Antiarrhythmic agents quinidine

The antiarrhythmic agent quinidine is metabolized by allylic hydroxylation to 3-hydroxyquinidinc. the principal plasma metabolite found in humans. This metabolite shows significant antiarrhythmic activity in animals and po.s-sibly in humans. -"... 

Concomitant use with thyroid medication, pimozole, and antiarrhythmic agents (quinidine, disopyramide, procainamide) may increase incidence of cardiac arrhythmias and conduction defects. 

The structures of two antiarrhythmic agents, quinidine, a natural product, and disopyramide (Searle Roussel, 1972) are shown in Figure 4.2. Quinidine was first isolated from cinchona bark but is now made by the epimerization of quinine at the carbon bearing the hydroxyl group. Its effects on arrhythmias were first noted more than 200 years ago when the drug was being used as an anti-malarial agent. 

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). 

AF often recurs after initial cardioversion because most patients have irreversible underlying heart or lung disease. A metaanalysis confirmed that quinidine maintained sinus rhythm better than placebo however, 50% of patients had recurrent AF within 1 year, and more importantly, quinidine increased mortality, presumably due in part to proarrhythmia. Type Ic (e.g., flecainide, propafenone) and type III (e.g., amiodarone, sotalol, dofetilide) antiarrhythmic agents may be alternatives to quinidine however, these agents are also associated with proarrhythmia. Consequently, chronic antiarrhythmic drugs should be reserved for patients with recurrent paroxysmal AF associated with intolerable symptoms during episodes of AF. 

Concurrent antiarrhythmic agents Concurrent antiarrhythmic agents may produce enhanced prolongation of conduction or depression of contractility and hypotension, especially in patients with cardiac decompensation. Reserve concurrent use of procainamide with other Class lA antiarrhythmic agents (eg, quinidine, disopyramide) for patients with serious arrhythmias unresponsive to a single drug and use only if close observation is possible. 

Cardiac toxicity Moxifloxacin and gatifloxacin have been shown to prolong the QT interval of the electrocardiogram in some patients. Avoid in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class lA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents. 

Quinidine Quinidex) was one of the first clinically used antiarrhythmic agents. Because of the high incidence of ventricular proarrhythmia associated with its use and numerous other equally efficacious agents, quinidine is now used sparingly. Quinidine shares all of the pharmacological properties of quinine, including an-timalarial, antipyretic, oxytocic, and skeletal muscle relaxant actions. 

At normal therapeutic plasma concentrations, quinidine prolongs the PR, the QRS, and the QT intervals. QRS and QT prolongations are more pronounced with quinidine than with most other antiarrhythmic agents. The magnitude of these changes is related directly to the plasma quinidine concentration. 

The depressant effects of propranolol on the A-V node are more pronounced than are the direct depressant effects of quinidine. This is due to propranolol s dual actions of p-blockade and direct myocardial depression. Propranolol administration results in a decrease in A-V conduction velocity and an increase in the A-V nodal refractory period. Propranolol does not display the anticholinergic actions of quinidine and other antiarrhythmic agents. 

Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure. 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

Antiarrhythmic agents such as quinidine, procainamide, and propranolol have all been shown to augment d-tubocurarine-induced blockade. Quinidine has also been reported to unmask or worsen the symptoms of myasthenia gravis and to cause postoperative respiratory depression after the use of muscle relaxants. 

Alkalosi.s tend.s to hyperpolarixc the cell membrane and. thereby, reduces the cfi ect of antiarrhythmic drugs. Because of this, alkalosis promotes the formation of mure of the free-base antiarrhythmic agent, increasing the rate of recovery from the block. Alkalo.sis-inducing salts such as. sodium lactate have been used to counteract toxicity caused by the antiarrhythmic quinidine. 

CARDIAC DEPRESSANTS are little used in medicine, however, some are used to slow the heartbeat in tachycardias and a number of these are often analogues or derivatives of other drugs with optimized activity for this purpose in the heart (e.g. procainamide, quinidine) - these are dealt with under antiarrhythmic agents. 

ANTIARRHYTHMIC agents (Class I agents, e.g. disopyramide, flecainide. lignocaine. procainamide, quinidine) are sodium-channel blockers and are mainly used to treat atrial and ventricular tachycardias (see antiarrhythmic agents). ANTIEPILEPTICS have a number of mechanisms of action, but some appear to have a component involving modulation of sodium-channel function, e.g. carbamaxepine and phenytoin (see anticonvulsants). 

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