Azimilide

This is a class ΙΙΙ antiarrhythmic drug, which is used in treatment for rhythm control of the heart. The agents from this heterogeneous group have an effect on the repolarization, they prolongs the duration of the action potential and the refractory period.Also they slow down the sponteneous discharge frequency of automatic pacemakers by deprssing the slope of diastolic depolarization.They shift the treshold towards zero or hyperpolarize the membrane potential. Although each agent has his own properties and will have thus a different function.

Heart potential

Azimilide dihydrochloride is a chlorophenylfranyl compound, which has an electrophysiological effect on the repolarization of the heart. This potential differs with a neural action potential in his refractory period, which is longer and will prohibit a to fast triggering of the next one. Hereby a tetania will be excluded. The ion channels present in the heart are the mediators off de-and repolarization, each channel has a ion current which has a function in a certain stage of the heartpotential.

The ion currents

The action of azimilide is directed on to the different currents present in most parts of the heart, it will block I_Kr,I_Ks, I_Na ,I_Ca ,I_NCX and I_K.Ach. The I_Kr(rapid)and I_Ks (slow) are rectifier potassium currents, however a higher concentration of azimilide is needed to block the IKs. Both blockages result in a increase of the QT interval, according to the dosage of azilimide, and a prolongation of atrial and ventricular refractory periods.Azimilide has a more balanced blockage of the slow as well as the rapid components of the I_K.I_K.Ach plays an important for the repolarization of atrial action potential. This current is induced by carbachol(CCh) and adenosine, but both act through their own membrane receptor ;namely the M2 muscarine receptor and the A1 adenosine receptor. The inhibition of the adenosine induced current needs a higher concentration.I_NCX(Na/Ca exchanger) is also blocked by azimilide even in the presence of trypsin. This suggests that NCX is inhibited from either the extra cellular side and/or the membrane.Azimilide blocks also the HERG channels with a affinity comparable with the one of I_Ks channels.This block is a reverse use-dependent,the possible explanation is an interaction of azimilide with K⁺ close to its binding site.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.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.

Pharmacology

The pharmacological use of azimilide is due to its proarrhythmic effect and the ability to convert and maintain a sinus rhythm. Like many other drugs its concentration is important.Azimilide is used as a treatment against atrial flutter and fibrillation.Generally it will lower the fibrillation values and doesn’t have any of the negative side effects of the β-blockers.There is a weak prolongation of the QT interval,but it does not give a meaningfull change to the ECG. Azimilide's most important adverse effect is the torsades de pointes,which is a form of ventricular tachycardia.

Pharmakinetics

The drug is administered oraly and will be completely absorbed. It shows none or very minor interactions with other drugs and it will be eventually cleared by the kidney.A peak in concentration in the blood is observed seven hours after the administration of Azimilide.The metabolic clearence is mediated through several pathways: *10% is found unchanged in the blood *30% will cleared by cleavage *25% by CYP 1A1 pathway *25% by CYP 3A4F-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,but this article will give only the plain scientific information about this drug.

References

* 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
*Watanabe Y.,Koide Y.,Kimura J.(2006).Topics on the Na⁺/Ca²⁺ exchanger:Pharmacological characterization of Na⁺/Ca²⁺ exchanger inhibitors. Journal of Pharmacological Sciences102,7-16
*Hanna I.,Langberg J. (2004).The shocking story of azimilide. Journal of the American Heart Association110,3624-3626
*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 Journal27,2224-2231
*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 Pharmacology123,23-30
*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 Therapeutics291,1324-1336
*Corey A.,Agnew J.,Valentine S.,Parekh N.,Powell J.,Thompson G.(2002).The British Journal of Pharmacology54,449-452