CHAPTER 17

Procainamide

VICTOR COHEN, BS, PharmD, BCPS, CGP

SAMANTHA P. JELLINEK-COHEN, PharmD, BCPS, CGP

OVERVIEW

Procainamide was introduced in 1951 as a Class 1a antiarrhythmic agent. Class 1a antiarrythmics, the oldest class of antiarrythmics on the market, are considered membrane-stabilizing agents that work by blocking sodium channels. Agents in this class include quinidine, procainamide, and disopyramide. Although these agents are quite effective in suppressing both atrial and ventricular ectopy, they are associated with significant toxicity, and thus, their use has fallen out of favor. Procainamide is indicated for the treatment of life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia.¹ Off-label uses of procainamide include conversion of atrial fibrillation/flutter to sinus rhythm.^1,2

Procainamide decreases the ability of incompletely repolarized fibers to generate an active response and delays completion of repolarization. These actions increase the effective refractory period of atrial and ventricular fibers, thereby accounting for its antifibrillatory effects.³ Converting from a unidirectional to a bidirectional block, procainamide decreases reentrant arrhythmias. Procainamide has been proven to be safe and effective against ventricular arrhythmias when administered orally and intramuscularly. Historically, the oral formulation was preferred for less urgent arrhythmias and for longterm maintenance after initial parenteral therapy. Intramuscular administration was reserved for patients unable to tolerate the oral formulation secondary to gastrointestinal toxicity (nausea and vomiting). In addition to the intolerable gastrointestinal adverse effects associated with oral procainamide, other extracardiac effects, including central nervous system symptoms (headache, dizziness, psychosis, hallucinations, and depression), fever, agranulocytosis, rash, myalgias, digital vasculitis, Raynaud’s phenomenon, and a systemic lupus-like syndrome, have been reported.³ Toxicity associated with oral formulations of procainamide, availability of alternative antiarrhythmic agents, and the lack of necessity of the drug led to the eventual discontinuation of this dosage form in the mid to late 2000s. Parenteral formulations 500 mg/1 ml in a 2 ml vial remain periodically available. Although undesirable infusion rate related cardiovascular side effects associated with the use of intravenous infusions of procainamide have made this mode of administration unpopular, the use of procainamide as an intravenous bolus remains a viable option. Procainamide exerts electrophysiological effects similar to those of quinidine. However, procainamide lacks quinidine’s vagolytic and alpha-adrenergic blocking activity, and as a result, is better tolerated when given intravenously.⁴

ELECTROPHYSIOLOGICAL EFFECTS

Procainamide produces increases in the QT_c interval and widening of the QRS complex in a concentration-dependent manner, usually starting at concentrations >12 mg/mL. Procainamide has been associated with life-threatening arrhythmias such as torsades de pointes and has resulted in sudden cardiac death. N-acetylprocainamide (NAPA), the acetyled metabolite of procainamide, which has been shown to have antiarrhythmic actions of its own, prolongs only the QT_c interval.^4-6 Because NAPA has Class III antiarrhythmic properties, it is of clinical importance to use the total concentrations of both procainamide and NAPA to assess pharmacological activity and toxicity; solely reviewing the procainamide level may be misleading.⁶

AVAILABILITY

Procainamide is available in an injectable formulation, which can be given intravenously for rapid control of serious arrhythmias. Dosage strengths include 100 mg/mL and 500 mg/mL.⁷ The oral formulation of procainamide is no longer available in the United States.

DOSING

The American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care recommend that adult patients with atrial fibrillation/flutter or stable monomorphic ventricular tachycardia receive 20–50 mg procainamide per minute intravenously until the arrhythmia is suppressed, hypotension ensues, or QRS complex is prolonged by 50 percent from its original duration, or a total cumulative dose of 17 mg/kg has been given. The maintenance infusion rate is 1–4 mg/min. Alternatively, 100 mg procainamide can be administered intravenously every 5 minutes until the arrhythmia is controlled or the other conditions already described are met.⁸ Manufacturer recommendations suggest that initial arrhythmia control can be accomplished by administering repeated bolus injections to be infused at a rate of no faster than 50 mg/min to a maximum advisable dose of 1 gram.¹ Once 500 mg has been administered, it is advisable to wait 10 minutes or longer before resuming treatment to allow for greater distribution into the tissues. Alternatively, a loading infusion containing procainamide 20 mg/mL (1 gram diluted to 50 mL with dextrose 5% injection) may be administered at a constant rate of 1 mL/min for 25–30 minutes to deliver 500–600 mg of procainamide. Some effects may be seen after infusion of the first 100 or 200 mg. It is unusual that more than 600 mg is needed to achieve satisfactory antiarrhythmic effects. To achieve maintenance of therapeutic procainamide levels, a diluted intravenous infusion of 2 mg/mL may be administered at 1–3 mL/min. The infusion rate will deliver 2–6 mg/min. In fluid-restricted patients, a 4 mg/mL concentration may be used. In a patient with normal renal function, a maintenance infusion of 50 mcg/kg/min will produce a procainamide plasma level of 6.5 mcg/mL. Procainamide loading and maintenance doses should be based on ideal body weight in morbidly obese patients.^9,10 Procainamide is not approved by the Food and Drug Administration for use in children.

