Azimilide: Difference between revisions

{{Cleanup-rewrite|date=May 2009}}

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 399535578

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = <!-- blanked - oldvalue: 149908-53-2 -->

| UNII_Ref = {{fdacite|changed|FDA}}

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| C=23 | H=28 | Cl=1 | N=5 | O=3

| molecular_weight = 457.953 g·mol⁻¹

| InChI = 1/C23H28ClN5O3/c1-26-12-14-27(15-13-26)10-2-3-11-28-22(30)17-29(23(28)31)25-16-20-8-9-21(32-20)18-4-6-19(24)7-5-18/h4-9,16H,2-3,10-15,17H2,1H3/b25-16+

| InChIKey = MREBEPTUUMTTIA-PCLIKHOPBQ

The action of azimilide is directed to the different currents present in atrial and ventricular cardiac myocytes. It principally blocks I_Kr, and I_Ks, with much weaker effects on I_Na ,I_Ca ,I_NCX and I_K.Ach. The I_Kr(rapid)and I_Ks (slow) are inward rectifier potassium currents, responsible for repolarizing cardiac myocytes towards the end of the cardiac action potential. A somewhat higher concentration of azimilide is needed to block the IKs current. Both blockages result in an increase of the QT interval and a prolongation of atrial and ventricular refractory periods.

Azimilide blocks hERG channels (which encode the I_Kr current) with an affinity comparable to that with which KvLQT1 / minK channels (which encode the I_Ks current) are blocked. This block exhibits reverse use-dependence, i.e. the channel blocking effect wanes at faster pulsing rates of the cell. A possible explanation is an interaction of azimilide with K⁺ close to its binding site in the ion channel. However there is an agonist effect as well, which is a voltage-dependent effect. This is a dual effect, a low voltage depolarization near the activation threshold will increase the current amplitude and higher depolarizing voltages will suppress the current amplitude.The effect comes from outside of the cell membrane and does not depend on [[G-proteins]] or kinase activity inside the cell. Azimilide binds on the extracellular domain of the hERG channel, this propagates a conformational change and inhbits the current. This change makes the activation gate open more easily by low voltage depolarization. Azimilide has two separate binding sites in hERG channel,one for its antagonist function and the other for the agonist function.

Azimilide has been studied for its anti-arrhythmic effects: its converts and maintains sinus rhythm in patients with atrial arrhythmias; and it reduces the frequency and severity of ventricular arrhythmias in patients with implanted cardioverter-defibrillators. Azimilide's most important adverse effect is [[torsades de pointes]], which is a form of [[ventricular tachycardia]].

F-1292 is the major metabolite of azimilide, it is formed cleavage of the aromethine bond. Unlike desmethyl azimilide, azimilide N-oxide and azimilide carboxylate F-1292 has no cardiovascular activity while the other three minor metabolites have a class ΙΙΙ antiarrhythmic activity. They only make out 10% of azimilde in the blood, so their contribution is not measurable.

This use of azimilide is very controversial subject,{{Citation needed|date=November 2009}} but this article will give only the plain scientific information about this drug.

* Nishida A.,Reien Y.,Ogura T.,Uemura H.,Tamagawa M.,Yabana H.,Nakaya H.(2007).Effects of azimilide on the muscarinic acetylcholine receptor-operated K⁺current and experimental atrial fibrillation in guinea-pig hearts.Journal of Pharmacological Sciences '''105''',229-239<k />

*Watanabe Y.,Koide Y.,Kimura J.(2006).Topics on the Na⁺/Ca²⁺ exchanger:Pharmacological characterization of Na⁺/Ca²⁺ exchanger inhibitors. Journal of Pharmacological Sciences'''102''',7-16<k />

*Hanna I.,Langberg J. (2004).The shocking story of azimilide. Journal of the American Heart Association'''110''',3624-3626<k />

*Lombardi F.,Borggrefe M.,Ruzyllo W.,Lüderitz B.(2006).Azimilide vs. placebo and sotalol for persistent atrial fibrillation:the A-COMET-2 trial. European Heart Journal'''27''',2224-2231<k />

*Braunwald E.,Zipes P.,Libby P.(2001) Heart Disease A Textbook of Cardiovascular Medicine 6th edition. W.B.Saunders Company '''717-736''',ISBN 0-7216-8561-7.

*Busch A.,Eigenberger B.,Jurkiewicz N.,Salata J.,Pica A.,Suessbrich H.,Lang F.(1998).Blockage of HERG channels by the class ΙΙΙ antiarrhythmic azimilide:mode of action.British Journal of Pharmacology'''123''',23-30<k />

*Jiang M.,Dun W.,Fan J.-S.,Tseng G.-N.(1999).Use-Dependent 'Agonist' Effect of Azimilide on the HERG Channels.The Journal of Pharmacology and Experimental Therapeutics'''291''',1324-1336<k />

*Corey A.,Agnew J.,Valentine S.,Parekh N.,Powell J.,Thompson G.(2002).The British Journal of Pharmacology'''54''',449-452<k />

[[Category:Organochlorides]]

[[it:Azimilide]]