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TOCAINIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tocainide, a primary amine analog of lidocaine, is a class IB antiarrhythmic agent. Tocainide is an orally bioavailable derivative of lidocaine. It is no longer sold in the United States.

Specific Substances

    1) 2 amino-2(1)-6(1)-propionxylidide HCl
    2) Propanamide, 2 amino-N-(2,6-dimethylphenyl)
    3) CAS 41708-72-9
    4) Molecular Formula: C11-H16-N2-O-HCl

Available Forms Sources

    A) FORMS
    1) Tonocard(R) (tocainide HCl, MSD); 400 and 600 mg tablets (Prod Info Tonocard(R), tocainide, 1999).
    2) An injectable preparation containing 50 mg/mL in 15 mL vials is available in the UK (JEF Reynolds , 1989).
    B) USES
    1) Tocainide is effective in the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia (Prod Info Tonocard(R), tocainide, 1999).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: Tocainide is no longer sold in the United States.
    B) WITH THERAPEUTIC USE
    1) Primary side effects are CNS (ie, dizziness, vertigo tremors, ataxia, and paresthesia), gastrointestinal (ie, nausea, anorexia, vomiting) , and dermatologic (diaphoresis, rash with long-term use) and blurred vision in long term use. Proarrhythmic effects (PVCs, ventricular tachycardia or fibrillation), nodal bradycardia, hypotension, and left ventricular failure are reported with ongoing use.
    2) Chronic intoxication is common, with CNS signs and symptoms usually preceding cardiovascular toxicity (increased ventricular dysrhythmias/PVCs).
    C) WITH POISONING/EXPOSURE
    1) Effects of an acute overdose are primarily CNS effects (ie, seizures, restlessness) or cardiopulmonary depression or arrest (ie, bradycardia, tachycardia, hypotension, heart block, asystole). Complete heart block with asystole was reported following a large overdose.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Diplopia and nystagmus may occur.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Proarrhythmic effects (PVCs, ventricular tachycardia or fibrillation), nodal bradycardia, hypotension, and left ventricular failure have been reported in patients treated therapeutically with tocainide.
    B) WITH POISONING/EXPOSURE
    1) Complete heart block with asystole was reported following a large overdose.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Interstitial pneumonitis and pulmonary fibrosis have been reported during chronic therapeutic use.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Restlessness is a common side effect during therapeutic use; tremor may be a clinical indicator that the maximum dose is being approached. Dizziness, ataxia, and confusion are common side effects during therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Seizures have been reported after overdose.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Vomiting occurs with both chronic and therapeutic use.
    2) Bleeding from the lips and gingivae has been reported with tocainide therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Abdominal pain and diarrhea have been reported after overdose.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatitis was reported during therapeutic use.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Leukopenia, agranulocytosis, thrombocytopenia, and aplastic anemia have been reported during therapeutic use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Various types of rashes, including Stevens-Johnson syndrome and exfoliative dermatitis, have been reported during therapeutic use. Generalized maculopapular lupoid eruption has been reported during tocainide therapeutic use.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Paranoid psychosis has been reported during therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Tocainide is classified in pregnancy risk category C.

Laboratory Monitoring

    A) Institute continuous cardiac monitoring and obtain an ECG.
    B) Determine serum electrolytes in patients with dysrhythmias, seizures or other toxic effects.
    C) Tocainide levels are available but are not likely to be helpful in guiding therapy. Therapeutic levels are 18 to 45 mcmol/L or 4 to 10 mcg/mL. Gas-liquid chromatography has been used to determine tocainide concentrations.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment should be aimed at controlling ventricular tachycardias, nodal bradycardia and seizures.
    B) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    E) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    F) Isoproterenol infusion was ineffective when tried in 1 case.
    G) DYSRHYTHMIAS
    1) Toxicity is similar to that of lidocaine, but the effects are much longer in duration. Nodal bradycardia and asystole may be difficult to bring under control using standard therapeutic agents. Temporary pacemaker insertion may be required.
    H) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    I) ENHANCED ELIMINATION - Acidification of the urine is not useful, alkalinization reduces renal clearance by 75%. Hemodialysis will reduce mean t1/2 to 8.5 +/- 4.0 hours.

