent evidence to note:
- A 2025 meta-analysis (PMID 40491110) examined nicorandil's effectiveness in heart failure — an emerging indication beyond angina.
- A 2025 meta-analysis (PMID 40340567) assessed nicorandil for contrast-induced nephropathy prevention.
- A 2026 network meta-analysis (PMID 41364063) evaluated intracoronary adjunctive therapies in STEMI, including nicorandil — suggesting possible emerging uses in acute coronary syndromes.
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