Nicorandil is a medicine used to treat stable angina - chest pain caused by reduced blood flow to the heart during physical activity or stress. It has a unique dual mechanism of action that sets it apart from most other antianginal drugs: it both relaxes blood vessels and protects heart muscle cells. Nicorandil is particularly valued for patients whose angina is inadequately controlled by beta-blockers or calcium channel blockers alone.

Drug Class: Potassium Channel Activator and Nitrate - Dual Action

Nicorandil belongs to two pharmacological classes simultaneously. First, it is a potassium channel activator - it opens ATP-sensitive potassium (KATP) channels in vascular smooth muscle, causing blood vessels to dilate. Second its nitrate-like component is converted in the body to nitric oxide (NO), which activates guanylate cyclase in smooth muscle cells, producing additional vasodilation. Most antianginal drugs work through only one of these mechanisms but nicorandil works through both, giving it a distinct pharmacological profile.

How Nicorandil Relieves Chest Pain (Angina)

Angina occurs when the heart muscle does not receive enough oxygen-rich blood usually because the coronary arteries are narrowed by atherosclerosis. Nicorandil relieves angina through two complementary mechanisms. Its potassium channel activation dilates the coronary arteries directly, increasing blood flow to the heart muscle. Its nitrate component dilates the large veins (venodilation), reducing the amount of blood returning to the heart and thereby reducing the heart's workload and oxygen demand.

Medical Uses

Doctors prescribe nicorandil for:

• Stable angina pectoris: The primary indication; used for prevention of angina episodes (taken regularly twice daily) and in some formulations for the relief of acute angina attacks; nicorandil reduces the frequency, duration and severity of angina episodes

• Add-on therapy: Used when beta-blockers, calcium channel blockers or long-acting nitrates are insufficient to control angina; various studies demonstrated that nicorandil significantly reduced the combined endpoint of cardiac events, non-fatal myocardial infarction and hospitalisation for chest pain.

Unique Feature: Nicorandil Protects Heart Muscle Cells

One of the most clinically important and distinctive properties of nicorandil is its ability to protect heart muscle cells (cardiomyocytes) from ischaemic injury known as cardiac preconditioning. When KATP channels in cardiac muscle cells are opened by nicorandil, the cells become more resistant to the damage caused by brief episodes of ischaemia. The IONA trial provided clinical evidence of this: patients randomised to nicorandil had significantly fewer acute coronary syndrome events than those receiving placebo, in addition to improved symptom control. This cardioprotective property distinguishes nicorandil from conventional nitrates, which provide vasodilation but no direct cellular protection.

Side Effects of Nicorandil

Common side effects are:

• Headache

• Dizziness on standing (orthostatic hypotension)

• Hypotension

• Warmth, redness, and flushing of the face 

• Nausea and abdominal discomfort.

Serious Risk: Gastrointestinal Ulceration

The most serious side effect of nicorandil is gastrointestinal (GI) ulceration - painful ulcers in the mouth, oesophagus, stomach, small intestine, colon or perianal region. The mechanism is not fully understood but is thought to involve impaired mucosal healing caused by nicorandil's vasodilatory effect on the mucosal blood supply. Ulcers can develop even at standard doses after months or years of treatment. Ulcers typically resolve within weeks of discontinuation

Who Should Not Take Nicorandil?

• Patients with cardiogenic shock or acute pulmonary oedema: Nicorandil's vasodilatory effects can dangerously reduce blood pressure in haemodynamically unstable patients

• Patients with hypotension (low blood pressure): Nicorandil should not be started if systolic blood pressure is below 90 mmHg; significant falls in blood pressure can cause syncope and precipitate myocardial ischaemia

• Patients taking PDE5 inhibitors (sildenafil, tadalafil, vardenafil): Combining nicorandil with a PDE5 inhibitor causes a severe and potentially life-threatening fall in blood pressure

• Pregnant women: Nicorandil is generally avoided in pregnancy due to limited safety data.

Drug Interactions

Key interactions are:

• PDE5 inhibitors (sildenafil/Viagra, tadalafil, vardenafil): The most important and dangerous drug interaction; PDE5 inhibitors block the breakdown of cyclic GMP, the intracellular messenger produced by the nitrate component of nicorandil; the combination causes a catastrophic fall in blood pressure that can be life threatening; the combination is absolutely contraindicated

• Other vasodilators and antihypertensives: Calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, alpha-blockers, and antihypertensive drugs all add to the blood pressure-lowering effect of nicorandil; additive hypotension can occur

• Tricyclic antidepressants and alcohol: Amitriptyline and other TCAs can enhance the hypotensive effect of nicorandil; alcohol potentiates the vasodilatory and blood pressure-lowering effects of nicorandil; patients should avoid excessive alcohol intake

Nicorandil vs Isosorbide Mononitrate vs Amlodipine 

Main differences are:

• Mechanism: Nicorandil has a dual mechanism (potassium channel activation plus nitrate-like effect); isosorbide mononitrate (ISMN) works exclusively through nitric oxide release and venodilation; amlodipine is a calcium channel blocker that reduces myocardial oxygen demand by dilating peripheral arteries and lowering blood pressure

• Nitrate tolerance: Organic nitrates develop tolerance with continuous use, losing effectiveness; nicorandil's potassium channel activation component does not develop tolerance, though its nitrate component can; this makes nicorandil more reliably effective for continuous prevention than organic nitrates, which require nitrate-free intervals

• Cardioprotective effect: Only nicorandil has the additional property of cardiac preconditioning; ISMN and amlodipine have no direct cardioprotective mechanism beyond symptom control; nicorandil's most serious specific risk is GI ulceration; ISMN's main limitation is nitrate tolerance and headaches; amlodipine commonly causes peripheral oedema (ankle swelling)

Long-Term Use - What Cardiac Patients Should Monitor

When using nicorandil for long term patients should monitor:

• Blood pressure: Nicorandil lowers blood pressure; checked at every cardiology review to avoid sustained systolic blood pressure below 90 to 100 mmHg; home blood pressure monitoring is recommended

• Oral mucosal inspection: Patients on long-term nicorandil should regularly inspect their mouth; any ulcer lasting more than 2 weeks should be reported to the treating doctor

• Perianal and bowel symptoms: Patients should report persistent rectal pain, rectal bleeding or difficulty sitting; these symptoms should prompt consideration of nicorandil-associated perianal or intestinal ulceration before more invasive diagnoses are pursued.