Range Of Toxicity

    A) The minimal toxic dose of tocainide is unknown. Patients with underlying cardiac disease or dysrhythmias and those already taking other antidysrhythmic agents are probably more susceptible to toxicity.
    B) Severe toxicity (coma, severe hypotension, seizures, respiratory depression) developed in an adult after ingestion of 8.4 g. He survived with intensive supportive care.
    C) In a fatal case resulting from ingestion of 16 g, the blood level was 384.8 mcmol/L and the urinary level was 2860 mcmol/L. Oral LD50 in rodents ranges from 1000 to 1500 mg/kg.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Tocainide is no longer sold in the United States.
    B) WITH THERAPEUTIC USE
    1) Primary side effects are CNS (ie, dizziness, vertigo tremors, ataxia, and paresthesia), gastrointestinal (ie, nausea, anorexia, vomiting) , and dermatologic (diaphoresis, rash with long-term use) and blurred vision in long term use. Proarrhythmic effects (PVCs, ventricular tachycardia or fibrillation), nodal bradycardia, hypotension, and left ventricular failure are reported with ongoing use.
    2) Chronic intoxication is common, with CNS signs and symptoms usually preceding cardiovascular toxicity (increased ventricular dysrhythmias/PVCs).
    C) WITH POISONING/EXPOSURE
    1) Effects of an acute overdose are primarily CNS effects (ie, seizures, restlessness) or cardiopulmonary depression or arrest (ie, bradycardia, tachycardia, hypotension, heart block, asystole). Complete heart block with asystole was reported following a large overdose.

Vital Signs

    3.3.3) TEMPERATURE
    A) Fever has been reported with tocainide therapeutic use (Dunn et al, 1988).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Both tachycardia and bradycardia have occurred after tocainide overdose.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Diplopia and nystagmus may occur.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) DIPLOPIA or nystagmus may be seen (Prod Info TONOCARD(R) oral tablet, 2000; Denaro & Benowitz, 1989).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Proarrhythmic effects (PVCs, ventricular tachycardia or fibrillation), nodal bradycardia, hypotension, and left ventricular failure have been reported in patients treated therapeutically with tocainide.
    B) WITH POISONING/EXPOSURE
    1) Complete heart block with asystole was reported following a large overdose.
    3.5.2) CLINICAL EFFECTS
    A) ATRIOVENTRICULAR BLOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Complete heart block with asystole developed after ingestion of 16 grams by a 70-year-old man (Clarke & El-Mahdi, 1984).
    B) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) PROARRHYTHMIC EFFECTS (PVCs, ventricular tachycardia or fibrillation) have been reported in patients treated therapeutically with tocainide (Prod Info TONOCARD(R) oral tablet, 2000).
    b) CASE REPORTS - 2 patients had increases in ventricular tachycardia which led to ventricular fibrillation (Engler & LeWinter, 1981).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Nodal bradycardia has been reported with therapeutic doses in the elderly (Mandal & Datta, 1983).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported (Bastian et al, 1980).
    E) LEFT HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Left ventricular failure has been reported (Bastian et al, 1980).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Interstitial pneumonitis and pulmonary fibrosis have been reported during chronic therapeutic use.
    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Interstitial pneumonitis has been reported during chronic therapeutic use (Braude et al, 1982; Perlow et al, 1984).
    B) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Pulmonary fibrosis, fibrosing alveolitis, pulmonary edema, and pneumonia have been reported in patients receiving tocainide (Prod Info TONOCARD(R) oral tablet, 2000).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Restlessness is a common side effect during therapeutic use; tremor may be a clinical indicator that the maximum dose is being approached. Dizziness, ataxia, and confusion are common side effects during therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Seizures have been reported after overdose.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Restlessness is a common side effect during therapeutic use; tremor may be a clinical indicator that the maximum dose is being approached (Prod Info TONOCARD(R) oral tablet, 2000; Dunn et al, 1988).
    b) Dizziness, ataxia, and confusion are common side effects during therapeutic use (Prod Info TONOCARD(R) oral tablet, 2000).
    c) Vertigo and short-term memory loss have been reported with tocainide therapeutic use (Dunn et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) Seizures have been reported after overdose.
    b) CASE REPORTS - Seizures occurred 1 hour after ingestion of 16 grams (Clarke & El-Mahdi, 1984), and after ingestion of 8.4 grams in a 69-year-old male (Cohen, 1987).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Vomiting occurs with both chronic and therapeutic use.
    2) Bleeding from the lips and gingivae has been reported with tocainide therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Abdominal pain and diarrhea have been reported after overdose.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting may occur with both chronic and therapeutic use (Prod Info TONOCARD(R) oral tablet, 2000; Mandal & Datta, 1983).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain and diarrhea have also been described after an acute overdose (Cohen, 1987).
    C) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Bleeding from the lips and gingivae associated with a generalized rash has been reported with tocainide therapeutic use (Dunn et al, 1988).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatitis was reported during therapeutic use.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Hepatitis was reported in a 61-year-old man after taking 1200 mg/day with 200 mg of amiodarone (Nauta et al, 1984).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Leukopenia, agranulocytosis, thrombocytopenia, and aplastic anemia have been reported during therapeutic use.
    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Leukopenia was reported in a 79-year-old taking 1200 mg/day for several days (Harrison & Wathen, 1984).
    b) Agranulocytosis, aplastic/hypoplastic anemia, bone marrow depression, neutropenia, and thrombocytopenia have been reported (Prod Info TONOCARD(R) oral tablet, 2000).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Various types of rashes, including Stevens-Johnson syndrome and exfoliative dermatitis, have been reported during therapeutic use. Generalized maculopapular lupoid eruption has been reported during tocainide therapeutic use.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Various rashes, including exfoliative dermatitis and Stevens-Johnson syndrome have been reported during therapeutic use (Pottage, 1983; Arrowsmith et al, 1987).
    b) CASE REPORT - A 76-year-old man with benign paroxysmal premature ventricular contractions developed a generalized burgundy-colored maculopapular-vesicular rash on his abdomen, chest, and stomach after taking tocainide (400 mg three times daily) for 2 weeks. The skin lesions revealed necrolysis with weeping and denudation. Upon discontinuation of tocainide, symptoms completely resolved within 3 months with no permanent sequelae (Dunn et al, 1988).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) IMMUNE SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Three patients have been reported to have developed immune-mediated side effects. Anemia, fever and pericarditis in one patient, arthritis and arthralgia in another, and immune-complex glomerulonephritis in the third.
    1) These reactions developed after 7, 4 and 27 months of therapy. All 3 improved upon discontinuation of therapy (Winkle, 1980).
    B) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Lupus-like syndrome with fever, pleural effusion, and hepatosplenomegaly developed in a 75-year-old male following 3 weeks of therapy with tocainide. WBC count decreased to 3,500/mm(3) and platelet count to 113,000/mm(3), with a hematocrit of 30.7%. Serum antinuclear antibody (ANA) was positive with a titer of 1:640. The patient was discharged approximately 3 days after discontinuation of tocainide and was asymptomatic 3 weeks later (Gelfand et al, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Tocainide is classified in pregnancy risk category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    TOCAINIDEC
    Reference: Briggs et al, 1998

