Potassium channel blocker

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Tetraethylammonium is a commonly used potassium channel blocker Tetraethylammonium.svg
Tetraethylammonium is a commonly used potassium channel blocker

Potassium channel blockers are agents which interfere with conduction through potassium channels.

Contents

Medical uses

Arrhythmia

Effect of class III antiarrhythmic agent on cardiac action potential. Action potential Class III.svg
Effect of class III antiarrhythmic agent on cardiac action potential.

Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents. Atrial cardiomyocytes contain a specific subset of potassium ion channels which are absent in the ventricles. [1] Safety and efficacy of anti-arrhythmic potassium channel blockers will be improved by discovery of blockers specific to atria or ventricle. [1]

Mechanism

Class III agents predominantly block the potassium channels, thereby prolonging repolarization. [2] More specifically, their primary effect is on IKr. [3]

Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory).

Examples and uses

  • Amiodarone is indicated for the treatment of refractory VT or VF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals with cardiomyopathy and atrial fibrillation, to maintain normal sinus rhythm. Amiodarone prolongation of the action potential is uniform over a wide range of heart rates, so this drug does not have reverse use-dependent action. Amiodarone was the first agent described in this class. [4] Amiodarone should only be used to treat adults with life-threatening ventricular arrhythmias when other treatments are ineffective or have not been tolerated. [5]
  • Dofetilide blocks only the rapid K channels; this means that at higher heart rates, when there is increased involvement of the slow K channels, dofetilide has less of an action potential-prolonging effect.
  • Sotalol is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias.
  • Ibutilide is the only antiarrhythmic agent currently approved by the Food and Drug Administration for acute conversion of atrial fibrillation to sinus rhythm.
  • Azimilide
  • Bretylium
  • Clofilium
  • E-4031
  • Nifekalant [6]
  • Tedisamil
  • Sematilide

Side effects

These agents include a risk of torsades de pointes. [7]

Anti-diabetics

Sulfonylureas, such as gliclazide, are ATP-sensitive potassium channel blockers.

Other uses

Dalfampridine, A potassium channel blocker has also been approved for use in the treatment of multiple sclerosis. [8]

A study appears to indicate that topical spray of a selective Tandem pore Acid-Sensitive K+ (TASK 1/3 K+) (potassium antagonist) increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and obstructive sleep apnoea (OSA). [9] [10]

Reverse use dependence

Potassium channel blockers exhibit reverse use-dependent prolongation of the action potential duration. Reverse use dependence is the effect where the efficacy of the drug is reduced after repeated use of the tissue. [11] This contrasts with (ordinary) use dependence, where the efficacy of the drug is increased after repeated use of the tissue.

Reverse use dependence is relevant for potassium channel blockers used as class III antiarrhythmics. Reverse use dependent drugs that slow heart rate (such as quinidine) can be less effective at high heart rates. [11] The refractoriness of the ventricular myocyte increases at lower heart rates.[ citation needed ] This increases the susceptibility of the myocardium to early Afterdepolarizations (EADs) at low heart rates.[ citation needed ] Antiarrhythmic agents that exhibit reverse use-dependence (such as quinidine) are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm.[ citation needed ] Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic.

Drugs such as quinidine may be both reverse use dependent and use dependent. [11]

Calcium-activated potassium channel blockers

Examples of calcium-activated potassium channel blockers include:

Inwardly rectifying channel blockers

Examples of inwardly rectifying channel blockers include:

ROMK (Kir1.1)

Nonselective: Ba2+, [23] Cs+ [24]

GPCR regulated (Kir3.x)

ATP-sensitive (Kir6.x)

Tandem pore domain channel blockers

Examples of tandem pore domain channel blockers include:

Voltage-gated channel blockers

Examples of voltage-gated channel blockers include:

hERG (KCNH2, Kv11.1)-specific

KCNQ (Kv7)-specific

See also

Notes

  1. ↑ Amiodarone also blocks CACNA2D2-containing voltage gated calcium channels
  2. ↑ works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr)
  3. ↑ blocks potassium channels of the hERG-type
  4. ↑ Primarily inhibits outward voltage-gated Kv2.1 potassium channel currents.
  5. ↑ a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel

Related Research Articles

<span class="mw-page-title-main">Antiarrhythmic agent</span> Heart rhythm medication

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Dofetilide</span> Antiarrhythmic medication

Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 μg of dofetilide. It is not available in Europe or Australia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Torsades de pointes</span> Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.

<span class="mw-page-title-main">Potassium channel</span> Ion channel that selectively passes K+

Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cell functions.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

<span class="mw-page-title-main">Azimilide</span> Chemical compound

Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.

<span class="mw-page-title-main">Vanoxerine</span> Chemical compound

Vanoxerine is an investigational drug which is being evaluated for the treatment of heart arrhythmias and cocaine dependence. Vanoxerine is a piperazine derivative which has multiple pharmacological activities including acting as an dopamine reuptake inhibitor, serotonin transporter inhibitor, and as a blocker of the cardiac hERG repolarizing potassium channel (IKr).

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

<span class="mw-page-title-main">Dronedarone</span> Medication

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic medication developed by Sanofi-Aventis. It was approved by the US Food and Drug Administration (FDA) in July 2009. Besides being indicated in arrhythmias, it was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. The FDA label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure.

<span class="mw-page-title-main">Tedisamil</span> Chemical compound

Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium.

<span class="mw-page-title-main">Pilsicainide</span> Chemical compound

Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.

<span class="mw-page-title-main">E-4031</span> Chemical compound

E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.

<span class="mw-page-title-main">BRL-32872</span> Chemical compound

BRL-32872 is an experimental drug candidate that provides a novel approach to the treatment of cardiac arrhythmia. Being a derivative of verapamil, it possesses the ability to inhibit Ca+2 membrane channels. Specific modifications in hydrogen bonding activity, nitrogen lone pair availability, and molecular flexibility allow BRL-32872 to inhibit K+ channels as well. As such, BRL-32872 is classified as both a class III (K+ blocking) and class IV (Ca+2 blocking) antiarrhythmic agent.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

<span class="mw-page-title-main">AZD1305</span> Chemical compound

AZD1305 is an experimental drug candidate that is under investigation for the management and reversal of cardiac arrhythmias, specifically atrial fibrillation and flutter. In vitro studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa).

QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.

References

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