BIOAVAILABILITY

The absorption of intravenous procainamide is immediate with a bioavailability of 100 percent. Following intravenous administration, peak levels are reached within 20–30 minutes and are maintained for 1–2 hours.¹¹

VOLUME OF DISTRIBUTION

Approximately 10–20 percent of procainamide is protein bound, and the apparent volume of distribution is large (about 1.5–2.5 L/kg body weight).^4,12 However, the volume of distribution can be significantly reduced under conditions such as congestive heart failure or cardiogenic shock, resulting in higher concentrations from a dose.³ Procainamide has an octanol-to-water partition coefficient that would indicate a high lipid affinity; however, its volume of distribution is not influenced by obesity because the partition coefficient remains low enough to limit distribution into adipose tissue.¹³ Intravenous procainamide follows a two-compartment model. Initially after the loading dose, the concentration decreases rapidly as the drug is distributed, which is then followed by the elimination phase.

METABOLISM AND CLEARANCE/HALF-LIFE

Approximately 50 percent of procainamide is eliminated unchanged in the urine and the average half-life is approximately 3 hours in healthy subjects.¹⁴ Procainamide also undergoes hepatic metabolism. The major pathway for hepatic metabolism is conjugation of N-acetyl transferase, polymorphically distributed cytosolic enzyme, to form NAPA, which is renally eliminated and has an elimination half-life of approximately 7.5–10 hours in individuals with normal renal function.⁴ In cardiac patients with renal failure, NAPA can accumulate in the plasma and produce signs of clinical toxicity. Age also appears to affect both procainamide clearance and the NAPA:Procainamide concentration ratio, independent of the decline in renal function that occurs in elderly patients.^4,15 Increased urine pH can decrease renal elimination of procainamide.⁶ Both procainamide and NAPA are actively secreted by the proximal tubules of the kidney and competition between the two for renal secretion results in decreased elimination of procainamide.⁶

HEART FAILURE

In patients with heart failure, procainamide is not cleared as well, and therefore, a dose reduction of 30–50 percent in initial therapy is recommended for patients with severely compromised cardiac function.¹⁶ In patients with uncompensated heart failure, a reduction in hepatic blood flow decreases the clearance of procainamide. Furthermore, the volume of distribution is decreased. The half-life of procainamide may not be drastically increased because both the clearance and volume of distribution are decreasing (t_½ = 0.693V/Cl); however, a dose reduction of 25–50 percent may be necessary. Patients with compensated heart failure do not require dose adjustments.

LIVER DISEASE

N-acetyltransferase 2 (NAT2) is a liver enzyme responsible for the conversion of procainamide to NAPA. Despite limited data on the pharmacokinetics of procainamide in patients with liver disease, it is suggested that a dose reduction might be warranted in patients with liver disease. In patients with a Child-Pugh score of 8–10, most recommend a 25 percent reduction in the initial dosage. Those with a score >10, a 50 percent reduction is recommended. From there, doses may be titrated as needed.

