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PROCAINAMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Procainamide is a class 1A antidysrhythmic used to treat life-threatening ventricular dysrhythmias and may be used to maintain sinus rhythm after cardioversion of atrial fibrillation.

Specific Substances

    1) 4-Amino-N-(2-(diethylamino)ethyl) benzamide monohydrochloride
    2) Novocainamidum
    3) Procainamide Hydrochloride
    4) Procainamidi Hydrochloridum
    5) Procaine amide hydrochloride
    6) Procainamidi Chloridum
    7) CAS 614-39-1

Available Forms Sources

    A) FORMS
    1) CAPSULES: 250 mg (Prod Info PRONESTYL oral capsules, oral tablets, 2006)
    2) INJECTABLES: 100 mg/mL and 500 mg/mL (Prod Info procainamide HCl IV, IM injection solution, 2011)
    B) USES
    1) Procainamide is indicated for the treatment of life-threatening ventricular dysrhythmias (Prod Info procainamide HCl IV, IM injection solution, 2011).
    2) According to the American Heart Association consensus guidelines, procainamide can be used for treatment of non ventricular fibrillation (non-VF) or ventricular tachycardia (VT) arrest. Procainamide prolongs the refractory period of the atria and ventricles, thereby depressing conduction velocity (Neumar et al, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Procainamide is used to treat ventricular dysrhythmia and may be used to maintain sinus rhythm after cardioversion of atrial fibrillation.
    B) PHARMACOLOGY: It is a type IA antidysrhythmic with electrophysiological properties similar to quinidine. Its primary effect on the heart is to decrease electrical impulse conduction velocity through atrial and ventricular tissue; clinically this translates to prolongation of the PR and QRS intervals on the ECG.
    C) TOXICOLOGY: Procainamide binds to fast sodium channels and decreases cardiac excitability and conduction velocity while increasing the effective refractory period of the atria, His-Purkinje system, and ventricles. Toxic concentrations may prolong AV conduction or induce AV block. It has weak vagal blocking action, no alpha-adrenergic blockade, and less myocardial depression than quinidine. It also has anticholinergic properties. It has local anesthetic effects similar to procaine. The major metabolite (N-acetylprocainamide or NAPA) has type III antidysrhythmic activity.
    D) EPIDEMIOLOGY: Procainamide poisoning is rare, but severe cardiovascular toxicity and deaths can occur after inadvertent or deliberate exposures.
    E) WITH THERAPEUTIC USE
    1) Cardiovascular effects include atrial and ventricular dysrhythmias, junctional tachycardia, hypotension, and ventricular conduction delays, torsades de pointes, and ventricular fibrillation. Gastrointestinal effects may also occur. CNS effects include depression, cerebellar ataxia, and toxic psychosis. Drug-induced systemic lupus erythematosus (SLE), characterized by fever, arthralgias, myalgias, pleural effusion and pain, and serositis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, drowsiness, anticholinergic effects such as dry mouth, mydriasis, tachycardia, and decreased bowel sounds.
    2) SEVERE TOXICITY: Confusion, agitation, seizures, hypotension, conduction delays (eg, QRS and QTc prolongation, AV block), ventricular dysrhythmias (including ventricular tachycardia, fibrillation, and torsades de pointes), and respiratory depression.
    0.2.20) REPRODUCTIVE
    A) There were no harmful effects in an infant born to a mother taking procainamide. Procainamide and its active metabolite, N-acetyl procainamide (NAPA), are accumulated in breast milk. However, the long term toxic effects of exposure to the infant are unknown .