FAQs

1. What is nicorandil tablet used for?

   Nicorandil tablets are used to treat stable angina. It is used to prevent angina episodes (taken regularly twice daily) and in some formulations to relieve acute angina attacks. 

2. How does nicorandil work differently from other angina medicines?

   Nicorandil has a dual mechanism that most other antianginal drugs lack. It opens KATP channels in blood vessel walls, causing direct coronary artery dilation and increased blood flow to the heart. Simultaneously, its nitrate component releases nitric oxide, dilating large veins and reducing the heart's workload. Nicorandil also protects heart muscle cells from ischaemic damage (cardiac preconditioning) - a property that conventional nitrates, beta-blockers and calcium channel blockers do not have.

3. Can nicorandil cause mouth ulcers or stomach ulcers?

   Nicorandil is a well-recognised cause of gastrointestinal ulceration, including mouth ulcers, perianal ulcers, gastric ulcers and intestinal ulcers. These ulcers are typically large, persistent and painful and do not respond to standard treatments. The ulcers develop or worsen during nicorandil treatment and resolve completely after the drug is stopped.

4. Why does nicorandil cause headaches?

   Nicorandil causes headaches because its nitrate component releases nitric oxide, dilating blood vessels including intracranial blood vessels and producing a throbbing headache similar to that seen with isosorbide mononitrate or glyceryl trinitrate. These headaches are typically most severe during the first 1 to 2 weeks and usually improve substantially as the body develops tolerance to the nitrate component.

5. Is nicorandil the same as a nitrate medicine?

   Nicorandil is not the same as a conventional nitrate medicine. Conventional nitrates work exclusively through nitric oxide release and venodilation. Nicorandil's dual mechanism - its nitrate component producing nitric oxide-mediated vasodilation plus its potassium channel activator component opening KATP channels gives it advantages over conventional nitrates including less tolerance development and additional cardioprotective properties.

6. Can nicorandil be taken alongside other heart medicines?

   Yes nicorandil can be safely combined with beta-blockers (metoprolol, atenolol, bisoprolol), calcium channel blockers (amlodipine, diltiazem), statins, aspirin, ACE inhibitors,and angiotensin receptor blockers. However combining nicorandil with other vasodilators requires blood pressure monitoring. Concurrent use with PDE5 inhibitors (sildenafil, tadalafil, vardenafil) is absolutely contraindicated.

7. Can nicorandil be taken with erectile dysfunction medication?

   Nicorandil must never be taken alongside PDE5 inhibitors used for erectile dysfunction including sildenafil (Viagra), tadalafil and vardenafil. Both act on the nitric oxide-cyclic GMP pathway and combining them causes a severe, potentially fatal fall in blood pressure.

8. How quickly does nicorandil relieve chest pain?

   Nicorandil begins to reduce the frequency and severity of angina episodes within 1 to 2 weeks of starting regular treatment. The full antianginal benefit is typically established after 2 to 4 weeks at the effective dose. 

9. What should a patient do if they develop a new mouth sore on nicorandil?

   A patient who develops a new, persistent or enlarging mouth sore while taking nicorandil should inform their cardiologist immediately. Nicorandil-associated oral ulcers are typically larger and more painful than common mouth ulcers, do not respond to antiseptic mouthwash or topical corticosteroids and persist as long as the drug is continued. Nicorandil should be discontinued and the ulcer will resolve completely.

10. Is nicorandil safe for patients with low blood pressure?

    Nicorandil is not recommended for patients with low blood pressure (hypotension) as it further reduces blood pressure by dilating blood vessels. Patients with a systolic blood pressure below 90 mmHg should not take nicorandil. In patients with borderline blood pressure, nicorandil should be started at 5 mg twice daily with careful blood pressure monitoring. Dizziness on standing is a recognised side effect particularly at the start of treatment.

References

1. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002;359(9314):1269–75. https://doi.org/10.1016/S0140-6736(02)08265-X

2. Kasama S, Toyama T, Hatori T, et al. Effects of nicorandil on cardiac sympathetic nerve activity and left ventricular function in patients with dilated cardiomyopathy. J Nucl Med. 2005;46(7):1099–105. https://pubmed.ncbi.nlm.nih.gov/16000280

3. Jahangir A, Terzic A. KATP channel therapeutics at the bedside. J Mol Cell Cardiol. 2005;39(1):99–112. https://doi.org/10.1016/j.yjmcc.2005.04.006

4. Shirley M. Nicorandil-associated gastrointestinal ulceration. Drugs. 2017;77(2):233–40. https://doi.org/10.1007/s40265-016-0677-3

5. Markham A, Plosker GL, Goa KL. Nicorandil: an updated review of its use in ischaemic heart disease with emphasis on its cardioprotective effects. Drugs. 2000;60(4):955–74. https://doi.org/10.2165/00003495-200060040-00009