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 c ...

Medical uses

Arrhythmia

Potassium channel blockers used in the treatment of

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the Cardiac cycle, heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per mi ...

are classified as class III antiarrhythmic agents.

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's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the 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 Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrill ...

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 diseases that affect 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. ...

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.

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 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 Australi ...

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. It is only recommended in those with significant abnormal heart rhythms due to potentially serious side effects. Evidence ...

is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias. *

Ibutilide Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current ...

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 federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for acute conversion of atrial fibrillation to sinus rhythm. *

Azimilide Azimilide is a class ΙΙΙ antiarrhythmic drug Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation ...

* Bretylium * Clofilium * E-4031 *

Nifekalant Nifekalant (INN) is a class III antiarrhythmic agent approved in Japan for the treatment of arrhythmias and ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Altho ...

* Tedisamil * Sematilide

Side effects

These agents include a risk of

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

Anti-diabetics

Sulfonylureas, such as

gliclazide Gliclazide, sold under the brand name Diamicron among others, is a sulfonylurea type of anti-diabetic medication, used to treat type 2 diabetes. It is used when dietary changes, exercise, and weight loss are not enough. It is taken by mouth. ...

, 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 (SUR) ...

blockers.

Other uses

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

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) can be less effective at high heart rates. The

refractoriness In materials science, a refractory material or refractory is a material that is resistant to decomposition by heat, pressure, or chemical attack, and retains strength and form at high temperatures. Refractories are polycrystalline, polyphase, ...

of the ventricular

myocyte A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a m ...

increases at lower

heart rate Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and e ...

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 quinidine) 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 channel blockers

Examples of calcium-activated channel blockers include: *

Charybdotoxin Charybdotoxin (CTX) is a 37 amino acid neurotoxin from the venom of the scorpion '' Leiurus quinquestriatus hebraeus'' (''deathstalker'') that blocks calcium-activated potassium channels. This blockade causes hyperexcitability of the nervous syst ...

Iberiotoxin Iberiotoxin (IbTX) is an ion channel toxin purified from the Eastern Indian red scorpion '' Hottentotta tamulus''. Iberiotoxin selectively inhibits the current through large-conductance calcium-activated potassium channels. Chemistry Iberioto ...

Apamin Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin (bee venom). Dry bee venom consists of 2–3% of apamin. Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system. ...

* 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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

antagonists * Ifenprodil * Caramiphen * Cloperastine *

Clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate resp ...

Dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...

* Ethosuximide * Tertiapin * Tipepidine * Ba²⁺

ATP-sensitive (K_ir6.x)

* Meglitinides (Non-

Sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta ...

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

s **

Acetohexamide Acetohexamide (trade name Dymelor) is a first-generation sulfonylurea medication used to treat diabetes mellitus type 2, particularly in people whose diabetes cannot be controlled by diet alone. Mechanism of action Acetohexamide bind to an A ...

** Carbutamide **

Chlorpropamide Chlorpropamide is a drug in the sulfonylurea class used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea. Mechanism of action Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, ...

** Glycyclamide **

Metahexamide Metahexamide (INN) is an anti-diabetic drug from the group of sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of di ...

s (continued) **

Tolazamide Tolazamide is an oral blood glucose lowering drug used for people with Type 2 diabetes. It is part of the sulfonylurea family (ATC A10BB). Synthesis ''para''-Toluenesulfonamide is converted to its carbamate with ethyl chloroformate in the pres ...

Tolbutamide Tolbutamide is a first-generation potassium channel blocker, sulfonylurea oral hypoglycemic medication. This drug may be used in the management of type 2 diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin b ...

** Glibornuride **

Glisoxepide Glisoxepide (INN) is an orally available anti-diabetic drug from the group of sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the ...

Glyclopyramide Glyclopyramide (INN, marketed under the tradename Deamelin-S) is a sulfonylurea drug used in the treatment of diabetes. It has been marketed in Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asi ...

Gliclazide Gliclazide, sold under the brand name Diamicron among others, is a sulfonylurea type of anti-diabetic medication, used to treat type 2 diabetes. It is used when dietary changes, exercise, and weight loss are not enough. It is taken by mouth. ...

** Glibenclamide (glyburide) ** Glipizide **

Glimepiride Glimepiride, is an anti-diabetic medication used to treat type 2 diabetes. It is less preferred than metformin. Use is recommended together with diet and exercise. It is taken by mouth. Glimepiride takes up to three hours for maximum effect and l ...

** 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 feeling in a specific area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural space. It ...

* Quinidine *

Fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...

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

Almokalant Almokalant is a drug used to treat arrhythmia. It is a potassium channel blocker. It has been found to have teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-d ...

Amiodarone also blocks CACNA2D2-containing

voltage gated calcium channel Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabili ...

s *

* Bretylium *

Bunaftine Bunaftine (or bunaphtine) is an antiarrhythmic agent Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibril ...

* 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 bond In ...

s, such as κ-conotoxin, * Dalazatide *

works by selectively blocking the rapid component of the

delayed rectifier outward potassium current Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized c ...