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Institute continuous cardiac monitoring and perform serial ECGs.
    C) Monitor serum electrolytes (including magnesium) and renal function.
    D) Monitoring drug concentrations of procainamide and its active metabolite, N-acetylprocainamide, may be helpful in confirming the diagnosis of procainamide toxicity, but they are not useful to guide therapy.
    E) Toxicity increases as plasma procainamide concentrations exceed 10 mcg/mL and are common in patients with plasma concentrations above 15 mcg/mL.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with mild symptoms such as gastrointestinal effects following exposure should be treated with supportive care and be placed on a cardiac monitor. Avoid other type 1A antidysrhythmic medications. Replete magnesium and potassium.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) All patients with severe toxicity should have IV access and continuous cardiac monitoring. Avoid using other type IA antidysrhythmics. Cardiovert unstable rhythms. Treat wide complex dysrhythmias with hypertonic sodium bicarbonate (1 to 2 mEq/kg IV). Lidocaine is the antidysrhythmic agent of choice for persistent dysrhythmias. Hypotension should initially be treated with isotonic fluid resuscitation and inotropic medications. Seizures are treated with benzodiazepine. Treat torsade de pointes with standard interventions including magnesium and overdrive pacing. Pacemaker insertion should be considered for increasing AV block. Cardiopulmonary bypass or extracorporeal membrane oxygenation should be considered for patients with severe toxicity not responding to other interventions.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended because of potential for somnolence and seizures.
    2) HOSPITAL: In the serious toxicity, decontamination is an appropriate intervention. Gastric lavage (with airway management if needed) should be considered and activated charcoal should be administered to all potentially toxic ingestions.
    D) AIRWAY MANAGEMENT
    1) Maintain open airway and perform orotracheal intubation in patients with seizures, CNS depression or ventricular dysrhythmias.
    E) CONDUCTION DISORDER OF THE HEART
    1) SODIUM BICARBONATE
    a) Because procainamide binds to fast sodium channels, ventricular dysrhythmias may respond to IV sodium bicarbonate. Starting dose is 1 to 2 mEq/kg as an IV bolus. Monitor arterial blood gases and ECG.
    2) MECHANICAL CARDIORESPIRATORY SUPPORT
    a) Cardiopulmonary bypass or extracorporeal membrane oxygenation should be considered for patients with severe toxicity not responding to other interventions.
    F) ENHANCED ELIMINATION
    1) Hemodialysis or hemoperfusion should be performed early in patients with severe toxicity. Continuous arteriovenous hemofiltration may be of benefit in those patients that are hemodynamically unstable and when hemodialysis would not be feasible.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: All the overdose patients should be sent to the hospital.
    2) OBSERVATION CRITERIA: Overdose patients should be monitored for at least 8 hours for mental status changes, conduction delays, dysrhythmias or hypotension. Patients who ingested sustained release preparations should be monitored for at least 24 hours.
    3) ADMISSION CRITERIA: Admit all patients with CNS or cardiovascular effects to an ICU setting.
    H) PHARMACOKINETICS
    1) Bioavailability: 50% to 95%. Peak plasma concentrations: 1 to 2 hours after immediate release, 12 hours or longer after sustained release. Protein binding: 15%. Vd: 1.6 to 2.4 L/kg. Hepatically acetylated to the active metabolite N-acetylprocainamide (NAPA), which has a slightly different electrophysiologic profile from, and a longer half-life than, procainamide. Approximately 40% to 60% of procainamide and 84% of NAPA are excreted unchanged in the urine.
    I) PREDISPOSING CONDITIONS
    1) Amiodarone and cimetidine increase serum procainamide concentrations and development of clinical signs of toxicity. Renal insufficiency may allow NAPA to accumulate.
    J) PITFALLS
    1) Patients ingesting sustained release products should be monitored for 24 hours as delayed toxicity may develop. Dysrhythmias secondary to antidysrhythmic overdose are often refractory to other antidysrhythmic drugs.

Range Of Toxicity

    A) TOXICITY: 2 to 3 g dose is potentially dangerous in a child. Toxicity has occurred in adults after ingestion of 7 and 19 g.
    B) THERAPEUTIC DOSE: ADULT: IV BOLUS: A direct IV injection of 100 mg every 5 minutes at a rate not to exceed 50 mg/minute to a maximum dose of 1 g until dysrhythmia is suppressed or until 500 mg IV has been used. IV LOADING DOSE: 20 mg/mL (1 g diluted to 50 mL with D5W) IV infused at a constant rate of 1 mL/minute for 25 to 30 minutes to deliver 500 to 600 mg of procainamide; maximum dose 1 g. MAINTENANCE DOSE: 2 mg/mL IV infused at a rate of 1 to 3 mL/minute or 4 mg/mL at a rate of 0.5 to 1.5 mL/minute, delivering an equivalent to 2 to 6 mg/minute. PEDIATRIC: (Based on Pediatric Advanced Life Support Guidelines): Loading dose: 15 mg/kg over 30 to 60 min; Maintenance: Initiate at 20 mcg/kg/min and increase in 10 mcg/kg/min increments every 15 to 30 min until desired effect is achieved; up to 80 mcg/kg/min; Maximum 2 g/day.

