Antiarrhythmic compound

Electrophysiology- Mexiletine is a local anesthetic and a Class IB antiarrhythmic compound with electrophysiologic properties similar to lidocaine. 

Dynamic moisture sorption, in particular, provides an excellent opportunity to study solid form conversion Fig. 18.6 depicts a typical sorption curve of an antiarrhythmic compound that shows the conversion of an anhy-drate to a monohydrate. Moisture uptake by the anhydrous form is very small on the moisture uptake curve until a critical humidity of about 70% is achieved. At this point, rapid moisture uptake occurs and a hydrate form containing 10%moisture is generated. Subsequent reduction in the humidity (desorption) shows the hydrate to remain until approximately 5% RH, when it spontaneously converts to the anhydrous form. It is important to recognize, however, that conversion between solid forms is very time dependent. The relative humidities at which conversion was seen in Fig. 18.6 are significantly dependent on the length of time the solid material was equilibrated. For the material shown in Fig. 18.6, conversion from the anhydrous to the hydrate "at equilibrium" will occur somewhere between 10 and 70% RH. More precise determination of the critical humidity at which conversion occurs may be determined as described in Section 2.3.1. 

Figure 18.4. Moisture sorption as a function of relative humidity for an antiarrhythmic compound. (Reprinted from Ref 75 with permission from Elsevier Science.)...

Antiarrhythmic Compounds 12, 292 (1968) Prof. Dr. L. Szekeres Head of the Department of Pharmacology, School of Medicine, University of Szeged, Szeged, Hungary Dr. J.G.Papp Senior Lecturer, University Department of Pharmacology, Oxford, England... 

Zaidler Yal (1967) Search for antiarrhythmic compounds on an isolated rat atrium preparation. In Modeling, methods of study and experimental therapy of pathological conditions, part 3. Meditsina, Moscow, p 191... 

FLUORINECOMPOUNDS,ORGANIC - FLUORINATED AROMATIC COMPOUNDS] (Volll) -antiarrhythmic agent [CARDIOVASCULARAGENTS] (Vol 5)... 

Phiorog1iicino1-3,5-dimethyl-1-(2-amino-3-hydroxyhutyryl)ether is characterized by antiarrhythmic activity (176). 2,4-Diacylphloroglucinols were patented as compounds with pronounced anthelmintic activity (177). Phloroglucinol mono- and di-(2-chloroethyl) ethers have antispasmodic or tranquilizing activities (178). 2-(3,5-DiaLkoxyphenoxy)ethylamines have antispasmodic, choloretic, sedative, and vasodilating effects (179). 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Lldoc ine. Lidocaine hydrochloride, an anilide, was originally introduced as a local anesthetic in 1943 and found to be a potent antiarrhythmic in 1960. The compound is a reverse amide of procainamide. Lidocaine is generally considered to be the dmg of choice in the treatment of ventricular arrhythmias and those originating from digitalis glycoside toxicity (1,2,15—17). 

EoUowing po administration moricizine is completely absorbed from the GI tract. The dmg undergoes considerable first-pass hepatic metabolism so that only 30—40% of the dose is bioavailable. Moricizine is extensively (95%) bound to plasma protein, mainly albumin and a -acid glycoprotein. The time to peak plasma concentrations is 0.42—3.90 h. Therapeutic concentrations are 0.06—3.00 ]l/niL. Using radiolabeled moricizine, more than 30 metabolites have been noted but only 12 have been identified. Eight appear in urine. The sulfoxide metabolite is equipotent to the parent compound as an antiarrhythmic. Elimination half-life is 2—6 h for the unchanged dmg and known metabolites, and 84 h for total radioactivity of the labeled dmg (1,2). 

Pirmenol. Pirmenol hydrochloride, a pyridine methanol derivative, is a racemic mixture. It has Class lA antiarrhythmic activity, ie, depression of fast inward sodium current, phase 0 slowing, and action potential prolongation. The prolongation of refractory period may be a Class III property. This compound has shown efficacy in converting atrial arrhythmias to normal sinus rhythm (34,35). 

Acebutolol is well absorbed from the GI tract. It undergoes extensive hepatic first-pass metabohsm. BioavailabiUty of the parent compound is about 40%. The principal metaboflte, A/-acetylacebutolol, has antiarrhythmic activity and appears to be more cardioselective. Binding to plasma proteins is only 26%. Peak plasma concentrations of acebutolol are achieved in 2.5 h, 3.5 h for A/-acetylacebutolol. The elimination half-Hves of acebutolol and its metabohte are 3—4 and 8—13 h, respectively. The compounds are excreted by the kidneys (30—40%) and by the Hver into the bile (50—60%). About 40% of the amount excreted in the urine is unchanged acebutolol, the rest as metabofltes (32). 

Asoc inol. Asocainol, a diben2azonine derivative, has sodium channel (Class I) and calcium channel (Class IV) blocking activity that accounts for the antiarrhythmic activity. Preliminary studies indicate that the compound is effective against ventricular arrhythmias (88). Additional studies are needed to estabUsh efficacy, toxicological potential, and pharmacokinetic profile. 

If the compound is virtually insoluble (solubility mixed solvent approach can be tried [2, 28-30]. For example, the pka of the antiarrhythmic amiodarone, 9.06 0.14, was estimated from water-methanol... 

By contrast, an interesting antiarrhythmic activity was observed for compound 129 <1997EJM151>. 

A series of 1-substituted 3-phenylbenzazepines have been evaluated. It was found that the aminopropyl derivative (6, n = 3 R1 = R2 = Et) counteracted amphetamine toxicity, and that the piperazinyl derivative (6) (n = 2 NR R2 = N(CH2CH2)2 = NCH2CH2OH) gave protection against maximal electroshock seizures (MES) [12]. None of the other derivatives such as the 2-oxo derivatives showed any significant effects on the central nervous or cardiovascular system, nor did any of them exhibit any diuretic or hypo-glycaemic activity [12]. Several similar compounds possess antiarrhythmic and antihypertensive effects this will be mentioned in a later section. 

Some 2-amino derivatives (36) have been reported to show local anaesthetic, parasympathomimetic, long-lasting myorelaxant, brief hypotensive and mild antiarrhythmic activities [83]. Analogous cyclic amidines (37) with a 3-phenyl group were examined for potential hypoglycaemic agents [7]. Ten of 16 compounds showed weak to moderate activity in the rat. The most active compound was (37, R1 = OMe R2 = R3 = H, R4 = cyclopropyl), although it was less active than tolbutamide [84]. 

Amiodarone (11), a benzofuran derivative, was initially developed as a coronary vasodilator in the early 1960 s [11,12]. Several years later, the efficacy of the compound as an antiarrhythmic agent began to be exploited. The first clinical trials with amiodarone were reported in 1974 [13]. Amiodarone was effective in controlling the tachyarrhythmias of eleven patients with Wolff-Parkinson-White syndrome. Since that time the compound has been studied extensively [14,15]. Recently, in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), amiodarone was shown to reduce mortality during a mean 18 month period following myocardial infarction (13.8% deaths in placebo group vs. 2.1 % deaths in the treatment group) [16]. 

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