(I_Kr) *

Dronedarone Dronedarone, sold under the brand name Multaq, is a medication by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatmen ...

,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. * Hanatoxin *

HgeTx1 HgeTx1 (systematic name: α-KTx 6.14) is a toxin produced by the Mexican scorpion '' Hoffmanihadrurus gertschi'' that is a reversible blocker of the ''Shaker B'' K+-channel, a type of voltage-gated potassium channels. Etymology and Source The t ...

HsTx1 HsTx1 is a toxin from the venom of the scorpion ''Heterometrus spinifer''. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel. Etymology HsTx1 stands for ''Heterometrus spinifer'' Toxin 1. The systematic name for t ...

a very potent inhibitor of the rat Kv1.3

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

, * Inakalant * Kaliotoxin *

Linopirdine Linopirdine is a putative cognition-enhancing drug with a novel mechanism of action. Linopirdine blocks the KCNQ2\3 heteromer M current with an IC50 of 2.4 micromolar disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer c ...

Lolitrem B Lolitrem B is one of many toxins produced by a fungus called ''Epichloë festucae'' var. ''lolii''), which grows in '' Lolium perenne'' (perennial ryegrass). The fungus is symbiotic with the ryegrass; it doesn't harm the plant, and the toxins ...

Maurotoxin Maurotoxin (abbreviated MTX) is a peptide toxin from the venom of the Tunisian chactoid scorpion '' Scorpio maurus palmatus'', from which it was first isolated and from which the chemical gets its name. It acts by blocking several types of volt ...

* Notoxin * Paxilline * Pinokalant * Quinidine * ShK-186 *

* Tedisamil * Terikalant *

Tetraethylammonium Tetraethylammonium (TEA), () or (Et4N+) is a quaternary ammonium cation consisting of four ethyl groups attached to a central nitrogen atom, and is positively charged. It is a counterion used in the research laboratory to prepare lipophilic salts ...

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 ...

, * Vernakalant

hERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...
(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 AmmTX3, produced by ''Androctonus mauretanicus'', is a scorpion toxin of the α-KTX15 subfamily. The toxin is known for its ability to act as a specific Kv4 channel blocker, and thereby reducing the A-type potassium current through this channel. ...

Astemizole Astemizole (marketed under the brand name Hismanal, developmental code R43512) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It was withdrawn from the ma ...

* Azaspiracid * AZD1305 *

* Bedaquiline * BeKm-1 *

BmTx3 BmTx3 is a neurotoxin, which is a component of the venom of the scorpion ''Buthus Martensi'' Karsch. It blocks A-type potassium channels in the central nervous system and hERG-channels in the heart. Source/Isolation BmTx3 was originally purified f ...

* 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 di ...

Cisapride Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors i ...

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. Clar ...

Darifenacin Darifenacin (trade name Enablex in United States and Canada, Emselex in the European Union) is a medication used to treat urinary incontinence due to an overactive bladder. It was discovered by scientists at the Pfizer research site in Sandwich, ...

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 suppressant) ...

Diallyl trisulfide Diallyl trisulfide (DATS), also known as Allitridin, is an organosulfur compound with the formula S(SCH2CH=CH2)2. It is one of several produced by the hydrolysis of allicin, including diallyl disulfide and diallyl tetrasulfide, DATS is one of the ...

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 th ...

* 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 du ...

Gigactonine Gigactonine is a naturally occurring diterpene alkaloid first isolated from '' Aconitum gigas''. It occurs widely in the Ranunculaceae plant family. The polycyclic ring system of this chemical compound contains nineteen carbon atoms and one nitro ...

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 and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous can ...

Norpropoxyphene Norpropoxyphene is a major metabolite of the opioid analgesic drug dextropropoxyphene, and is responsible for many of the side effects associated with use of this drug, especially the unusual toxicity seen during dextropropoxyphene overdose. It h ...

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 P ...

Pimozide Pimozide (sold under the brand name Orap) is an antipsychotic 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 weight basis ...

PNU-282,987 PNU-282,987 is a drug that acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors. In animal studies, it shows nootropic effects, and derivatives may be useful in the treatment of schizophrenia, ...

Promethazine Promethazine is a first-generation antihistamine, antipsychotic, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating pe ...

* Quinidine * Ranolazine *

Roxithromycin Roxithromycin is a semi-synthetic macrolide antibiotic. It is used to treat respiratory tract, urinary and soft tissue infections. Roxithromycin is derived from erythromycin, containing the same 14-membered lactone ring. However, an N-oxime side ...

* Sertindole * Solifenacin * Tamulotoxin *

Terodiline Terodiline is a drug used in urology as an antispasmodic. It relaxes the smooth muscle and used to reduce bladder tone in treatment of urinary frequency and incontinence. Muscle relaxation caused by terodiline, is probably due to its anticholi ...

* Terfenadine *

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

* XE-991 * Spooky toxin (SsTx)

Notes

References

{{Antiarrhythmic agents