Clinical Effects

Summary Of Exposure

    A) USES: Procainamide is used to treat ventricular dysrhythmia and may be used to maintain sinus rhythm after cardioversion of atrial fibrillation.
    B) PHARMACOLOGY: It is a type IA antidysrhythmic with electrophysiological properties similar to quinidine. Its primary effect on the heart is to decrease electrical impulse conduction velocity through atrial and ventricular tissue; clinically this translates to prolongation of the PR and QRS intervals on the ECG.
    C) TOXICOLOGY: Procainamide binds to fast sodium channels and decreases cardiac excitability and conduction velocity while increasing the effective refractory period of the atria, His-Purkinje system, and ventricles. Toxic concentrations may prolong AV conduction or induce AV block. It has weak vagal blocking action, no alpha-adrenergic blockade, and less myocardial depression than quinidine. It also has anticholinergic properties. It has local anesthetic effects similar to procaine. The major metabolite (N-acetylprocainamide or NAPA) has type III antidysrhythmic activity.
    D) EPIDEMIOLOGY: Procainamide poisoning is rare, but severe cardiovascular toxicity and deaths can occur after inadvertent or deliberate exposures.
    E) WITH THERAPEUTIC USE
    1) Cardiovascular effects include atrial and ventricular dysrhythmias, junctional tachycardia, hypotension, and ventricular conduction delays, torsades de pointes, and ventricular fibrillation. Gastrointestinal effects may also occur. CNS effects include depression, cerebellar ataxia, and toxic psychosis. Drug-induced systemic lupus erythematosus (SLE), characterized by fever, arthralgias, myalgias, pleural effusion and pain, and serositis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, drowsiness, anticholinergic effects such as dry mouth, mydriasis, tachycardia, and decreased bowel sounds.
    2) SEVERE TOXICITY: Confusion, agitation, seizures, hypotension, conduction delays (eg, QRS and QTc prolongation, AV block), ventricular dysrhythmias (including ventricular tachycardia, fibrillation, and torsades de pointes), and respiratory depression.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION has been reported (Koch-Weser, 1971).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) BLURRED VISION was reported in a 21-year-old receiving a combined oral and intravenous dose of procainamide 6320 mg daily for 2 days (Prendergast & Nasca, 1984).
    2) MYDRIASIS: A 14-year-old presented with dilated pupils (10 mm bilaterally) that were sluggishly reactive to light after procainamide overdose (White et al, 2002).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) DYSPHAGIA
    a) DYSPHAGIA for liquids was reported in a 64-year-old man, with chronic renal insufficiency, who was given sustained-release procainamide, 750 mg 4 times daily, to treat atrial flutter and unstable angina.
    1) Over the next 3 months, the dysphagia worsened. The patient was hospitalized and the procainamide was discontinued 7 days later. Two days after discontinuation of the procainamide, the patient noticed improvement in his dysphagia (Miller et al, 1993).
    B) WITH POISONING/EXPOSURE
    1) DRY MOUTH
    a) Dry mouth was reported in a 21-year-old receiving a combined oral and intravenous dose of procainamide 6320 mg daily for 2 days (Prendergast & Nasca, 1984).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported (Koch-Weser, 1971).
    2) WITH POISONING/EXPOSURE
    a) Hypotension may occur with overdose (Kim & Benowitz, 1990).
    b) CASE REPORT: A 67-year-old woman developed junctional tachycardia, intraventricular conduction delay, severe hypotension with prerenal azotemia, mental obtundation, and gastrointestinal irritation after ingesting approximately 7 g of procainamide. Following supportive care, including hemodialysis, she recovered gradually and was discharged 33 days later (Atkinson et al, 1976).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Serious disturbances of cardiac rhythm such as ventricular asystole or fibrillation are more common with IV administration of procainamide than with intramuscular administration. Additionally, abnormal conduction patterns (QRS widening, QT interval prolongation, PR interval prolongation, lowering of the R and T waves, increasing atrioventricular (AV) block, ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation) may be associated with doses that are excessive for a given patient (Prod Info procainamide HCl IV, IM injection solution, 2011; Raja et al, 1984).
    b) Intraventricular conduction delay, premature ventricular depolarization, torsades de pointes, and ventricular fibrillation have been reported. Adverse effects from therapeutic doses include cardiac dysrhythmias and conduction disturbances (Habbab & El-Sherif, 1990; Kim & Benowitz, 1990; Stratmann et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Life-threatening dysrhythmias may occur with overdose (Kim & Benowitz, 1990).
    b) CASE REPORT: A 67-year-old woman developed junctional tachycardia, intraventricular conduction delay, severe hypotension with prerenal azotemia, mental obtundation, and gastrointestinal irritation after ingesting approximately 7 g of procainamide. Following supportive care, including hemodialysis, she recovered gradually and was discharged 33 days later (Atkinson et al, 1976).
    C) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) Torsades de pointes has reportedly been associated with elevated concentrations of both procainamide and N-acetylprocainamide (NAPA) (Kim & Benowitz, 1990; Vlasses et al, 1986; Stratmann et al, 1985; Chow et al, 1984; Raja et al, 1984).
