Treatment antiarrhythmics

Antiarrhythmic treatment is based upon modulation of the ionic currents mentioned above. A principal problem with this therapy is that the electrophysiology of all cells is targeted and not specifically the arrhythmogenic focus. As a consequence, all antiar-rhythmics acting at transmembrane ionic channels possess a risk for elicitation of arrhythmia (= proar-rhythmic risk). 

Class IB drugs like lidocaine, phenytoin or mex-iletine preferentially bind to the inactivated state. Lidocaine, a local anaesthetic, can be used intravenously for antiarrhythmic treatment. It is one of the classical dtugs used in emergency medicine for the... 

Antiarrhythmic treatment with intravenously administered phenytoin as well as correction of the electrolyte balance (K+, Ca " ", Na+) should be performed. AV block may require a temporary pacemaker. Digitalis antibodies may be used as a specific antidote. 

Besides acute arrhythmia, chronic arrhythmia is a common and important clinical problem and chronification of arrhythmia is only poorly understood, although this might be the basis for new antiarrhythmic treatments from a more pathophysiological viewpoint. 

For the problem of prophylactic antiarrhythmic treatment these antiarrhythmic peptides are probably not the final solution. Because of their peptide nature they are not well suited for in vivo studies and they are probably only indicated for the prevention of arrhythmias due to reduced coupling, but they are a first step in the direction of a new class of drugs influencing gap junctional coupling. 

Patients with chronic atrial fibrillation—a common supraventricular arrhythmia—routinely receive warfarin to prevent the development of blood clots in the poorly contracting atrium and to decrease the risk of embolism of such clots to the brain or other tissues. Such patients are also often treated with anti arrhythmic drugs. The primary goals of antiarrhythmic treatment are to slow the atrial rate and, most importantly, control the ventricular rate. 

Bradycardia-tachycardia syndrome with the need to long-term antiarrhythmic treatment with drugs other than digoxin... 

QuinidJne. Quinidine, an alkaloid obtained from cinchona bark (Sinchona sp.), is the dextrorotatory stereoisomer of quinine [130-95-0] (see Alkaloids). The first use of quinidine for the treatment of atrial fibrillation was reported in 1918 (12). The sulfate, gluconate, and polygalacturonate salts are used in clinical practice. The dmg is given mainly by the oral (po) route, rarely by the intravenous (iv) route of adniinistration. It is the most frequentiy prescribed po antiarrhythmic agent in the United States. The clinical uses of quinidine include suppression of atrial and ventricular extrasystoles and serious ventricular arrhythmias (1 3). 

Disopyr mide. Disopyramide phosphate, a phenylacetamide analogue, is a racemic mixture. The dmg can be adininistered po or iv and is useful in the treatment of ventricular and supraventricular arrhythmias (1,2). After po administration, absorption is rapid and nearly complete (83%). Binding to plasma protein is concentration-dependent (35—95%), but at therapeutic concentrations of 2—4 lg/mL, about 50% is protein-bound. Peak plasma concentrations are achieved in 0.5—3 h. The dmg is metabolized in the fiver to a mono-AJ-dealkylated product that has antiarrhythmic activity. The elimination half-life of the dmg is 4—10 h. About 80% of the dose is excreted by the kidneys, 50% is unchanged and 50% as metabolites 15% is excreted into the bile (1,2). 

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). 

Phenytoin. Phenytoin sodium is sodium diphenylhydantoin [630-93-3] which is stmcturally related to the barbiturates. It was originally introduced as an anticonvulsant (18) (see Hypnotics, sedatives, and anticonvulsants) and later found to have antiarrhythmic properties (19), although not approved by the PDA for any arrhythmic indications. Phenytoin is effective in the treatment of ventricular arrhythmias associated with acute MI and with digitalis toxicity (20). It is not very effective in treatment of supraventricular arrhythmias (20). 

Propranolol. Propranolol (Table 1), a Class II antiarrhythmic agent, is usefiil in the management of hypertrophic subaortic stenosis, especially for the treatment of exertional or other stress-induced angina by improving blood flow. The dmg can increase exercise tolerance in patients suffering from angina. Propranolol has been shown to have cardioprotective action in post-MI patients (37—39,98,99,108). 

Treatment of 2,6-dimethylaniline (121) with phosgene and triethylamine affords the corre-S]ionding isocyanate (122). Condensation of that reactive intermediate with N-isopropylpropyl-cne-1,3-diamine leads to formation of urea 123. This product, recainam (123), acts as membrane Stabilizing agent and thus exhibits both local anesthetic and antiarrhythmic activity [30]. 

A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary vasodilators for the treatment of angina. The most recent of these interestingly incorporates a 2,6-dichloroaniline moiety reminiscent of antiarrhythmic agents. Treatment of the piperazine carboxamide 124 with acetone leads to formation of the nitrogen analogue of an acetal, the aminal 125. Alkylation of the remaining secondary nitrogen with chloroamide 126 leads to the intermediate 127. Exposure to aqueous acid leads to hydrolysis of the aminal function... 

Class IV antiarrhythmic drugs are Ca2+ channel blockers, which predominantly slow sinus rate and atrioventricular conduction and thus are used in the treatment of supraventricular tachyarrhythmias. These drugs exert a pronounced negative inotropic effect. 

Dantrolene is the mainstay of MH treatment. It has long been available for the treatment of muscle spasm in cerebral palsy and similar diseases. It is a hydantoin derivative that was first synthesized in 1967, and reported to be effective in the treatment of porcine MH in 1975. Also in 1975, dantrolene was shown to be more effective than procainamide in the treatment of human MH, which until that time was the drug of choice. However, the intravenous preparation was not made available until November 1979. It significantly lowered mortality. The half-life of dantrolene is estimated to be 6-8 hr. Dantrolene s primary mode of action is the reduction in calcium release by the sarcoplasmic reticulum. Dantrolene also exerts a primary antiarrhythmic effect by increasing atrial and ventricular refractory periods. Side effects of dentrolene include hepatotoxicity, muscle weakness, ataxia, blurred vision, slurred speech, nausea, and vomiting. Dantrolene is not contraindicated in pregnancy, but it does cross into breast milk and its effect on the neonate is unknown. 

After acute PSVT is terminated, long-term preventive treatment is indicated if frequent episodes necessitate therapeutic intervention or if episodes are infrequent but severely symptomatic. Serial testing of antiarrhythmic agents can be evaluated in the ambulatory setting via ambulatory ECG recordings (Holter monitors) or telephonic transmissions of cardiac rhythm (event monitors) or by invasive electrophysiologic techniques in the laboratory. 

FIGURE 6-2. Algorithm for the treatment of acute (top portion) paroxysmal supraventricular tachycardia and chronic prevention of recurrences (bottom portion). Note For empiric bridge therapy prior to radiofrequency ablation procedures, calcium channel blockers (or other atrioventricular [AV] nodal blockers) should not be used if the patient has AV reentry with an accessory pathway. (AAD, antiarrhythmic drugs AF, atrial fibrillation AP, accessory pathway AVN, atrioventricular nodal AVNRT, atrioventricular nodal reentrant tachycardia AVRT, atrioventricular reentrant tachycardia DCC, direct-current cardioversion ECG, electrocardiographic monitoring EPS, electrophysiologic studies PRN, as needed VT, ventricular tachycardia.)... 

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