Potassium Channel Activators

Synonyms: potassium channel openers, KCOs, KATP activators

The only potassium-channel activator currently licensed for use in the UK is nicorandil.¹ Nicorandil is a hybrid compound with potassium-channel activator and organic nitrate effects.²

ATP-sensitive potassium channels are expressed in many tissues including brain, pancreatic β-cells, heart and smooth muscle. Activation of potassium channels in vascular smooth muscle causes membrane hyperpolarisation and arterial vasodilation.³ Nicorandil also has nitrate-like venodilatory effects. The dual mechanism results in reduced cardiac preload and afterload and increased coronary blood flow.⁴ In contrast to nitrates, effects of nicorandil are sustained with continued use.^5,6

Angina

• Nicorandil is licensed for prophylaxis and treatment of angina.¹ Betablockers, nitrates and calcium channel blockers are still considered first line, and nicorandil is mainly used in patients who are intolerant of nitrates, or in patients with refractory angina already on a number of different medications. It is a useful alternative treatment if beta-blockers are contraindicated.⁷
• It can be used safely in those with hypertension, diabetes mellitus, heart failure (without pulmonary oedema), chronic obstructive airways disease and cardiac conduction disorders.
• Nicorandil significantly reduces anginal symptoms and increases exercise tolerance. It is as effective as other anti-anginal drugs but is more expensive than other standard preparations.⁸
• It may be used safely in combination with beta-blockers, calcium-channel blockers or nitrates although the accepted additive anti-anginal benefits are unproven.⁷
• There is some evidence that the use of intravenous nicorandil prior to percutaneous coronary interventions has a cardioprotective effect.⁹

• Cardiogenic shock
• Left ventricular failure with low filling pressure
• Hypotension
• Breast-feeding

• Hypovolaemia
• Acute pulmonary oedema
• Acute myocardial infarction with acute left ventricular failure and low filling pressure
• Pregnancy
• Potassium-channel - syndrome - the use of nicorandil has been reported to be associated with life-threatening hyperkalaemia and cardiovascular disturbance.¹⁰ Treatment includes the use of sulfonylureas such as glibenclamide and glimepiride which counteract effects of nicorandil on potassium channel blockade. The action of gliclazide however is specific to pancreatic B2-cells and so does not interfere with nicorandil receptors.¹¹

See Summary of Product Characteristics.¹ Adverse effects are common on commencement of nicorandil, prompting up to 14% of patients to discontinue treatment. The frequency of unwanted effects can be minimised by reducing the initial dose and cautious subsequent dose increases. Patients should also be aware that side-effects are often transient and encouraged to persist with treatment despite initial problems.⁸ Nicorandil is generally well tolerated in the elderly and those with chronic hepatic and renal dysfunction but side-effects may include⁵:

• Headache (up to 36% of patients) ⁸
• Dizziness, hypotension, flushing and tachycardia
• Gastrointestinal disturbances⁷ and occasional anal ulceration. There is a putative link with ulceration higher up the gastro-intestinal tract.¹²

• Nicorandil should be prescribed twice daily and doses are titrated up slowly until symptoms are controlled or maximum dose is reached. ⁷ Bear in mind that if chest pain has become more frequent consider referring to a cardiologist.
• Although nicorandil alone is unlikely to cause symptomatic hypotension, additive effects may occur with other antihypertensive agents and other drugs. Concurrent use of alcohol, antidepressants and phosphodiesterase inhibitors (e.g. sildenafil) should be avoided.⁴
• Review after 1-4 weeks of therapy for monitoring of side-effects and dose adjustment. Referral to a cardiologist should be considered at any stage if chest pain is not responding to treatment.
• Continue regular aspirin and as required GTN and ensure other cardiovascular risk factors are managed appropriately.⁷
• Patients must not drive or operate machinery whilst taking nicorandil, until it is established that their performance is not impaired by dizziness or headache.¹

Evidence suggests that nicorandil possesses cardioprotective properties to limit myocardial infarct size by mimicking innate ischaemic preconditioning mechanisms. This would not only confer protection in acute ischaemic syndromes but during coronary bypass surgery and angioplasty.⁵ A recent trial also claimed that the addition of nicorandil to standard anti-anginal therapy reduces the frequency of coronary events in high-risk patients.¹³However, further research is needed before such conclusions can be verified.⁸

Conventional potassium channel activators may also be useful in the future management of asthma, hypertension, epilepsy, chronic pain, and urinary incontinence.²