    b) CASE REPORT: A 34-year-old woman with chronic glomerulonephritis developed ventricular bigeminy 4 days after undergoing mitral valve replacement. She received procainamide (concentrations 2.7 to 5.6 mcg/mL) for 6 days until she developed frequent episodes of polymorphic ventricular tachycardia lasting from 3 to 22 complexes. An ECG revealed a QRS of 0.16 seconds and a QT of 0.44 seconds (QTc 0.47 seconds). At this time, procainamide and N-acetylprocainamide (NAPA) plasma levels were 3.6 and 43 mcg/mL, respectively. Although overdrive pacing was started, she experienced 4 episodes of torsades de pointes degenerating into ventricular fibrillation in the next 2 hours. She underwent 4 hours of hemodialysis and procainamide and NAPA plasma levels decreased to 3.1 and 20 mcg/mL, respectively. She gradually improved and overdrive pacing was discontinued (Nguyen et al, 1986).
    D) PERICARDIAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) Cardiac tamponade was reported as the initial manifestation of procainamide-induced systemic lupus erythematosus in one case. It was successfully treated with high-dose hydrocortisone and pericardiocentesis. The patient had been taking 500 mg procainamide every 6 hours for 3 years prior to the onset of SLE (Mohindra et al, 1989).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH THERAPEUTIC USE
    a) Venkayya et al (1993) reported a case of respiratory failure, secondary to necrotizing myopathy with diaphragm involvement, in a patient on procainamide therapy. The patient's condition improved after discontinuation of the medication (Venkayya et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) Respiratory failure secondary to diaphragmatic paralysis was reported in a patient with procainamide intoxication. The patient's condition resolved upon discontinuation of the drug. Serum procainamide and NAPA concentrations were 15 mcg/mL and 112 mcg/mL, respectively (Javaheri et al, 1989).
    B) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) Respiratory insufficiency, secondary to muscle weakness, occurred in a patient who underwent a cardiopulmonary bypass and was given sustained-release procainamide, 500 mg 4 times daily, to prevent recurrent dysrhythmias. Although the procainamide and NAPA concentrations were always within the therapeutic range, the patient was unable to be removed from the ventilator. Ten days after discontinuation of procainamide, the patient was able to be weaned from the ventilator (Putnam et al, 1991).
    b) CASE REPORT: Extreme weakness and respiratory failure occurred in a 53-year-old man with amiodarone-induced peripheral neuropathy who was given procainamide infusion 3 mg/min. On admission, serum procainamide was 73.6 mcg/mL (therapeutic range, 10 to 30 mcg/mL). Following supportive care and 50 hours after procainamide discontinuation, his procainamide concentration decreased to 32.6 mg/dL (Miller et al, 1988).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Lethargy and obtundation have been observed.
    2) WITH POISONING/EXPOSURE
    a) Lethargy and confusion have been reported with overdose (Atkinson et al, 1976).
    B) ATAXIA
    1) WITH THERAPEUTIC USE
    a) Cerebellar ataxia developed acutely in a patient receiving high-dose procainamide therapy. Resolution occurred within 3 days after discontinuation of therapy (Schwartz et al, 1984).
    C) PSYCHOTIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Toxic psychosis was reported in a 67-year-old man who was prescribed sustained-release procainamide, 500 mg every 6 hours. The patient developed auditory hallucinations and paranoid ideations within 48 hours of initiating drug therapy (Harrison, 1993).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 14-year-old boy developed a brief tonic-clonic seizure after procainamide overdose (White et al, 2002).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may occur (Koch-Weser, 1971).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have been reported after overdose (White et al, 2002; Atkinson et al, 1976).
    B) CONSTIPATION
    1) WITH POISONING/EXPOSURE
    a) Constipation was reported in a 21-year-old receiving a combined oral and intravenous dose of procainamide 6320 mg daily for 2 days (Prendergast & Nasca, 1984).
    C) INTESTINAL OBSTRUCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 65-year-old man complained of abdominal pain, distention, nausea, and vomiting 2 weeks after initiating therapy with sustained-release procainamide, 500 mg 4 times daily. An obstruction series revealed multiple dilated small bowel loops consistent with small bowel obstruction. The oral procainamide was stopped and intravenous procainamide (3 mg/min) was started. During the next 3 days, the patient's abdominal distention worsened. Procainamide was discontinued and, 48 hours later, the patient's abdominal distention diminished and finally disappeared (Peterson et al, 1991).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Chuang et al (1993) reported a case of a 77-year-old woman who became jaundiced, had elevated serum procainamide and NAPA concentrations, and had elevated liver enzyme concentrations 6 weeks after initiation of sustained-release procainamide therapy, 500 mg every 6 hours.
    1) The patient's aminotransferase levels slowly returned to normal several weeks after discontinuation of the procainamide (Chuang et al, 1993).
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Elevated aminotransferase and serum bilirubin levels, fever, chills, arthralgia, and abdominal pain were reported in a patient who had a hypersensitivity reaction to intravenous procainamide, 1.5 g, given 6 hours earlier.
    1) The patient's serum bilirubin concentration and aminotransferase levels increased over the next several days, and then decreased towards normal values (Worman et al, 1992)

