Propafenone, structure

Propafenone possesses (3-adrenoceptor antagonistic effects due to its structural similarity to propranolol. 

Schmid, D., Ecker, G., Kopp, S., Hitzler, M., Chiba, P., Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements, Biochem. Pharmacol. 1999, 58, 1447-1456. 

Approved indications for propafenone include treatment of supraventricular arrhythmias and life-threatening ventricular arrhythmias in the absence of structural heart disease. Propafenone has been shown to increase mortality in patients with structural heart disease, and so extreme caution must be used in this subset of patients. As with flecainide, the patient should be hospitalized for initiation of therapy. 

Propafenone has some structural similarities to propranolol and possesses weak 3-blocking activity. Its spectrum of action is very similar to that of quinidine, but it does not prolong the action potential. Its sodium channel-blocking kinetics are similar to that of flecainide. Propafenone is metabolized in the liver, with an average half-life of 5-7 hours. The usual daily dosage of propafenone is 450-900 mg in three divided doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation arrhythmia exacerbation can also occur. 

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... 

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p.206 exception phenytoin, p.191). Possible molecular mechanisms of their inhibitory effects are outlined on p.202 in more detail. Their low structural specificity is reflected by a low selectivity toward different cation channels. Besides the Na channel. Carotid 1C channels are also likely to be blocked. Accordingly, cationic amphiphilic antiarrhythmics affect both the depolarization and repolarization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC). Antiarrhythmics representative of these categories include Class IA—quinidine, procainamide, ajmaline, disopyramide Class IB—lidocaine, mexile-tine, tocainide Class IC—flecainide, propafenone. 

Figure 2.20 The general structure 72, with different residues X, describes the prototype of a (3-adrenergic antagonist. Cyclization of the side chain produced the antidepressant viloxazine 73, whereas the N-n-propyl analog propafenone 74 turned out to be a class Ic antiarrhythmic with only weak P-antagonistic activity. An attempt to cyclize P-blockers to structures of the prototype 75 finally produced levocromakalim 76 as expected, it had antihypertensive activity but its mode of action is different instead of being a P-blocker, it is a potassium channel opener.

Propafenone 143, a drug in clinical use as an antiarrhythmic, has activity in the modulation of cancer multidrug resistance. A series of benzofuran analogues of propafenone, such as compound 144, have been synthesized and evaluated in a daunomycin cytotoxicity assay <1996JME4767>. The results of this work were later the subject of a comparative molecular field analysis (3-D quantitative structure-activity relationship (QSAR)) <1998QSA301>. 

In patients taking long-term propafenone for supraventricular dysrhythmias adverse effects were more common and have been reported in 14-60% of cases. Cardiac adverse effects were more common in patients with structural heart disease. The non-cardiac effects were either gastrointestinal (nausea, vomiting, taste disturbances) or neurological (dizziness). Adverse effects are dose-related. In one large study there was no difference between propafenone and placebo in the risk of death. 

The safety of oral propafenone in the treatment of dysrhythmias has been studied retrospectively in infants and children (40). There were significant electrophysiolo-gical adverse effects and prodysrhythmia in 15 of 772 patients (1.9%). These included sinus node dysfunction in four, complete atrioventricular block in two, aggravation of supraventricular tachycardia in two, acceleration of ventricular rate during atrial flutter in one, ventricular prodysrhythmia in five, and unexplained sjmcope in one. Cardiac arrest or sudden death occurred in five patients (0.6%) two had a supraventricular tachycardia due to Wolff-Parkinson-White syndrome the other three had structural heart disease. Adverse cardiac events were more common in the presence of structural heart disease and there was no difference between patients with supraventricular and ventricular dysrhythmias. 

Clinical uses PVC, paroxysmal atrial tachycardia, AF, VT Documented life-threatening ventricular arrhythmias. Flecainide also may be used for AF and supraventricular tachycardias in patients without structural heart disease. Propafenone is also indicated for paroxysmal AF. 

Ecker G, Chiba P, Hitzler M, Schmid D, Visser K, Cordes HP, Csollei J, Seydel JK, Schaper KJ. Structure-activity relationship studies on benzofurane analogs of propafenone-type modulators of tumor cell multidrug resistance. J Med Chem 1996 39 4767-74. 

Chiba P, Ecker G, Schmid D, Drach J, Tell B, Goldenberg S, Gekeler V. Structural requirements for activity of propafenone type modulators in PGP-mediated multidrug resistance. Mol Pharmacol 1996 49 1122-30. 

Figure 7.7 Summa of the results of structure-activity relationship studies on propafenone-type inhibitors of P-gp.

Chiba. P.. Hitzler, M., Richter, E., Huber, M.. Tmej. C.. and Ecker, G. (1997) Studies on propafenone-type modulators of multidrug resistance. III. Variations on the nitrogen. Quantitative Structure-Activity Relationships, 16, 361-366. 

Pajeva, I.K. and Wiese, M. (1998) A comparative molecular field analysis of propafenone-type modulators of cancer multidrug resistance. Quantitative Structure-Activity Relationships, 17, 301-312. 

Two new IC compounds should be mentioned. Propafenone (Rhythmol) (No. 14), introduced in the United States in 1989, has the structural components to be a (3-blocker. It is a weak one. It also possesses Ca2+ blocking properties and slows conduction in the atria and ventricles, the node between them, and the Purkinje-His areas. This earns the drug IC status. Over 80% of first-pass metabolism following oral absorption gives it poor bioavailability. Nevertheless, it is used orally as well as IV for ventricular arrhythmias. 

Propafenone, l- 2-[2-hydroxy-3-(propylamino)propoxy]phenyl -3-phenylpropan-l-one, is a conunonly used sodium and potassium channel blocker for the treatment of ventricular tachycardia and atrial fibrillation [15]. Propafenone hydrochloride is a class IC antiarrhy tmic agent that shows structural similarity and activity related to p-adrenoly tic agents. The drug is efficacious in suppressing supraventricular and ventricular rhythm disorders [15] (Figure 14.12). 

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