PROCAINAMIDE Procainamide is useful as an antidysrhythmic agent in the treatment of various ventricular and supraventricular dysrrhythmias. Procainamide was developed after the antidysrhythmic effects of the local anesthetic agent procaine were realized. However, procaine's short duration of action and its prominent central nervous system (CNS) effects rule it out for its clinical use.
Like all class I agents, procainamide blocks sodium channels and depresses the speed of impulse conduction (phase 0) of the cardiac action potential. It prolongs the duration of the action potential and the effective refractory period. This is reflected on the electrocardiogram (ECG) as QRS, QT, and PR interval prolongation. These effects directly depress myocardial conduction, suppress fibrillatory activity in the atria and ventricles, and prevent ectopic or reentrant dysrhythmias. These electrophysic effects of procainamide are more pronounced at faster heart rates.
Procainamide suppresses automaticity (phase 4), especially of ectopic pacemakers, secondary to its anticholinergic properties. The effects on AV node conduction are variable. Sodium channel blockade slows AV node conduction time. However, anticholinergic stimulation tends to speed AV node conduction. The antimuscarinic effects are dose dependent. Large doses of procainamide will provide extensive anticholinergic effects and may even increase automaticity (inducing a prodysrhythmic effect). Unlike quinidine, procainamide produces more local anesthetic effects but less vagolytic effects. Procainamide is less depressing to cardiac contractility than quinidine; negative inotropy is most pronounced in ischemic tissue.
Pharmacokinetics The onset of action of procainamide is 5 to 10 min following intravenous administration and 15 to 60 min following intramuscular injection. Procainamide has an elimination half-life of 2.5 to 4.7 h (in normal renal function) and an apparent volume of distribution (Vd) of 2 L/kg. However, in patients with congestive heart failure (CHF) and renal dysfunction, the elimination half-life may increase and the Vd may decrease (i.e., requiring smaller doses). Procainamide is metabolized to an active compound, N-acetyl procainamide (NAPA), in the liver via N-acetyltransferase. This active metabolite has an average half-life of 7 h in patients with normal renal function. Rapid acetylators convert greater amounts of procainamide to NAPA than do slow acetylators. Plasma procainamide levels of approximately 4 to 10 mg/mL are usually required to suppress ventricular dysrhythmias. Refractory dysrhythmias may require levels up to 20 mg/mL (usually 10 to 15
mg/mL). Adverse effects often appear with levels greater than 12 mg/mL.
Common Emergency Department (ED) Indications Procainamide is a second-line agent generally used to treat and prevent recurrence of ventricular dysrhythmias, specifically stable ventricular tachycardia (VT) and premature ventricular contractions (PVCs) that are unresponsive to lidocaine. It is infrequently used in ventricular fibrillation (VF) or pulseless VT because it takes so long to achieve therapeutic concentrations. Procainamide may also be used for slowing or converting supraventricular tachycardias (SVT) including atrial flutter and fibrillation [especially in Wolff-Parkinson-White (WPW) syndrome], paroxysmal supraventricular tachycardia (PSVT), paroxysmal atrial tachycardia (PAT), and paroxysmal atrioventricular (AV) junctional rhythm. Contraindications include complete AV heart block, second- or third-degree heart block (without an electrical pacemaker present), long QT intervals, and torsades de pointes. The drug should be used cautiously in patients with systemic lupus erythematosus, CHF, and hepatic or renal disease and avoided in those with allergies to procaine or amide-type drugs.
Dosing and Administration In the past, the recommendation for intravenous loading of procainamide for treating ventricular dysrhythmias was as a bolus injection. However, a continuous infusion has been shown to be safer (fewer adverse effects) than a bolus injection until the dysrhythmia is controlled, hypotension develops, the QRS complex widens more than 50 percent, prolongation of the QT interval develops, or a total of 17 mg/kg (1.2 g for a 70-kg patient) has been given. The recommended infusion rate is 20 mg/min; in urgent situations, however, 30 mg/min may be given cautiously. Blood pressure and QRS complex must be monitored during intravenous administration. If procainamide suppresses the VT, initiate a continuous infusion at 1 to 4 mg/min to maintain the suppression. Lower doses are generally necessary for patients with CHF, hypotensive states, and hepatic or renal failure. Measurement of daily serum levels of procainamide or NAPA should be considered in patients with risk factors for impaired clearance.
