Potassium Channel Openers

POTASSIUM CHANNEL OPENERS

Minoxidil and diazoxide are K+ channel openers which were used earlier in severe hypertension and hypertensive emergencies. Novel K+ channel openers like nicorandil, pinacidil, cromakalim and others have been developed in the 1990s.

Since intracellular concentration of K+ is much higher (150 mM) compared to extracellular (4–5 mM), K+ channel opening results in outflow of K+ ions and hyperpolarization. There are multiple types of K+ channels, e.g. voltage dependent, Ca2+ activated, receptor operated, ATP sensitive, Na+ activated and cell volume sensitive which serve diverse functions and exhibit different sensitivities to drugs. As such, K+ channel openers exhibit considerable diversity in action.

The most prominent action of K+ channel openers is smooth muscle relaxation—vascular as well as visceral: their potential clinical applications (see box) are primarily based on this property. Diazoxide and some other K+ channel openers reduce insulin secretion, while sulfonylureas (glibenclamide) cause hypoglycaemia by blocking K+ channels in pancreatic β cells and promoting insulin release.

Potential Clinical Applications Of K+ Channel Openers

·              Angina pectoris

·              Hypertension

·              Congestive heart failure

·              Myocardial salvage in MI

·              Antihypoglycaemic (Insulinoma)

·              Alopecia

·              Bronchial asthma

·              Urinary urge incontinence

·              Peripheral vascular disease (Raynaud’s, cerebrovascular)

·              Erectile dysfunction

·              Premature labour

Nicorandil

This novel antianginal drug activates ATP sensitive K+ channels— hyperpolarizing vascular smooth muscle. The vasodilator action is partly antagonized by K+ channel blocker glibenclamide. Like nitrates it also acts as a NO donor—relaxes blood vessels by increasing cGMP. Thus, arterial dilatation is coupled with venodilatation. Coronary flow is increased; dilatation of both epicardial conducting vessels and deeper resistance vessels has been demonstrated. No significant cardiac effects on contractility and conduction have been noted.

Beneficial effects on angina frequency and exercise tolerance comparable to nitrates, β blockers and CCBs have been obtained in stable as well as vasospastic angina. Mitochondrial K+ATP channel opening by nicorandil is believed to exert myocardial protection by a process of ischaemic preconditioning which appears to reduce myocardial stunning, arrhythmias and infarct size when a coronary artery is suddenly blocked. Myocardial recovery from ischaemic damage after MI as measured by left ventricular wall motion is improved by nicorandil.

The cardioprotective property of nicorandil, has been supported by the large ‘Impact of nicorandil in angina’ (IONA, 2002) randomized trial which found nicorandil to reduce acute coronary events in high risk stable angina patients.

Side Effects are flushing, palpitation, weakness, headache, dizziness, nausea and vomiting. Large painful aphthous ulcers in the mouth, which heal on stopping nicorandil have been reported.

Dose: 5–20 mg BD; NIKORAN, 5, 10 mg tabs, 2 mg/vial, 48 mg/vial inj; KORANDIL 5, 10 mg tabs.