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Urinary retention was reported in a 21-year-old receiving a combined oral and intravenous dose of procainamide 6320 mg daily for 2 days (Prendergast & Nasca, 1984).
    B) AZOTEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 67-year-old woman developed junctional tachycardia, intraventricular conduction delay, severe hypotension with prerenal azotemia, mental obtundation, and gastrointestinal irritation after ingesting approximately 7 g of procainamide. Following supportive care, including hemodialysis, she recovered gradually and was discharged 33 days later (Atkinson et al, 1976).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Thrombocytopenia developed in a 77-year-old man 23 days after initiation of extended-release procainamide. The patient's platelet count continued to decline despite discontinuation of the procainamide. Severe thrombocytopenia persisted for approximately 2 weeks before the platelet count slowly began to increase. Full recovery of the patient's platelet count occurred 33 days after the procainamide was discontinued (Landrum et al, 1994).
    b) CASE REPORT: Freeman et al (1995) reported a case of a patient who developed thrombocytopenia and a lupus anticoagulant simultaneously within 2 months of beginning procainamide therapy. Several weeks after procainamide was discontinued, the patient's platelet count and partial thromboplastin time slowly returned to normal values.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Skeletal muscle weakness and diaphragmatic paralysis leading to respiratory failure were described in a 65-year-old man receiving 750 mg procainamide twice a day. Admission procainamide and NAPA concentrations were 15 mcg/mL and 112 mcg/mL, respectively (Javaheri et al, 1989).
    b) CASE REPORT: Extreme weakness and respiratory failure occurred in a 53-year-old man with amiodarone-induced peripheral neuropathy who was given procainamide infusion 3 mg/min. On admission, serum procainamide was 73.6 mcg/mL (therapeutic range, 10 to 30 mcg/mL). Following supportive care and 50 hours after procainamide discontinuation, his procainamide concentration decreased to 32.6 mg/dL (Miller et al, 1988).
    c) Several other authors have reported myositis, muscle weakness, or myopathy associated with therapeutic use of procainamide (Miller et al, 1993; Sayler & DeJong, 1991; Lewis et al, 1986; Niakan et al, 1981; Fontiveros et al, 1980) .
    d) CASE REPORT: Venkayya et al (1993) reported a case of a 74-year-old man who developed necrotizing myopathy with diaphragm involvement and respiratory failure 7 days after discontinuing a 2-week procainamide therapy. One month later, the patient's respiratory indices improved and there was marked improvement in muscle strength (Venkayya et al, 1993).
    e) CASE REPORT: Muscle weakness associated with respiratory insufficiency was reported in a 46-year-old man who underwent a cardiopulmonary bypass and was given sustained-release procainamide, 500 mg 4 times daily, to prevent recurrent dysrhythmias. The patient was unable to be removed from the ventilator. The patient was successfully removed from the ventilator 10 days after the discontinuation of the procainamide (Putnam et al, 1991).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: McDonald and Marino (1993) reported 2 cases of procainamide-induced lupus (McDonald & Marino, 1993).
    1) The first case reported was of a 71-year-old man who presented to the ED with a fever, left-sided pleuritic chest pain, and a nonproductive cough 1 year after beginning procainamide therapy, 500 mg 3 times daily, to treat a ventricular dysrhythmia. Symptoms persisted for several weeks after discontinuation of the procainamide. Drug-induced lupus was the presumed diagnosis. Symptoms resolved following prednisone therapy.
    2) The second case reported was of a 67-year-old woman who presented with diffuse myalgias, musculoskeletal pain in her hands, episodic bilateral pleuritic chest pain, a pruritic skin rash, and a low-grade fever 1 year after beginning procainamide therapy, 750 mg 3 times daily, to treat a postinfarction dysrhythmia. Procainamide was discontinued and symptoms persisted until prednisone therapy was started.
    b) CASE REPORT: Procainamide-induced lupus was diagnosed in a 74-year-old man who presented with asymptomatic left pleural effusion. The patient had been taking sustained-release procainamide every 6 hours for 1 year. The effusion resolved following 2 months of steroid therapy after discontinuing the procainamide (Klimas et al, 1992).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 23-year-old man received 1.5 g procainamide intravenously and complained of chills, fever, nausea, vomiting, diffuse red rash, abdominal pain, headache, tightness in throat, myalgia, and arthralgia 6 hours later. Aminotransferase and bilirubin levels were also elevated. The symptoms were explained as a hypersensitivity reaction due to the procainamide. The symptoms resolved several days later(Worman et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) There were no harmful effects in an infant born to a mother taking procainamide. Procainamide and its active metabolite, N-acetyl procainamide (NAPA), are accumulated in breast milk. However, the long term toxic effects of exposure to the infant are unknown .
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) CASE REPORT - There were no harmful effects in an infant born to a mother taking procainamide 250 mg to 375 mg every 4 hours and propranolol 10 mg every 6 hours for 8 days prior to delivery. At delivery, the infant's blood level was below therapeutic (Lima et al, 1978).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    PROCAINAMIDEC
    Reference: Briggs et al, 1998.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Procainamide and its active metabolite, N-acetyl procainamide (NAPA), are accumulated in breast milk. However, the long term toxic effects of exposure to the infant are unknown (Briggs et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Institute continuous cardiac monitoring and perform serial ECGs.
    C) Monitor serum electrolytes (including magnesium) and renal function.
    D) Monitoring drug concentrations of procainamide and its active metabolite, N-acetylprocainamide, may be helpful in confirming the diagnosis of procainamide toxicity, but they are not useful to guide therapy.
    E) Toxicity increases as plasma procainamide concentrations exceed 10 mcg/mL and are common in patients with plasma concentrations above 15 mcg/mL.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor liver function tests, serum electrolyte levels, and renal function tests in symptomatic patients.
    2) Monitoring drug levels for procainamide and its active metabolite, N-acetyl procainamide, may be helpful in the diagnosis of procainamide toxicity.
    a) When N-ACETYLPROCAINAMIDE CONCENTRATIONS are not available, it is important to note that patients receiving procainamide chronically may occasionally have NAPA levels 5 to 6 times as great as their procainamide concentrations.
    b) Routine monitoring of NAPA concentrations is NOT indicated in patients with normal renal function (Follath et al, 1983).
    3) Toxicity increases as plasma procainamide concentrations exceed 10 mcg/mL and are common in patients with plasma concentrations above 15 mcg/mL (Prod Info procainamide HCl IV, IM injection solution, 2011).