RENAL FAILURE AND END-STAGE RENAL DISEASE

As creatinine clearance decreases, the clearance of procainamide is reduced proportionally. The half-life of procainamide in renal failure is approximately 6 hours.¹⁴ In end-stage renal disease, the half-life of procainamide is prolonged to about 14 hours. The volume of distribution of procainamide in end-stage renal disease has been calculated to be about 1.4 L/kg.¹⁶

NAPA

NAPA, the acetylated metabolite of PA, has been shown to have antiarrhythmic actions of its own. It is 85 percent eliminated by the kidneys, and the half-life in patients with normal renal function is about twice that of PA (6–8 hours).¹⁷ The expected half-life in patients with renal failure is 35 hours.¹⁴ Hepatic conjugation of procainamide to NAPA exhibits genetic polymorphism. The fast acetylator phenotype occurs in 10–20 percent of Asians; 50 percent of Americans; and 60–70 percent of Northern Europeans. In fast acetylators, NAPA may accumulate and exceed that of procainamide. The impairment of acetylation in chronic liver disease also seems to be phenotype specific, with a more prominent effect in fast acetylators than in slow acetylators.¹⁸ A fast acetylator is considered a patient without renal impairment who has a NAPA concentration equal to or greater than procainamide three hours after dosing.^2,6 A lower incidence of lupus-like syndrome occurs or a higher dose is needed for this adverse event to occur in patients who are fast acetylators. In patients with normal renal function, the steady-state concentration ratio, or acetylator ratio, of NAPA:PA can be used to possibly determine those who are slow or fast acetylators. A ratio ≥1.2 can be considered a fast acetylator, while a ratio of ≤0.8 a slow acetylator.

ADVERSE EVENTS

The frequency of toxic manifestations, such as depression of cardiac output and blood pressure, vascular collapse, depression of cardiac impulse formation and conduction, prolongation of the QRS and QT intervals, and induction of ventricular arrhythmias has been identified with intravenous administration of procainamide. Toxicity typically occurs at infusion rates of 100 mg or more per minute and is likely secondary to inadequate drug distribution. It is generally accepted that infusion rates of 25–50 mg/min are safe and associated with a low incidence of toxicity.¹⁹ Such undesirable effects have led to the recommendation that during intravenous procainamide therapy, the blood pressure be continually monitored and phenylephrine or norepinephrine either be readily available or actually given. Furthermore, to avert potentially dangerous drug-induced alterations in the ECG, constant electrocardiographic monitoring and equipment to treat ventricular asystole, fibrillation, or both has been advised.²⁰ The small molecular size and low protein binding of procainamide and NAPA are desirable attributes for extracorporeal drug removal. Procainamide toxicity has been treated, with varying degrees of efficiency, by several modalities, including peritoneal dialysis, hemodialysis, hemoperfusion, and continuous arteriovenous hemofiltration/hemodiafiltration.¹⁶

THERAPEUTIC DRUG MONITORING

Plasma levels of procainamide correlate well with the clinical effects of the drug.²¹ When monitoring procainamide therapy, it is customary to measure serum levels of both procainamide and NAPA, which has significant antiarrhythmic action, particularly Class III activity (prolongation of the action potential via potassium channel blockade).²² Serum concentrations of procainamide should not be assessed alone. NAPA should also be analyzed (on the same sample), and each analyte should be quantified with reference to its own reference range. The common practice of summing their concentrations should be avoided.⁶ The therapeutic plasma concentration of procainamide is generally thought to be in the range of 4–10 mg/L. However, this range varies up to a maximum of 32 mg/L and is controversial and poorly determined from small-scale studies that lacked standardized sampling procedures.^4,23 Therapeutic plasma levels of less than 4 mg/L suppress arrhythmias in only a minority of patients. Toxic manifestations are common with concentrations greater than 10 mg/L. At levels >10 mg/L, procainamide produces hypotension and reductions in efferent vasoconstrictor sympathetic outflow that are thought to be the result of ganglionic blockade and/or central nervous system sympathetic inhibition.⁴ The clinical importance of toxic effects on circulatory function depends largely on the patient’s previous cardiovascular status. Most patients can easily compensate for some depression of myocardial contractility by toxic concentrations of procainamide, but the same is not true for patients with preexisting circulatory depression.²¹ The fluorescence polarization immunoassay and enzyme immunoassays are used most commonly for therapeutic drug monitoring of procainamide and of the active metabolite NAPA.²² Measurement of plasma concentrations is helpful in all patients with cardiac or renal failure and in critically ill patients.²¹ When the desired antiarrhythmic effect is not achieved or when toxic effects are suspected, knowledge of the plasma level can greatly clarify the situation.²¹ In routine therapeutic monitoring, a sample collected one hour before the next dose (trough) is recommended for determination of both procainamide and NAPA. The effective range of concentrations of NAPA is 2–22 mg/L, and levels as high as 40 mg/L appear to be well tolerated.¹⁶ Typically, lupus-like syndrome is one of the adverse events not seen with NAPA. (See Table 17-1)

Stay updated, free articles. Join our Telegram channel

Join