Alternatively, oral therapy may be started after intravenous loading with procainamide (375 to 500 mg PO q3-4h) or a sustained-release preparation may be used (Procan SR or Pronestyl-SR in a dose of between 500 and 1000 mg q6-8h).
Adverse-Effects Profile The most serious adverse effects of procainamide are from myocardial depression. ECG changes may include prolongation of the QRS and QT intervals, impairment of AV conduction, VF, and torsades de pointes. High doses or rapid infusion can cause severe hypotension. It should be initiated cautiously in patients with acute myocardial infarction (AMI) owing to its potential prodysrhythmic effect. Procainamide and NAPA levels should be monitored in the following patients: (1) those on procainamide longer than 24 h, (2) those on a maintenance infusion of 3 mg/min or higher, and (3) those with acute CHF or renal failure. Symptoms of systemic lupus erythematosus (SLE) have been reported with chronic administration. Hypersensitivity reactions—characterized by angioedema, acute bronchoconstriction, vascular collapse, febrile episodes, and respiratory arrest—may occur. In addition, idiosyncratic reactions—including agranulocytosis, hepatomegaly, confusion, nausea, vomiting, urticaria, fever, maculopapular eruptions, and thrombocytopenia—may develop with procainamide.
QUINIDINE (GLUCONATE OR SULFATE) Actions Quinidine is a class IA antidysrhythmic agent with essentially the same mechanism of action as procainamide. However, anticholinergic effects are more pronounced with quinidine. These anticholinergic effects may facilitate conduction across the AV node.
Pharmacokinetics Onset of action following intravenous administration is within minutes, whereas the onset for the intramuscular and oral routes usually occurs in 1 to 3 h. Therapeutic cardiovascular effects last for the half-life of the drug, 6 to 8 h. The oral sustained-release gluconate preparation, however, can last up to 12 h. Therapeutic serum levels range between 2 and 7 mg/mL. Quinidine has an average Vd of 2 L/kg in healthy adults. It is metabolized in the liver to two active metabolites. Approximately 10 to 50 percent of a dose is excreted as unchanged drug in the urine within 24 h.
Common ED Indications Quinidine is effective in the treatment of atrial and ventricular dysrhythmias and thus has the same indications as procainamide. It is not commonly used parentally in the ED, since other agents such as procainamide are safer alternatives.
Dosing and Administration The oral route is preferred in administering quinidine. Oral quinidine is available in three salts: sulfate (83 percent active drug), gluconate (62 percent active drug), and polygalacturonate (60 percent active drug). Only the gluconate and sulfate salts are available for parenteral use. Intramuscular administration is effective in acute but not in critical dysrhythmias. Intravenous administration is now rarely used. The dosage of quinidine varies, depending on the indication and salt used. For example, the adult dosage for suppressing atrial, AV junctional, and ventricular complexes is 324 to 600 mg PO of extended-release quinidine gluconate q8-12h, while the dosage for quinidine sulfate to maintain sinus rhythm after conversion is 200 to 400 mg three or four times daily. The initial IM dose is 600 mg PO of quinidine gluconate, then 400 mg PO as often as q2h until desired effects are seen. Generally, the intravenous dosage required to abolish ventricular dysrhythmias is 300 mg or less; however, 500 to 750 mg may be needed. The rate of infusion should not exceed 16 mg/min, and the ECG and blood pressure should be continuously monitored to gauge the efficacy and safety of treatment.
Adverse-Effects Profile The adverse-effect profile of quinidine is similar to that of procainamide (including a prodysrhythmic effect) and includes QT prolongation, torsades de pointes, SLE, and hypersensitivity reactions. Toxicity usually impairs therapeutic effectiveness. High serum levels of quinidine may result in cinchonism, which includes tinnitus, blurred vision, headache, nausea, and deafness. Severe cases may lead to delirium and psychosis. Quinidine may also cause SA or AV nodal block and decrease cardiac contractility. It is also associated with acute hemolytic hemolysis, thrombocytopenia, and hepatitis. Hypotension, heart failure, and hepatic disease decrease clearance. Quinidine has also been implicated in raising serum digoxin levels two- to threefold.
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