Methods

    A) IMMUNOASSAY
    1) An EMIT(R) homogeneous enzyme immunoassay is available for quantitation of procainamide and NAPA in serum or plasma. The assay's range of quantitation is 1.0 to 16.0 mcg/mL (4.2 to 59.5 mcmol/L) procainamide.
    a) Clinical studies show this method to correlate well with HPLC and spectrofluorometry.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit all patients with CNS or cardiovascular effects to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) All the overdose patients should be sent to the hospital.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Overdose patients should be monitored for at least 8 hours for mental status changes, conduction delays, dysrhythmias or hypotension. Patients who ingested sustained release preparations should be monitored for at least 24 hours.

Monitoring

    A) Monitor vital signs and mental status.
    B) Institute continuous cardiac monitoring and perform serial ECGs.
    C) Monitor serum electrolytes (including magnesium) and renal function.
    D) Monitoring drug concentrations of procainamide and its active metabolite, N-acetylprocainamide, may be helpful in confirming the diagnosis of procainamide toxicity, but they are not useful to guide therapy.
    E) Toxicity increases as plasma procainamide concentrations exceed 10 mcg/mL and are common in patients with plasma concentrations above 15 mcg/mL.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Not recommended because of potential for somnolence and seizures.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: In the serious toxicity, decontamination is an appropriate intervention. Gastric lavage (with airway management if needed) should be considered and activated charcoal should be administered to all potentially toxic ingestions.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    D) WHOLE BOWEL IRRIGATION
    1) Consider whole bowel irrigation with a polyethylene glycol balanced electrolyte solution after ingestion of sustained-release products.
    a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.
    1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.
    b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
    c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
    d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Institute continuous cardiac monitoring and perform serial ECGs.
    3) Monitor serum electrolytes (including magnesium) and renal function.
    4) Monitoring drug concentrations of procainamide and its active metabolite, N-acetylprocainamide, may be helpful in confirming the diagnosis of procainamide toxicity, but they are not useful to guide therapy.
    5) Toxicity increases as plasma procainamide concentrations exceed 10 mcg/mL and are common in patients with plasma concentrations above 15 mcg/mL.
    B) WIDE QRS COMPLEX
    1) Cardiac toxicity may respond to intravenous sodium bicarbonate. A reasonable starting dose is 1 to 2 milliequivalents/kilogram as an intravenous bolus repeated as needed to reverse QRS widening and dysrhythmias and maintain an arterial pH of 7.45 to 7.55. Monitor serial ECGs, arterial blood gases and serum potassium.
    a) Membrane hyperpolarization and extracellular alkalosis are possible therapeutic mechanisms (Gay & Brown, 1974).
    2) LIDOCAINE
    a) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010a). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010a).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    b) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a).
    c) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) Persistent cardiac toxicity will most efficiently be managed with insertion of a temporary pacemaker.
    C) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010a; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010a). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010a). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010a). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010a).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010a). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010a). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010a).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010a).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) SUMMARY
    1) Resin hemoperfusion or hemodialysis are the methods of choice for removal of procainamide and N-acetylprocainamide.
    2) Continuous arteriovenous hemofiltration may be of benefit in those patients that are hemodynamically unstable and when hemodialysis would not be feasible (Mitnick, 1987).
    B) HEMODIALYSIS
    1) Hemodialysis has been reported to increase the clearance of both procainamide and NAPA (Prod Info procainamide HCl IV, IM injection solution, 2011).
    2) CASE REPORT: A 67-year-old woman developed junctional tachycardia, intraventricular conduction delay, severe hypotension with prerenal azotemia, mental obtundation, and gastrointestinal irritation after ingesting approximately 7 g of procainamide. Hemodialysis increased the elimination rates of procainamide (doubled) and NAPA (4-fold) significantly and removed 340 mg of procainamide and 470 mg of NAPA in 4 hours. Without hemodialysis in this patient, the elimination half-life of procainamide and NAPA would have been 10.5 hours (normal value, 3 hours) and 35.9 hours (normal value, 6 hours), respectively. The apparent Vd of procainamide and NAPA were 0.76 L/kg (normal value, 2 L/kg) and 0.63 L/kg (normal value, 1.4 L/kg), respectively. (Atkinson et al, 1976).
    3) CASE REPORT: A 34-year-old woman with chronic glomerulonephritis developed ventricular bigeminy 4 days after undergoing mitral valve replacement. She received procainamide (concentrations 2.7 to 5.6 mcg/mL) for 6 days until she developed frequent episodes of polymorphic ventricular tachycardial lasting from 3 to 22 complexes. An ECG revealed a QRS of 0.16 seconds and a QT of 0.44 seconds (QTc 0.47 seconds). At this time, procainamide and NAPA plasma levels were 3.6 and 43 mcg/mL, respectively. Although overdrive pacing was started, she experienced 4 episodes of torsade de pointes degenerating into ventricular fibrillation in the next 2 hours. She underwent 4 hours of hemodialysis and procainamide and NAPA plasma levels decreased to 3.1 and 20 mcg/mL, respectively. She gradually improved and overdrive pacing was discontinued (Nguyen et al, 1986).
    C) HEMOPERFUSION
    1) Resin hemoperfusion is recommended over hemodialysis for the treatment of life-threatening complications of N-acetylprocainamide toxicity.
    2) Braden et al (1986) reported the superiority of hemoperfusion over hemodialysis in the treatment of N-acetylprocainamide intoxication in a 60-year-old man receiving intravenous procainamide for ventricular tachycardia. Resin hemoperfusion (XAD-4 cartridge) for 4 hours was followed for 4 hours of hemodialysis (1.6 square meter parallel plate dialyzer). N-acetylprocainamide levels decreased by 19 mcg/mL with hemoperfusion as compared to 2 mcg/mL after 4 hours of hemodialysis, and the plasma clearance of N-acetylprocainamide was much greater (3.5 times) with hemoperfusion as compared to hemodialysis (Braden et al, 1986).
    3) Intermittent, rather than continuous hemodialysis-hemoperfusion may be more efficacious in removing both procainamide and NAPA in the face of renal failure, due to prolonged rebound of NAPA levels from redistribution (Rosansky & Brady, 1986).
    4) Three patients with renal failure and severe procainamide toxicity were treated with 3 to 4 hours of resin hemoperfusion. Although all patients improved during resin hemoperfusion, 2 patients developed persistent cardiogenic shock and died several hours after the termination of hemoperfusion. The third patient developed cardiac arrest and died 6 hours after hemoperfusion, probably due to drug rebound and continued absorption of the drug from the GI tract (Raja et al, 1984).
    D) COMBINED HEMOPERFUSION/HEMODIALYSIS
    1) Hemoperfusion increased the clearance of NAPA by approximately 36% over hemodialysis. Combined hemodialysis-hemoperfusion with amberlite was approximately 3 times as effective as hemodialysis alone in the removal of NAPA (Rosansky & Brady, 1986).
    2) Hemoperfusion was found to be clearly superior to hemodialysis in removing NAPA in a patient with chronic renal failure (Braden et al, 1986a).
    E) PERITONEAL DIALYSIS
    1) Peritoneal dialysis is not considered effective in removing significant amounts of the drug.
    a) In one case, a 79-year-old man ingested approximately 19 grams of procainamide. Peritoneal dialysis was instituted, but contributed little to the removal of procainamide (Villalba-Pimentel et al, 1973).
    F) DIURESIS
    1) Forced diuresis has never been shown to be of value in treatment of procainamide overdose.
    G) HEMOFILTRATION
    1) CONTINUOUS ARTERIOVENOUS HEMOFILTRATION: Was used to enhance elimination of N-acetylprocainamide in a hemodynamically unstable, 57 year old patient in whom dialysis was not feasible. Urine output was less than 100 milliliters/day.
    a) N-acetylprocainamide levels decreased from 68 micrograms/milliliter on day 0 to 29.5 micrograms/milliliter on day 4 (Domoto et al, 1987). No free clearance or dialysance was reported.