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Institute continuous cardiac monitoring and obtain an ECG.
    B) Determine serum electrolytes in patients with dysrhythmias, seizures or other toxic effects.
    C) Tocainide levels are available but are not likely to be helpful in guiding therapy. Therapeutic levels are 18 to 45 mcmol/L or 4 to 10 mcg/mL. Gas-liquid chromatography has been used to determine tocainide concentrations.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Therapeutic levels are 18 to 45 mcmol/L (Clarke & El-Mahdi, 1984), or 4 to 10 mcg/mL (Pottage, 1983).
    a) Serum tocainide level in a 26-year-old who died from an overdose was 68 mcg/mL (Sperry et al, 1987). A 69-year-old male who survived an overdose of 8.4 grams of tocainide had a blood tocainide level of 34 mcg/mL (Cohen, 1987).

Methods

    A) CHROMATOGRAPHY
    1) Gas-liquid chromatography and high pressure liquid chromatography have been used to determine levels of tocainide (Sedman & Gal, 1984; (Sperry et al, 1987).
    2) Tocainide can be detected quantitatively by thin-layer chromatography; mass spectrum analysis can confirm the presence of tocainide and metabolites (Sperry et al, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Institute continuous cardiac monitoring and obtain an ECG.
    B) Determine serum electrolytes in patients with dysrhythmias, seizures or other toxic effects.
    C) Tocainide levels are available but are not likely to be helpful in guiding therapy. Therapeutic levels are 18 to 45 mcmol/L or 4 to 10 mcg/mL. Gas-liquid chromatography has been used to determine tocainide concentrations.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) 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).
    B) 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.
    6.5.3) TREATMENT
    A) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    B) ISOPROTERENOL
    1) Isoprenaline (isoproterenol) infusion was ineffective, and may have contributed to asystole, in 1 patient (Clarke & El-Mahdi, 1984).
    C) BRADYCARDIA
    1) Toxicity is similar to that of lidocaine, but effects are much longer. Nodal bradycardia and asystole may be difficult to bring under control using standard therapeutic agents. Pacemaker insertion may be the treatment of choice (Denaro & Benowitz, 1989).
    2) ATROPINE
    a) ATROPINE/DOSE
    1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    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).
    E) VENTRICULAR ARRHYTHMIA
    1) SUMMARY
    a) VENTRICULAR DYSRHYTHMIAS SUMMARY
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) 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, 2010). 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, 2010).
    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).
    c) 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, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Will reduce mean half-life to 8.5 plus or minus 4.0 hours (Wiegers et al, 1980).
    2) Tocainide hemodialysis clearance is approximately equivalent to its renal clearance (Prod Info TONOCARD(R) oral tablet, 2000) .
    B) HEMOPERFUSION
    1) May be effective in removing tocainide. However, because of its large volume of distribution (2 to 4 liters/kilogram), hemoperfusion may need to be continued for several hours (Denaro & Benowitz, 1989).
    C) OTHER
    1) Acidification of the urine is not useful (Lalka et al, 1980).
    2) Alkalinization reduces renal clearance by 75% (Lalka et al, 1980).

