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Pathway Description
Ibutilide Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2013-08-22
Last Updated: 2019-09-12
This pathway illustrates the ibutilide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cellsÈ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f).
Ibutilide is a Class III antiarrhythmic drug that blocks potassium current through the voltage-gated rapid delayed rectifying potassium channel (I-Kr). I-Kr is partially responsible for the final repolarization phase of the cardiac myocyte action potential. As such, I-Kr antagonism delays repolarization and increases action potential duration. Ibutilide also activates a slow inward sodium current (not shown) which likely contributes to action potential prolongation. Ibutilide may be used to treat atrial fibrillation or atrial flutter. It may cause Torsades de Pointes in up to 6% of patients.
References
Ibutilide Pathway References
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Striated Muscle Contraction References
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Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J: KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J. 2000 Dec 1;19(23):6326-30. doi: 10.1093/emboj/19.23.6326.
Pubmed: 11101505
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Pubmed: 15368194
Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, Lipska BK, Hyde TM, Song J, Rujescu D, Giegling I, Mayilyan K, Proust MJ, Soghoyan A, Caforio G, Callicott JH, Bertolino A, Meyer-Lindenberg A, Chang J, Ji Y, Egan MF, Goldberg TE, Kleinman JE, Lu B, Weinberger DR: A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med. 2009 May;15(5):509-18. doi: 10.1038/nm.1962. Epub 2009 May 3.
Pubmed: 19412172
Warmke JW, Ganetzky B: A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3438-42. doi: 10.1073/pnas.91.8.3438.
Pubmed: 8159766
Itoh T, Tanaka T, Nagai R, Kamiya T, Sawayama T, Nakayama T, Tomoike H, Sakurada H, Yazaki Y, Nakamura Y: Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome. Hum Genet. 1998 Apr;102(4):435-9. doi: 10.1007/s004390050717.
Pubmed: 9600240
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