Abstracts

Case Reports

    A) ADULT
    1) An anticholinergic syndrome was described in a 21-year-old man following combined oral and IV procainamide therapy (6320 mg daily) for 2 days. This syndrome was heralded by the onset of blurred vision, constipation, dry mouth, and urinary retention, which required bladder catheterization. Transient sinus node arrest was observed on the cardiac monitor with EKG revealing prolonged QT interval. Procainamide serum concentration was 31.8 mcg/mL (NAPA concentration 26 mcg/mL). Anticholinergic symptoms subsided within 12 hours after withdrawal of procainamide (Prendergast & Nasca, 1984).

Range Of Toxicity

Summary

    A) TOXICITY: 2 to 3 g dose is potentially dangerous in a child. Toxicity has occurred in adults after ingestion of 7 and 19 g.
    B) THERAPEUTIC DOSE: ADULT: IV BOLUS: A direct IV injection of 100 mg every 5 minutes at a rate not to exceed 50 mg/minute to a maximum dose of 1 g until dysrhythmia is suppressed or until 500 mg IV has been used. IV LOADING DOSE: 20 mg/mL (1 g diluted to 50 mL with D5W) IV infused at a constant rate of 1 mL/minute for 25 to 30 minutes to deliver 500 to 600 mg of procainamide; maximum dose 1 g. MAINTENANCE DOSE: 2 mg/mL IV infused at a rate of 1 to 3 mL/minute or 4 mg/mL at a rate of 0.5 to 1.5 mL/minute, delivering an equivalent to 2 to 6 mg/minute. PEDIATRIC: (Based on Pediatric Advanced Life Support Guidelines): Loading dose: 15 mg/kg over 30 to 60 min; Maintenance: Initiate at 20 mcg/kg/min and increase in 10 mcg/kg/min increments every 15 to 30 min until desired effect is achieved; up to 80 mcg/kg/min; Maximum 2 g/day.

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL DOSE
    1) IV BOLUS: The recommended dose is a direct IV injection of 100 mg every 5 minutes at a rate not to exceed 50 mg/minute to a maximum dose of 1 g until dysrhythmia is suppressed or until 500 mg IV has been used (Prod Info procainamide HCl intravenous injection solution, intramuscular injection solution, 2013)
    2) IV LOADING DOSE: The recommended dose is 20 mg/mL (1 g diluted to 50 mL with D5W) IV infused at a constant rate of 1 mL/minute for 25 to 30 minutes to deliver 500 to 600 mg of procainamide; maximum dose 1 g (Prod Info procainamide HCl intravenous injection solution, intramuscular injection solution, 2013).
    B) MAINTENANCE DOSE
    1) IV: The recommended dose is 2 mg/mL IV infused at a rate of 1 to 3 mL/minute or 4 mg/mL at a rate of 0.5 to 1.5 mL/minute, delivering an equivalent to 2 to 6 mg/minute (Prod Info procainamide HCl intravenous injection solution, intramuscular injection solution, 2013).
    7.2.2) PEDIATRIC
    A) INITIAL DOSE
    1) IV LOADING DOSE: 15 mg/kg over 30 to 60 minutes (based on PALS Guidelines) (Kleinman et al, 2010; Bouhouch et al, 2008; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Luedtke et al, 1997)
    2) Smaller loading doses of 10 to 15 mg/kg have also been used for arrhythmias that were not life-threatening (Bouhouch et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    B) MAINTENANCE DOSE
    1) IV: Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute. Maximum 2 g/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    2) In a retrospective study (n=17) in children with postoperative junctional tachycardia, mean effective (to keep heart rate below 180 beats/minute) procainamide infusion rate was 68 mcg/kg/minute with doses greater than 80 mcg/kg/minute (up to 120 mcg/kg/minute) required in some children (Mandapati et al, 2000).