Abstracts

Case Reports

    A) ADULT
    1) Clarke & El-Mahdi (1984) reported a case of tocainide overdose in a 70-year-old man (Clarke & El-Mahdi, 1984).
    2) The patient was admitted following a seizure 1 hour after taking 40 tocainide 400 mg tablets. The patient became deeply comatose with exaggerated tendon reflexes and extensor plantar reflexes.
    3) The patient developed complete heart block with three episodes of asystole. The patient died despite an isoproterenol infusion and cardiac pacing. Postmortem serum tocainide concentrations was 384 mcmol/L (therapeutic 18 to 45 mcmol/L).

Range Of Toxicity

Summary

    A) The minimal toxic dose of tocainide is unknown. Patients with underlying cardiac disease or dysrhythmias and those already taking other antidysrhythmic agents are probably more susceptible to toxicity.
    B) Severe toxicity (coma, severe hypotension, seizures, respiratory depression) developed in an adult after ingestion of 8.4 g. He survived with intensive supportive care.
    C) In a fatal case resulting from ingestion of 16 g, the blood level was 384.8 mcmol/L and the urinary level was 2860 mcmol/L. Oral LD50 in rodents ranges from 1000 to 1500 mg/kg.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) INITIAL DOSE - 400 mg ORALLY every 8 hours; the usual dose is 1200 to 1800 mg/day in a three dose daily divided regimen. A twice daily regimen may also be used, but requires close monitoring (Prod Info TONOCARD(R) oral tablet, 2000).
    2) Doses beyond 2400 mg/day have been used infrequently (Prod Info TONOCARD(R) oral tablet, 2000).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) The safety and effectiveness have not been established (Prod Info TONOCARD(R) oral tablet, 2000).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) A fatality was reported in a 70-year-old man who took 16 grams (Clarke & El Mahdi, 1984; (Barnfield & Kemmenoe, 1986).
    2) A 26-year-old woman who ingested an unknown amount became unconscious and died 4 hours later (Sperry et al, 1987).

Maximum Tolerated Exposure

    A) CASE REPORT - A 69-year-old man with a history of ischemic heart disease, diabetes, peripheral vascular disease, and sick sinus syndrome with complex cardiac dysrhythmias and a ventricular demand pacer developed coma, seizures, severe hypotension, and respiratory depression after ingesting 8.4 grams tocainide (Cohen, 1987). He survived with intensive supportive care including intubation, mechanical ventilation, diazepam and phenobarbital, dopamine, and hemodialysis. Tocainide level on admission was 34 micrograms/mL.

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Four to 10 micrograms/milliliter, or 18 to 45 micromoles/liter, is considered therapeutic (Prod Info Tonocard(R), tocainide, 1999; Pottage, 1983).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) In a fatal case resulting from the ingestion of 16 grams, the antemortem blood level was 384.8 micromoles/liter, and the urinary level was 2,860 micromoles/liter (Clarke & El-Mahdi, 1984).
    1) Postmortem tocainide levels in this case were 74 micrograms/milliliter in blood and 550 micrograms/milliliter in urine (Barnfield & Kemmenoe, 1986).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 1500 mg/kg (Holmes et al, 1983)
    2) 800 mg/kg (Tech Info, 1984)
    B) LD50- (ORAL)RAT:
    1) 1200 mg/kg (Holmes et al, 1983)
    2) 1000/kg (Tech Info, 1984)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tocainide shortens action potential duration and refractory periods of the atria, atrioventricular node and ventricles (Pottage, 1983).
    B) Tocainide has minimal effect on intracardiac conduction or sinus nodal automaticity (Pottage, 1983).
    C) PR and QRS are seldom changed, but QT intervals may be smaller (Young et al, 1980).

Physicochemical

Physical Characteristics

    A) White crystalline powder with a bitter taste (Prod Info Tonocard(R), tocainide, 1999)

Molecular Weight

    A) Base: 192.3 (Budavari, 1996)
    B) HCl: 228.72 (Prod Info Tonocard(R), tocainide, 1999)

References

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