Antiarrhythmic drugs structure

Andreoli TE Ion transport disorders introductory comments. Am J Med 1998 104 85. (First of a series of articles on ion transport disorders published between January and August, 1998. Topics covered were structure and function of ion channels, arrhythmias and antiarrhythmic drugs, Liddle syndrome, cholera, malignant hyperthermia, cystic fibrosis, the periodic paralyses and Bartter syndrome, and Gittelman syndrome.)... 

Several drug classes, including tetracycline, sulfonamide, and quinolone antibiotics, as well as chlorothiazide, chlorpromazine, and amiodarone hydrochloride, have been shown to be photoantigens. Photosensitivity may persist even after withdrawal of the drug, as has been observed with the antiarrhythmic drug amiodarone hydrochloride, since it is lipophilic and can be stored for extended periods in the body fat (Unkovic et al., 1984). In addition, it is quite common for cross-reactions to occur between structurally related drugs of the same class. 

The class lb antiarrhythmic drug mexilitine is structurally related to the local anesthetic agent lidocaine and also shows a voltage- and frequency-dependent block of sodium channels. Mexilitine is not selective for any painrelevant subtype of sodium channel. As an advantage over lidocaine, mexilitine can be given orally. 

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... 

Flecainide slows conduction in all cardiac cells including the anomalous pathways responsible for the Wolff-Parkinson-White (WPW) syndrome. Together with encainide and moricizine, it underwent clinical trials to establish if suppression of asymptomatic premature beats with antiarrhythmic drugs would reduce the risk of death from arrhythmia after myocardial infarction. The study was terminated after preliminary analysis of 1727 patients revealed that mortality in the groups treated with flecainide or encainide was 7.7% compared with 3.0% in controls. The most likely explanation for the result was the induction of lethal ventricular arrhythmias possibly due to ischaemia by flecainide and encainide, i.e. a proarrhythmic effect. In the light of these findings the indications for flecainide are restricted to patients with no evidence of structural heart disease. The most common indication, indeed where it is the drug of choice, is atrioventricular re-entrant tachycardia, such as AV nodal tachycardia or in the tachycardias associated with the WPW syndrome or similar conditions with anomalous pathways. This should be as a prelude to definitive treatment with radiofrequency ablation. Flecainide may also be useful in patients with paroxysmal atrial fibrillation. 

Cook, C.S. Zhang, L. Osis, J. Schoenhard, G.L. Karim, A. Mechanism of compound-and species-specific food effects of structurally related antiarrhythmic drugs, disopyr-amide and bidisomide. Pharm. Res. 1998,15 (3), 429-433. 

Drugs The most common source of iodine excess in the United States is amiodarone, a widely used antiarrhythmic drug. Amiodarone contains 37% iodine and shows a structural similarity with the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4) (Hermann, 2004 Kennedy et al, 1989 Martino et al, 2001). 

In many clinical situations, antiarrhythmic drugs have given way to implantable defibrillators for potentially life-threatening arrhythmias, but they are still commonly used both as adjunct therapy and in other arrhythmias, such as atrial fibrillation. The sheer number of antiarrhythmic agents with diverse mechanisms of action and the possibility of serious or even lethal adverse effects makes understanding how the structure of these drugs contributes to their efficacy and toxicity a high priority for pharmacists. 

Azimilde is another Class III antiarrhythmic agent structurally unrelated to any of the above agents (Fig. 26.15). Azimilide is not available in the United States it is only available in Europe. Following oral administration, the drug is oompletely absorbed, with no effect of food. Protein binding is 94%. It is metabolized in the liver to an aotive carboxylate metabolite, but its concentration in plasma is less than 5% of the parent oompound. Thus, it is considered to be therapeutically inactive. Renal excretion is approximately 10%. Its elimination half-life is 3 to 4 days. 

Figure 5 Chemical structure of major chiral antiarrhythmic drugs. The asterisk denotes the chiral carbon.

Class I Indications for an ICD (1) Survivors of cardiac arrest secondary to ventricular tachycardia and ventricular fibrillation except when due to a reversible cause. (2) Sustained vaitricular tachycardia associated with structural heart disease. (3) Syncope of unclear etiology with an inducible ventricular tachycardia or ventricular fibrillation at electrophysiology study. (4) Nonsustained ventricular tachycardia in patients with coronary artery disease, left ventricular dysfunction, and inducible ventricular tachycardia or fibrillation at electrophysiology study that is not suppressed will by an antiarrhythmic drug. (5) Spontaneous sustained ventricular tachycardia in patients without structural heart disease who are not amenable to medical therapy. 

Figure 16.4 shows the chemical structures of a variety of molecules with potent activity against the hERG channel, including withdrawn drugs and Class III antiarrhythmics. Below are some examples of different structures associated with hERG inhibition. 

Hi-receptor but also at muscarinic cholinoceptors, serotonin receptors, and adrenoceptors. This explains the atropine-like side effects of those drugs. The cationic amphophilic structure of these substances resemble that of antiarrhythmic agents which might explain the arrhythmogenic properties seen with some of these Hi-antagonists. 

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