Maximum Tolerated Exposure

    A) ACUTE
    1) Plasma concentrations above 15 mcg/mL are commonly associated with toxicity. Symptoms may result following a single 2 g dose while 3 g are likely to produce significant toxicity (especially in a patient that is a slow acetylator, decreased renal function, or underlying heart disease) (Prod Info PRONESTYL oral capsules, oral tablets, 2006; Prod Info PROCANBID(R) extended-release oral tablets, 2002).
    2) One study reported that severe cardiac toxicity may occur with total procainamide and n-acetylprocainamide (NAPA) levels of 42 mcg/mL or more and lethargy with profound hypotension with levels totaling 60 mcg/mL (Atkinson et al, 1976).
    B) CASE REPORTS
    1) In one case, a 79-year-old man ingested approximately 19 g of procainamide. Peritoneal dialysis was instituted, but contributed little to the removal of procainamide (Villalba-Pimentel et al, 1973).
    2) Acute onset of cerebellar ataxia occurred in a patient with a serum procainamide level of 42 mcg/mL (NAPA, 26 mcg/mL) (Schwartz et al, 1984).
    3) CASE REPORT: A 67-year-old woman developed junctional tachycardia, intraventricular conduction delay, severe hypotension with prerenal azotemia, mental obtundation, and gastrointestinal irritation after ingesting approximately 7 g of procainamide. Following supportive care, including hemodialysis, she recovered gradually and was discharged 33 days later (Atkinson et al, 1976).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SUMMARY
    a) The therapeutic range for procainamide levels alone are 6 to 14 mcg/mL (25.5 to 59.5 micromoles/L) with the higher concentrations required in patients with recurrent sustained tachycardia (Follath et al, 1983).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) PROCAINAMIDE
    1) Cerebellar ataxia was associated with a procainamide level of 42 mcg/mL (NAPA, 26 mcg/mL) (Schwartz et al, 1984).
    2) Adverse effects, including cardiac, gastrointestinal, and CNS effects, are most commonly seen at total serum concentrations above 10 micrograms/ milliliter (Miller et al, 1993).
    3) Toxicity increases as plasma procainamide concentrations exceed 10 mcg/mL and are common in patients with plasma concentrations above 15 mcg/mL (Prod Info procainamide HCl IV, IM injection solution, 2011).
    4) One study reported that severe cardiac toxicity may occur with total procainamide and n-acetylprocainamide (NAPA) levels of 42 mcg/mL or more and lethargy with profound hypotension with levels totaling 60 mcg/mL (Atkinson et al, 1976).
    5) CASE REPORT: A 67-year-old woman developed junctional tachycardia, intraventricular conduction delay, severe hypotension with prerenal azotemia, mental obtundation, and gastrointestinal irritation after ingesting approximately 7 g of procainamide. Hemodialysis increased the elimination rates of procainamide (doubled) and NAPA (4-fold) significantly and removed 340 mg of procainamide and 470 mg of NAPA in 4 hours(Atkinson et al, 1976).
    b) PROCAINAMIDE/N-ACETYLPROCAINAMIDE
    1) One report suggests that combined total procainamide and N-acetylprocainamide levels exceeding 30 to 40 mcg/mL (127.5 to 169.9 micromoles/liter) may often be associated with cardiac disturbances, depending upon the patients cardiovascular status.
    2) Combined total levels exceeding 60 mcg/mL (254.9 micromoles/liter) are likely to be associated with lethargy and severe hypotension.

Pharmacology Toxicology

Toxicologic Mechanism

    A) PROCAINAMIDE is an antidysrhythmic agent with electrophysiologic properties similar to that of quinidine.
    1) Its primary effects on the heart are (1) to decrease electrical impulse conduction velocity through atrial and ventricular tissue manifested by a widened QRS and PR interval in the electrocardiogram and (2) to prolong the effective refractory period.
    B) While N-ACETYLPROCAINAMIDE (NAPA) retains some of the same clinical effects as procainamide, it has a slightly different electrophysiologic profile. It increases the effective refractory period with a selective lengthening of the action potential by prolonging repolarization.
    1) There is no effect on depolarization, which is thought to result from its inability to block fast sodium channels and depress phase 4 depolarization. Thus, the drug has been described as a Class III antidysrhythmic (Singh et al, 1986).

Physicochemical

Physical Characteristics

    A) Procainamide hydrochloride is a white to tan-colored, odorless, hygrgoscopic, crystalline powder which is very soluble in water and soluble to freely soluble in alcohol (JEF Reynolds , 2000).

Molecular Weight

    A) Procainamide: 235.33

References

General Bibliography

    1) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    2) Atkinson AJ Jr & Ruo TI: Pharmacokinetics of n-acetylprocainamide. Angiology 1986; 37:959-967.
    3) Atkinson AJ Jr, Krumlovsky FA, Huang CM, et al: Hemodialysis for severe procainamide toxicity: clinical and pharmacokinetic observations. Clin Pharmacol Ther 1976; 20(5):585-592.
    4) Bouhouch R, El Houari T, Fellat I, et al: Pharmacological therapy in children with nodal reentry tachycardia: when, how and how long to treat the affected patients. Curr Pharm Des 2008; 14(8):766-769.
    5) Braden GL, Fitzgibbons JP, & Germain MJ: Hemoperfusion for the treatment of N-acetylprocainamide intoxication. Ann Intern Med 1986a; 105:64-65.
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    60) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    61) Product Information: PROCANBID(R) extended-release oral tablets, procainamide hcl extended-release oral tablets. Monarch Pharmaceuticals,Inc, Bristol, TN, 2002.
    62) Product Information: PRONESTYL oral capsules, oral tablets, procainamide hcl oral capsules, oral tablets. Apothecon, Princeton, NJ, 2006.
    63) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    64) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    65) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    66) Product Information: procainamide HCl IV, IM injection solution, procainamide HCl IV, IM injection solution. Hospira, Inc (per DailyMed), Lake Forest, IL, 2011.
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