Potassium channel blocker

Tetraethylammonium is a commonly used potassium channel blocker

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

Medical uses

Arrhythmia

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.

Mechanism

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.[1] More specifically, their primary effect is on IKr.[2]

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.[3] Amiodarone should only be used to treat adults with life-threatening ventricular arrhythmias when other treatments are ineffective or have not been tolerated.[4]
  • 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[5]
  • Tedisamil
  • Sematilide

Side effects

These agents include a risk of torsades de pointes.[6]

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.[7]

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.[8] 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.[8] The refractoriness of the ventricular myocyte increases at lower heart rates. 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.[8]

Calcium-activated channel blockers

Examples of calcium-activated channel blockers include:

Inwardly rectifying channel blockers

Examples of inwardly rectifying channel blockers include:

ROMK (Kir1.1)

Nonselective: Ba2+,[20] Cs+[21]

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

References

  1. ↑ Lenz TL, Hilleman DE (July 2000). "Dofetilide, a new class III antiarrhythmic agent". Pharmacotherapy. 20 (7): 776–86. doi:10.1592/phco.20.9.776.35208. PMID 10907968. S2CID 19897963.
  2. ↑ Riera AR, Uchida AH, Ferreira C, et al. (2008). "Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome". Cardiol J. 15 (3): 209–19. PMID 18651412.
  3. ↑ "Milestones in the Evolution of the Study of Arrhythmias".
  4. ↑ "FDA MedWatch". Food and Drug Administration.
  5. ↑ Sahara M, Sagara K, Yamashita T, Iinuma H, Fu LT, Watanabe H (August 2003). "Nifekalant hydrochloride, a novel class III antiarrhythmic agent, suppressed postoperative recurrent ventricular tachycardia in a patient undergoing coronary artery bypass grafting and the Dor approach". Circ. J. 67 (8): 712–4. doi:10.1253/circj.67.712. PMID 12890916.
  6. ↑ "Introduction: Arrhythmias and Conduction Disorders: Merck Manual Professional".
  7. ↑ Judge SI, Bever CT (July 2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacol. Ther. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864.
  8. 1 2 3 Hondeghem, L. M. (1995), Breithardt, Günter; Borggrefe, Martin; Camm, A. John; Shenasa, Mohammad (eds.), "Use Dependence and Reverse Use Dependence of Antiarrhythmic Agents: Pro- and Antiarrhythmic Actions", Antiarrhythmic Drugs: Mechanisms of Antiarrhythmic and Proarrhythmic Actions, Springer Berlin Heidelberg, pp. 92–105, doi:10.1007/978-3-642-85624-2_6 (inactive 31 October 2021), ISBN 9783642856242{{citation}}: CS1 maint: DOI inactive as of October 2021 (link)
  9. ↑ Thompson J, Begenisich T (May 2000). "Electrostatic interaction between charybdotoxin and a tetrameric mutant of Shaker K(+) channels". Biophysical Journal. 78 (5): 2382–91. Bibcode:2000BpJ....78.2382T. doi:10.1016/S0006-3495(00)76782-8. PMC 1300827. PMID 10777734.
  10. ↑ Naranjo D, Miller C (January 1996). "A strongly interacting pair of residues on the contact surface of charybdotoxin and a Shaker K+ channel". Neuron. 16 (1): 123–30. doi:10.1016/S0896-6273(00)80029-X. PMID 8562075. S2CID 16794677.
  11. ↑ Yu M, Liu SL, Sun PB, Pan H, Tian CL, Zhang LH (January 2016). "Peptide toxins and small-molecule blockers of BK channels". Acta Pharmacologica Sinica. 37 (1): 56–66. doi:10.1038/aps.2015.139. PMC 4722972. PMID 26725735.
