Potassium channel blockers are agents which interfere with conduction through

potassium channel 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 ...

Medical uses

Arrhythmia

Potassium channel blockers used in the treatment of

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beat ...

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

Mechanism

Class III agents predominantly block the potassium channels, thereby prolonging repolarization. More specifically, their primary effect is on I_Kr. Since these agents do not affect the

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

, 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 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 paroxys ...

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 Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

and

atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...

, 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.

was the first agent described in this class. Amiodarone should only be used to treat adults with life-threatening ventricular arrhythmias when other treatments are ineffective or have not been tolerated. *

Dofetilide Dofetilide is a class III antiarrhythmic agents, 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 microgram, μg of dofetilide. It is not a ...

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 Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into ...

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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

for acute conversion of

to sinus rhythm. * Azimilide *

Bretylium Bretylium (also bretylium tosylate) is an antiarrhythmic agent. It blocks the release of noradrenaline from nerve terminals. In effect, it decreases output from the peripheral sympathetic nervous system. It also acts by blocking K+ channels and ...

* Clofilium * E-4031 * Nifekalant * Tedisamil * Sematilide

Side effects

These agents include a risk of

torsades de pointes ''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP; also called ''torsades'') (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorph ...

Anti-diabetics

Sulfonylureas Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea, ...

, such as gliclazide, are

ATP-sensitive potassium channel An ATP-sensitive potassium channel (or KATP channel) is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (S ...

blockers.

Other uses

Dalfampridine, A potassium channel blocker has also been approved for use in the treatment of

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

. 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).

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. 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 Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

) can be less effective at high heart rates. The refractoriness of the ventricular

myocyte A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...

increases at lower

heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...

s. This increases the susceptibility of the myocardium to early Afterdepolarizations (EADs) at low heart rates. Antiarrhythmic agents that exhibit reverse use-dependence (such as

) are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm. 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.

Calcium-activated potassium channel blockers

Examples of calcium-activated potassium channel blockers include: * Charybdotoxin * Iberiotoxin * Apamin * Kaliotoxin, * Lolitrem, * BK_Ca-specific ** GAL-021 ** Ethanol (alcohol)

Inwardly rectifying channel blockers

Examples of inwardly rectifying channel blockers include:

ROMK (K_ir1.1)

Nonselective: Ba²⁺, Cs⁺

GPCR regulated (K_ir3.x)

* GPCR antagonists * Ifenprodil * Caramiphen *

Cloperastine Cloperastine ( INN) or cloperastin, in the forms of cloperastine hydrochloride ( JAN) (brand names Hustazol, Nitossil, Seki) and cloperastine fendizoate, is an antitussive and antihistamine that is marketed as a cough suppressant in Japan, Hong K ...

Clozapine Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...

Dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

* Ethosuximide * Tertiapin *

Tipepidine Tipepidine (International Nonproprietary Name, INN; also known as tipepidine hibenzate (Japanese Accepted Name, JAN); brand names Asverin, Antupex, Asvelik, Asvex, Bitiodin, Cofdenin A, Hustel, Nodal, and Sotal) is a Organic compound#Synthetic co ...

* CGP-7930 * Ba²⁺

ATP-sensitive (K_ir6.x)

* Meglitinides (Non-

Sulfonylurea Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea ...

s) ** Mitiglinide ** Nateglinide ** Repaglinide *

s ** Acetohexamide ** Carbutamide **

Chlorpropamide Chlorpropamide is an antidiabetic drug, belonging to the sulfonylurea class of organic compounds. It is used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea. Mechanism of action Like other sulfonylureas, ch ...

** Glycyclamide ** Metahexamide *

s (continued) ** Tolazamide ** Tolbutamide ** Glibornuride ** Glisoxepide ** Glyclopyramide ** Gliclazide ** Glibenclamide (glyburide) ** Glipizide ** Glimepiride ** Glicaramide

Tandem pore domain channel blockers

Examples of tandem pore domain channel blockers include: *

Bupivacaine Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease sensation in a specific small area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural ...

Quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

Fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

* Seproxetine (Norfluoxetine) * 12-''O''-tetradecanoylphorbol-13-acetate (TPA) (phorbol 12-myristate 13-acetate).

Voltage-gated channel blockers

Examples of voltage-gated channel blockers include: *Some types of

dendrotoxin Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes ('' Dendroaspis'') that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctio ...

s * 3,4-Diaminopyridine (amifampridine) * 4-Aminopyridine (fampridine/dalfampridine) * Adekalant * Almokalant *

Amiodarone also blocks CACNA2D2-containing voltage gated calcium channels * Azimilide *

* Bunaftine * Charybdotoxin * Clamikalant *

Conotoxin A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus '' Conus''. Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. C ...

s, such as κ-conotoxin, * Dalazatide *

works by selectively blocking the rapid component of the delayed rectifier outward potassium current (I_Kr) * Dronedarone,Guillemare E, Marion A, Nisato D, Gautier P, “Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells,” in Journal of Cardiovascular Pharmacology, 2000 7 * E-4031blocks

s of the hERG-type * GuangxitoxinPrimarily inhibits outward voltage-gated K_v2.1

currents Currents, Current or The Current may refer to: Science and technology * Current (fluid), the flow of a liquid or a gas ** Air current, a flow of air ** Ocean current, a current in the ocean *** Rip current, a kind of water current ** Current (hy ...

. * Hanatoxin * HgeTx1 * HsTx1 a very potent inhibitor of the rat Kv1.3

voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...

* Ibutilide, * Inakalant * Kaliotoxin * Linopirdine * Lolitrem B * Maurotoxin * Nifekalant * Notoxin * Parabutoxin * Paxilline * Pinokalant *

* ShK-186 *

* Tedisamil * Terikalant *

Tetraethylammonium Tetraethylammonium (TEA) is a quaternary ammonium cation with the chemical formula , consisting of four ethyl groups (, denoted Et) attached to a central nitrogen atom. It is a counterion used in the research laboratory to prepare lipophilic salt ...

B. Hille (1967). "The selective inhibition of delayed potassium currents in nerve by tetraethylammonium ions." ''J. Gen. Physiol.'' 50 1287-1302.C. M. Armstrong (1971). "Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons." ''J. Gen. Physiol.'' 58 413-437. *

Verapamil Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be use ...

* Vernakalant

hERG (KCNH2, K_v11.1)-specific

Ajmaline Ajmaline (also known by trade names Gilurytmal, Ritmos, and Aritmina) is an alkaloid that is classified as a 1-A antiarrhythmic agent. It is often used to induce arrhythmic contraction in patients suspected of having Brugada syndrome. Individuals ...

* AmmTX3 * Astemizole * Azaspiracid * AZD1305 * Azimilide * Bedaquiline * BeKm-1 * BmTx3 * BRL-32872 *

Chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

* Cisapride *

Clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...

* Darifenacin *

Dextropropoxyphene Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive (cough suppressan ...

* Diallyl trisulfide *

Domperidone Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the ...

* E-4031 * Ergtoxins *

Erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...

* Gigactonine *

Haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

Ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

* Norpropoxyphene *

Orphenadrine Orphenadrine (sold under many brand names) is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is a muscle relaxant that is used to treat muscle pain and to help with motor control in ...

Pimozide Pimozide (sold under the brand name Orap) is a neuroleptic medication, drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weigh ...

* PNU-282,987 *

Promethazine Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold a ...

* Ranolazine * Roxithromycin * Sertindole * Solifenacin * Tamulotoxin * Terodiline *

Terfenadine Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triluda ...

Thioridazine Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwid ...

* Tolterodine * Vanoxerine * Vernakalant

KCNQ (K_v7)-specific

* Linopirdine * XE-991 * Spooky toxin (SsTx)

Notes

References

{{Antiarrhythmic agents