Procainamide, structure

Binding of nitroso-procainamide to histone proteins may perturb chromatin structure or catabolism, resulting in immunogenic forms of DNA-free histones. In fact, all sera of patients (n = 24) with procainamide-induced Lupus showed IgG and IgM antibody activity against various histone components of chromatin (chromosome subunits)122. The nature of the procainamide adduct to histone proteins still awaits elucidation. 

Classes I, III, and IV all involve transmembrane ion channels Classes I and III involve Na+ channels. Class I compounds are designed to block cardiac Na channels in a voltage-dependent manner, similar to local anesthetics. Not surprisingly, many of these Class I agents are either local anesthetics or are structurally based on local anesthetics. Class I compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of these compounds possess two or three of the fundamental structural building blocks found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III compounds include molecules that block outward K channels, such as sotalol (7.22) and dofetilide (7.23), and molecules that enhance an inward Na current, such as... 

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... 

A series of dibenzazonines with the general structure 111 (R, R, = H, alkyl, alkoxy, halo R2 = H, alkyl R3 = H, alkyl, alkanoyl n = 1,2) were prepared from thebaine (45) and found to have antiarrhythmic activity similar to that of procainamide and local anaesthetic activity lasting longer than that of tetracaine (45). One compound of this series, named asocainol (111, R = R, = H, R2 = Me, R3 = H, n = 2), is a useful drug whose mechanism of action in isolated guinea pig papillary muscles has been studied in detail (78, 79). 

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. 

SCHEME 11.5 The structures of procaine, procainamide, and A-a cetyl procainamide exemplify drug development based upon understanding principles of drug metabolism. 

Metoclopramide (Reglan) and other substituted benza-mides are derivatives of paraaminobenzoic acid and are structurally related to procainamide. 

In screening the structurally modified compounds for biological activity, scientists were surprised to find that replacing the ester linkage of procaine with an amide linkage led to a compound— procainamide hydrochloride—that had activity as a cardiac depressant as well as activity as a local anesthetic. Procainamide hydrochloride is currently used clinically as an antiarrhythmic. 

Disopyramide phosphate is used orally for the treatment of certain ventricular and atrial arrhythmias. Despite its structural dissimilarity to procainamide (Fig. 26.10), its cardiac effects are very similar. Disopyramide is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma level is usually reached within 1 to 3 hours, and a plasma half-life of 5 to 7 hours is common. Approximately half of an oral dose is excreted unchanged in the urine. The remaining drug undergoes hepatic metabolism, principally to the corresponding N-dealkylated form. This metabolite retains approximately half the antiarrhythmic activity of disopyramide and also is subject to renal excretion. Adverse effects of disopyramide frequently are observed. These effects are primarily anticholinergic in nature and include dry mouth, blurred vision, constipation, and urinary retention. 

The interpretation of these data has been complicated by the findings and conclusions of Davies et al. (1975), who claim that it is the rapid acetylation which predispose to the formation of ANAs and that acetyl procainamide might be the inducing stimulus for the disease process. Moreover, they point out the structural similarity between acetyl procainamide and practolol and suggest that an acety-lated product might be an etiological agent in practolol-induced lupus. 

These hemiacetal structures presumably are sufficiently stable to protect the carbonyl at C-3 position for nucleophilic attack by procainamide. In similar reactions with dialdehydo-dextran, where a stable intraresidual hemiacetal can not be formed, up to 80 percent of the aldehydes could be coupled with procainamide, as mentioned before. 

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