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  13. ↑ Candia, S; Garcia, ML; Latorre, R (1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel". Biophysical Journal. 63 (2): 583–90. Bibcode:1992BpJ....63..583C. doi:10.1016/S0006-3495(92)81630-2. PMC 1262182. PMID 1384740.
  14. ↑ M. Stocker; M. Krause; P. Pedarzani (1999). "An apamin-sentisitive Ca2+-activated K+ current in hippocampal pyramidal neurons". PNAS. 96 (8): 4662–4667. Bibcode:1999PNAS...96.4662S. doi:10.1073/pnas.96.8.4662. PMC 16389. PMID 10200319.
  15. ↑ Baldus, Marc; Becker, Stefan; Pongs, Olaf; Martin-Eauclaire, Marie-France; Hornig, Sönke; Giller, Karin; Lange, Adam (April 2006). "Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR". Nature. 440 (7086): 959–962. Bibcode:2006Natur.440..959L. doi:10.1038/nature04649. ISSN 1476-4687. PMID 16612389. S2CID 4429604.
  16. ↑ Martin-Eauclaire, M. F.; Mansuelle, P.; Rochat, H.; Benslimane, A.; Zerrouk, H.; Gola, M.; Jacquet, G.; Crest, M. (1992-01-25). "Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom". Journal of Biological Chemistry. 267 (3): 1640–1647. doi:10.1016/S0021-9258(18)45993-5. ISSN 0021-9258. PMID 1730708.
  17. ↑ Philippe, G (15 February 2016). "Lolitrem B and Indole Diterpene Alkaloids Produced by Endophytic Fungi of the Genus Epichloë and Their Toxic Effects in Livestock". Toxins. 8 (2): 47. doi:10.3390/toxins8020047. PMC 4773800. PMID 26891327.
  18. ↑ McLeod, JF; Leempoels, JM; Peng, SX; Dax, SL; Myers, LJ; Golder, FJ (November 2014). "GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers". British Journal of Anaesthesia. 113 (5): 875–83. doi:10.1093/bja/aeu182. PMID 24989775.
  19. ↑ Dopico AM, Bukiya AN, Kuntamallappanavar G, Liu J (2016). "Modulation of BK Channels by Ethanol". International Review of Neurobiology. 128: 239–79. doi:10.1016/bs.irn.2016.03.019. ISBN 9780128036198. PMC 5257281. PMID 27238266.
  20. 1 2 Patnaik, Pradyot (2003). Handbook of inorganic chemicals. McGraw-Hill. pp. 77–78. ISBN 978-0-07-049439-8.
  21. ↑ Sackin, H; Syn, S; Palmer, L G; Choe, H; Walters, D E (Feb 2001). "Regulation of ROMK by extracellular cations". Biophysical Journal. 80 (2): 683–697. Bibcode:2001BpJ....80..683S. doi:10.1016/S0006-3495(01)76048-1. ISSN 0006-3495. PMC 1301267. PMID 11159436.
  22. ↑ Kobayashi T, Washiyama K, Ikeda K (March 2006). "Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil". Neuropsychopharmacology. 31 (3): 516–24. doi:10.1038/sj.npp.1300844. PMID 16123769. S2CID 10093765.
  23. ↑ Soeda, Fumio; Fujieda, Yoshiko; Kinoshita, Mizue; Shirasaki, Tetsuya; Takahama, Kazuo (2016). "Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels". Pharmacology Biochemistry and Behavior. 144: 26–32. doi:10.1016/j.pbb.2016.02.006. ISSN 0091-3057. PMID 26892760. S2CID 30118634.
  24. ↑ YAMAMOTO, Gen; SOEDA, Fumio; SHIRASAKI, Tetsuya; TAKAHAMA, Kazuo (2011). "Is the GIRK Channel a Possible Target in the Development of a Novel Therapeutic Drug of Urinary Disturbance?". Yakugaku Zasshi. 131 (4): 523–532. doi:10.1248/yakushi.131.523. ISSN 0031-6903. PMID 21467791.
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  27. ↑ Kawaura, Kazuaki; Ogata, Yukino; Inoue, Masako; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo (2009). "The centrally acting non-narcotic antitussive tipepidine produces antidepressant-like effect in the forced swimming test in rats". Behavioural Brain Research. 205 (1): 315–318. doi:10.1016/j.bbr.2009.07.004. ISSN 0166-4328. PMID 19616036. S2CID 29236491.
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  31. 1 2 Meadows HJ, Randall AD (Mar 2001). "Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel". Neuropharmacology. 40 (4): 551–9. doi:10.1016/S0028-3908(00)00189-1. PMID 11249964. S2CID 20181576.
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