Disopyramide (Norpace) can suppress atrial and ven-tricular arrhythmias and is longer acting than other drugs in its class.
The effects of disopyramide on the myocardium and specialized conduction tissue (Table 16.2) are a com-posite of its direct actions on cardiac tissue and its indi-rect actions mediated by competitive blockade of mus-carinic cholinergic receptors.
The direct depressant actions of disopyramide on the sinoatrial node are antagonized by its anticholiner-gic properties, so that at therapeutic plasma concentra-tions, either no change or a slight increase in sinus heart rate is observed. Both the anticholinergic and direct de-pressant actions of disopyramide on sinus automaticity appear to be greater than those of quinidine.
Disopyramide reduces membrane responsiveness in atrial muscle and the amplitude of the action potential. Excitability of atrial muscle is decreased. These changes decrease atrial muscle conduction velocity. Action po-tential duration in atrial muscle fibers is prolonged by disopyramide administration. This occurrence increases ERP. Postrepolarization refractoriness does not occur with disopyramide, and it appears to differ from quini-dine and procainamide in this respect.
Abnormal atrial automaticity may be abolished at disopyramide plasma concentrations that fail to alter ei-ther conduction velocity or refractoriness. Disopyramide increases atrial refractoriness in patients pretreated with atropine, suggesting that the primary action of disopyra-mide is a direct one and not a consequence of its anti-cholinergic effect.
Disopyramide depresses conduction velocity and in-creases the ERP of the A-V node through a direct ac-tion. Its anticholinergic actions, however, produce an in-crease in conduction velocity and a decrease in the ERP. The net effect of disopyramide on A-V nodal transmission therefore will be determined by the sum of its direct depression and indirect facilitation of trans-mission.
Disopyramide administration reduces membrane responsiveness in Purkinje fibers and ventricular mus-cle and reduces the action potential amplitude. Even greater depression may occur in damaged or injured myocardial cells. Action potentials are prolonged after disopyramide administration, and this results in an in-crease in the ERPs of His-Purkinje and ventricular muscle tissue. Unlike procainamide and quinidine, disopyramide does not produce postrepolarization re-fractoriness.
The effect of disopyramide on conduction velocity depends on extracellular K+ concentrations. Hypo-kalemic patients may respond poorly to the antiar-rhythmic action of disopyramide, whereas hyper-kalemia may accentuate the drug’s depressant actions.
The electrocardiographic changes observed after disopyramide administration are identical to those seen with quinidine and procainamide.
Disopyramide directly depresses myocardial contractil-ity. The negative inotropic effect may be detrimental in patients with compromised cardiac function. Some pa-tients develop overt congestive heart failure. At usual therapeutic doses, depression of myocardial function is not a problem in most patients with normal ventricular function.
Despite the decrease in cardiac output produced by disopyramide, blood pressure is well maintained by a reflex increase in vascular resistance. Catecholamine administration can reverse the myocardial depression.
The salient pharmacokinetic features of disopyramide:
Oral bioavailability : 87–95%
Onset of action : 30 minutes–3.5 hours
Peak response : 30 minutes–3 hours
Duration of action : 1.5–8.5 hours
Plasma half-life : 4–10 hours
Primary route of metabolism: Hepatic, active metabolite
Primary route of : 80% renal (50% unchanged);
excretion : 15% biliary
Therapeutic serum Concentration : 1–5 μg /mL
The indications for use of disopyramide are similar to those for quinidine, except that it is not approved for use in the prophylaxis of atrial flutter or atrial fibrilla-tion after DC conversion. The indications are as follows: unifocal premature (ectopic) ventricular contractions, premature (ectopic) ventricular contractions of multifo-cal origin, paired premature ventricular contractions (couplets), and episodes of ventricular tachycardia. Persistent ventricular tachycardia is usually treated with DC conversion.
The major toxic reactions to disopyramide administra-tion include hypotension, congestive heart failure, and conduction disturbances. These effects are the result of disopyramide’s ability to depress myocardial contractil-ity and myocardial conduction. Although disopyramide initially may produce ventricular tachyarrhythmias or ventricular fibrillation in some patients, the incidence of disopyramide-induced syncope in long-term therapy is not known. Most other toxic reactions (e.g., dry mouth, blurred vision, constipation) can be attributed to the an-ticholinergic properties of the drug.
CNS stimulation and hallucinations are rare. The in-cidence of severe adverse effects in long-term therapy may be lower than those observed with quinidine or procainamide.
Disopyramide should not be administered in cardio-genic shock, preexisting second- or third-degree A-V block, or known hypersensitivity to the drug. Neither should it be given to patients who are poorly compen-sated or those with uncompensated heart failure or se-vere hypotension. Because of its ability to slow cardiac conduction, disopyramide is not indicated for the treat-ment of digitalis-induced ventricular arrhythmias. Patients with congenital prolongation of the QT interval should not receive quinidine, procainamide, or disopyra-mide because further prolongation of the QT interval may increase the incidence of ventricular fibrillation.
Because of its anticholinergic properties, disopyra-mide should not be used in patients with glaucoma. Urinary retention and benign prostatic hypertrophy are also relative contraindications to disopyramide therapy. Patients with myasthenia gravis may have a myasthenic crisis after disopyramide administration as a result of the drug’s local anesthetic action at the neuromuscular junction. The elderly patient may exhibit increased sen-sitivity to the anticholinergic actions of disopyramide.
Caution is advised when disopyramide is used in conjunction with other cardiac depressant drugs, such asverapamil, which may adversely affect atrioventricular conduction.
In the presence of phenytoin, the metabolism of disopy-ramide is increased (reducing its effective concentra-tion) and the accumulation of its metabolites is also increased, thereby increasing the probability of anti-cholinergic adverse effects. Rifampin also stimulates the hepatic metabolism of disopyramide, reducing its plasma concentration.
Unlike quinidine, disopyramide does not increase the plasma concentration of digoxin in patients receiv-ing a maintenance dose of the cardiac glycoside. Hypoglycemia has been reported with the use of disopyramide, particularly in conjunction with moder-ate or excessive alcohol intake.
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