Dronedarone

III Block of repolarizing potassium channels, prolongation of action potential Amiodarone, Dronedarone, Sotalol, Dofetilide, Ibutilide... 

Since alterations of thyroid fimction by amiodarone are related to the iodine substitution of the drug, the iodine-free derivative dronedarone has been developed with similar electrophysiological effects as amiodarone. It seems to act also as a T3-anatgonist, but does not provoke hyperthyreoidism [1]. 

Van Beeren HC, Jong WMC, Kaptein E et al (2003) Dronedarone acts as a selective inhibitor of 3,5,3 -triiodothyronine binding to thyroid hormone receptor-a. in vitro and in vivo evidence. Endocrinology 144 552-558... 

Dronedarone, 5 103, 106 Drop breakage, 16 696-697 Drop breakup, by turbulence, 16 697 Drop diameter, 10 763-764 Drop dispersions, 10 755 nonuniformity of, 10 765... 

Ridley, J.M., Milnes, J.T., Witchel, H.J. and Hancox, J.C. (2004) High affinity HERG K+ channel blockade by the antiarrhythmic agent dronedarone resistance to mutations of the S6 residues Y652 and F656. Biochemical and Biophysical Research Communications, 352, 883-891. 

In the USA, amiodarone is approved for oral and intravenous use to treat serious ventricular arrhythmias. However, the drug is also highly effective for the treatment of supraventricular arrhythmias such as atrial fibrillation. As a result of its broad spectrum of antiarrhythmic action, it is very extensively used for a wide variety of arrhythmias. Amiodarone has unusual pharmacokinetics and important extracardiac adverse effects. Dronedarone, an analog that lacks iodine atoms, is under investigation. 

Dronedarone is a structural analog of amiodarone and lacks iodine atoms. The design was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the drug. Dronedarone has multiple actions like amiodarone, blocking IKr, IKs, ICa, INa, and adrenoceptors. The drug has a half-life of 24 hours and was administered twice daily in the initial clinical trials. No thyroid or pulmonary toxicity has been noted during early use. 

Dronedarone doubled the interval between episodes of atrial fibrillation recurrence in patients with paroxysmal or persistent atrial fibrillation. It is the first antiarrhythmic drug to demonstrate a reduction in mortality or hospitalization in patients with atrial fibrillation. 

Dronedarone Investigational amiodarone derivative multichannel actions, reduces mortality in patients with atrial fibrillation... 

Conversion of AF to NSR can also be accomplished with a subset of antiarrhythmic drugs (including 2-7) that act directly on cardiac muscle cells (myocytes) and antagonize either the sodium channel-mediated propagation currents (procainamide 2, flecainide 3, propafenone 4), or the inwardly rectifying (7 ) potassium channel currents (ibutilide 5, dofetilide 6). Some of the antiarrhythmics have actions at both potassium and sodium channels (i.e., dronedarone 7 and its close structural progenitor... 

Non cardiac effects with important consequences on the course of the ischemic heart disease are elicited in a thyroid hormone receptor iso form manner. In fact, TRal blockade by dronedarone prevented body weight gain by reducing food intake, an ef-... 

C. Pantos, I. Mourouzis, V. Malliopoulou, I. Paizis, S. Tzeis, P. Moraitis, K. Sfakianoudis, D. Varonos and D.V. Cokkinos, Dronedarone administration prevents body weight gain and increases tolerance of the heart to ischemic stress a possible involvement of thyroid hormone receptor al, Thyroid 15, 16-23 (2005). 

Tamargo et al gave a very recent review.139 They point out that KATP channels are inhibited by ATP and activated by Mg ADP, so that the channel activity is influenced by the ATP/ADP ratio. They also draw attention to the fact that mitochondrial KATp channel is responsible for ischemic preconditioning. They suggest that these channels are not blocked only by sulfonylureas, but also by many antiarrhythmic drugs, such as bretylium, disopyramide, flecainide and propafenone, and also by diltiazem and verapamil, but not by amiodarone or dronedarone, which will be addressed later. 

Debutyldronedarone is the active metabolite of dronedarone, an antiarrhythmic drug developed by Sanofi-Aventis. Apart from its action as a cardiac multichannel blocker, it acts as a TH Ra and TH R(3 blocker, with some preference for TH Ra. In line with these data, dronedarone was shown to mimic the cardioprotective effects of hypothyroidism in rats [50]. 

Dronedarone is a derivative of amiodarone and has similar properties. However, it has less organ toxicity. 

Antiarrhythmic drugs in Phase III clinical trials are shown in Figure 26.16. Nifekalant is a pyrimidinone Class III agent. Sematilide is a Class III agent that is a benzamide derivative of ibutilide, and SSR-149744c and dronedarone are noniodinated analogues of amiodarone, reportedly with fewer adverse effects than amiodarone. 

---