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Potassium channels inhibitors or closers

The drugs which induce the closure of potassium channels have, in theory, the inverse effects of the openers. According to their preferential affinity for potassium channels of the various organs, they increase insulin secretion, increase the duration of the cardiac action potential and could increase peripheral vascular resistance.

Their therapeutic uses result from their hypoglycemic effect and their antiarrhythmic effect.

K+-channel closers with hypoglycemic effect 

The drugs of this group are sulfonylureas and repaglinide.

At the level of pancreatic beta cells, they induce the closure of ATP-dependant   potassium channels, which induces an increase in the intracellular concentration of K+, depolarization, and the opening of voltage-dependant calcium channels .

The main sulfonylureas are tolbutamide, chlorpropamide, carbutamide, glipizide, glibenclamide, glibornuride, gliclazide and glimepiride ( See “Sulfonylureas”. ).

K+-channel closers with antiarrhythmic effect 

The drugs which have antiarrhythmic effects by inducing the closure of potassium channels constitute group III of Vaughan-Williams classification. By inducing the closure of potassium channels of cardiac conducting tissue, they slow the efflux of potassium and prolong the duration of the action potential and, consequently, the duration of the refractory period, without modifying the rate of conduction.

The two drugs which, in addition to their other properties, induce the closure of potassium channels are amiodarone and sotalol.

  1. Amiodarone.
    Amiodarone is the main antiarrhythmic drug of group III.
    Apart from its effect on potassium channels, amiodarone has alpha and beta-blocker effects, inducing a decrease of the peripheral resistances.
    Concerning pharmacokinetics, amiodarone which is an iodized molecule, binds to certain tissues and has a plasma half-life of about a one month. It is partly metabolized by deiodination and the released iodine is found in plasma and urine in the form of iodide.
    Amiodarone, (Cordarone*), is indicated for the treatment of supraventricular and ventricular arrhythmias refractory to the other antiarrhythmics.
    Having a bradycardic effect, amiodarone is contra-indicated in patients with sinus bradycardia and with sino-atrial and atrioventricular block.
    The combination of amiodarone with certain drugs is disadvised:
    • class I antiarrhythmic, because the risk of torsades de pointes.
    • beta-blockers, because there is an increased risk of excessive bradycardia.

    Hypokalemia increases the frequency of these effects.
    Amiodarone can induce several undesirable effects, many of them being dose-related:

    • ophthalmic symptoms linked to corneal deposits giving coloured haloes,
    • frequent thyroid disturbances, generally hyperthyroidism sometimes requiring discontinuation of amiodarone and treatment by synthetic antithyroids or corticoids, and more rarely hypothyroidism.
    • photosensivity disadvising the exposure to sunlight.
    • diffuse interstitial pneumopathies.
    • hepatic disorders, with rise in transaminases.

    In spite of its considerable adverse effects, amiodarone, because of its efficacy, is still frequently used for the treatment of the cardiac arrhythmias resistant to the other treatments.

  2. Sotalol
    Sotalol induces the closure of potassium channels but has in addition nonselective beta-blocking properties, without beta-mimetic activity.
    Sotalol is a racemic: only one of  the isomers has beta-blocking activity, but the two isomers prolong the duration of the cardiac action potential by inhibition of the opening of potassium channels, which prolongs the repolarization. It thus has the therapeutic uses and the contraindications of the beta-blockers and of class III antiarrhythmics. Sotalol (Sotacor*, Betapace*) is used for the management of supraventricular and ventricular arrhythmias. It prolongs the Qt interval and can cause torsades de pointes.
    Notice
    Ibutilide, whose chemical structure is related to sotalol, prolongs the duration of the action potential by inhibiting the opening of potassium channels with delayed opening and also by increasing the duration of opening of voltage-dependant sodium channels, which prolong QT interval. Ibutilide (Corvert*), a class III antiarrthyhmic, is used in the management of atrial fibrillation and atrial flutter. It can cause torsades de pointes and ECG should be monitored during its infusion.
    Dofetilide,Tykosin*, a class III antiarrthyhmic, used in the treatment of atrial fibrillation. Its principal danger is to elicit torsades de pointes.

  3. Bretylium 
    Bretylium prolongs the action potential and modifies catecholamine release: initially, it increases their release, and subsequently it blocks it. Bretylium, Bretylate*, is used for the treatment of relapses of severe, ventricular arrhythmias refractory to the other treatments, and the curative treatment of the ventricular tachycardias.
    Many drugs whose principal property is not to act on potassium channels can however inhibit them. By slowing the potassium efflux from the cardiac cells, they prolong the QT interval and are likely to give torsades de pointes. Among these drugs one can quote cisapride, various antihistamines and neuroleptics.

Remarks:

  1. Modifiers of the opening of potassium channels can inhibit the cellular proliferation, that of the melanoma for example, which shows the possibility for new therapeutic applications.
  2. Potassium and cardiac glycosides are in competition for binding to Na+/K+-ATPASE: a decrease of kalemia increases the effects of cardiac glycosides and conversely.
  3. T hallium was and is sometimes used topically as depilatory. It is in addition used as rodenticide. It is a very toxic element, which elicits in case of poisoning different disorders, among which neurological ones and alopecia which appears two or three weeks after the onset of the poisoning.
    Taking into account the similarity of the thallium ion Tl+(and not Tl 3+ ) with the K+ion, one can suppose that its depilatory effect results from the closure of potassium channels. The effect of thallium is opposed to that of minoxidil which is an opener of potassium channels.
  4. Aminopyridines such as the 4-amidopyridine and the 3-4-diamidopyridine inhibit voltage-gated potassium channels at the level of the synaptic terminations, which induces depolarization, influx of calcium and increase in the release of acetylcholine. They could have an interest in the treatment of certain disorders of neuromuscular transmission, in particular of toxic origin.

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  Last update : July 2007  
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