Quinidine, procainamide, and disopyramide are type Ia antiarrhythmic agents. These agents are used primarily for suppression of supraventricular arrhythmias and occasionally to treat ventricular arrythmias. Quinidine has also been used to treat malaria. Disopyramide is also used to treat hypertrophic obstructive cardiomyopathy. Procainamide oral preparations are not available in the United States but are available in some other countries. All three agents have a low toxic-to-therapeutic ratio and may produce fatal intoxication (Table II-53). See the description of other antiarrhythmic agents.

1. Type Ia agents depress the fast sodium-dependent channel, slowing phase zero of the cardiac action potential. At high concentrations, this results in reduced myocardial contractility and excitability and severe depression of cardiac conduction velocity. Type Ia agents also inhibit the outward potassium channel, delaying repolarization, and resulting in a prolonged QT interval that may be associated with polymorphic ventricular tachycardia (torsade de pointes).
2. Quinidine and disopyramide also have anticholinergic activity; quinidine has alpha-adrenergic receptor-blocking activity, and procainamide has ganglionic and neuromuscular blocking activity.

Acute adult ingestion of 1 g of quinidine, 5 g of procainamide, or 1 g of disopyramide and any ingestion in children should be considered potentially lethal.

The primary manifestations of toxicity involve the cardiovascular and central nervous systems.

1. Cardiotoxic effects of the type Ia agents include sinus bradycardia; sinus node arrest or asystole; PR-, QRS-, or QT-interval prolongation; sinus tachycardia (caused by anticholinergic effects); polymorphous ventricular tachycardia (torsade de pointes); and depressed myocardial contractility, which, along with alpha-adrenergic or ganglionic blockade, may result in hypotension and occasionally pulmonary edema. Anticholinergic effects may result in a rapid ventricular response with emergence of atrial fibrillation or flutter.
2. Central nervous system toxicity. Quinidine and disopyramide can cause anticholinergic effects such as dry mouth, dilated pupils, and delirium. All type Ia agents can produce seizures, coma, and respiratory arrest.
3. Other effects. Quinidine commonly causes nausea, vomiting, and diarrhea after acute ingestion and, especially with chronic doses, cinchonism (tinnitus, vertigo, deafness, and visual disturbances), and is associated with thrombocytopenia and hepatitis. Procainamide may cause GI upset and, with chronic therapy, a lupus-like syndrome and agranulocytosis. Anticholinergic effects of type Ia drugs can result in urinary retention and precipitation of acute glaucoma.

Is based on a history of exposure and typical cardiotoxic features such as QRS- and QT-interval prolongation, atrioventricular (AV) block, and polymorphous ventricular tachycardia.

1. Specific levels. Serum levels for each agent are generally available through reference laboratories. Serious toxicity with these drugs usually occurs only with levels above the therapeutic range; however, some complications, such as QT prolongation and polymorphous ventricular tachycardia, may occur at therapeutic levels.
   1. Methods for detecting quinidine may vary in specificity, with some also measuring metabolites and contaminants.
   2. Procainamide has an active metabolite, N-acetylprocainamide (NAPA); with therapeutic procainamide dosing, NAPA levels can range from 15 to 25 mg/L.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, arterial blood gases or oximetry, cardiac troponin, and ECG monitoring.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat hypotension, arrhythmias, coma, and seizures if they occur. Replete potassium and magnesium if deficient.
   3. Treat recurrent ventricular tachycardia with magnesium, overdrive pacing and, if persistent, electrical cardioversion. Do not use other type Ia or Ic agents because they may worsen cardiac toxicity.
   4. Mechanical support of the circulation (eg, extracorporeal membrane oxygenation or cardiopulmonary bypass) may be useful in stabilizing patients with refractory shock, allowing time for the body to eliminate some of the drug.
   5. Continuously monitor vital signs and ECG for a minimum of 6 hours and admit symptomatic patients until the ECG returns to normal.
2. Specific drugs and antidotes. Treat cardiotoxic effects such as wide QRS intervals and hypotension with sodium bicarbonate, 1-2 mEq/kg by rapid IV bolus, repeated every 5-10 minutes and as needed. Markedly impaired conduction or high-degree AV block unresponsive to bicarbonate therapy is an indication for insertion of a cardiac pacemaker. Lipid emulsion therapy may be considered for quinidine based on its lipophilicity, although efficacy has not been empirically demonstrated.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination
   1. Quinidine has a very large volume of distribution, and therefore it is not effectively removed by dialysis. Acidification of the urine may enhance excretion but is not recommended as it may aggravate cardiac toxicity.
   2. Procainamide, and NAPA have smaller volumes of distribution and are removed by dialysis.
   3. The efficacy of repeat-dose activated charcoal has not been studied for the type Ia agents.