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AJMALINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ajmaline is a group 1 antiarrhythmic that depresses the conductivity of the heart and at high doses can result in heart block (S Sweetman , 2002).
    B) Ajmaline (Gilurytmal(R)) is a derivative of the rauwolfia plant (Ben-Shachar & Kishon, 1979). Prajmaline (Neo-Gilurytmal(R)) is a chemical modification of ajmaline used as an antiarrhythmic (Somberg, 1985).
    C) In a report from the Paris Poison Center, 24% of their ajmaline overdoses resulted in death, compared to 3% for digitoxin and 6.5% for chloroquine (Riboulet et al, 1979).

Specific Substances

    1) Ajmaline
    2) Ajmalina
    3) Ajmalinum
    4) Cardiorythine(R)
    5) Gilurytmal(R)
    6) Rauwolfine
    7) Tachmalcor
    8) Prajmaline
    9) Kali-Chemie Pharma GmbH
    10) Neo-Gilurytmal(R)
    11) N-propyl ajmaline hydrogen tartrate
    12) CAS 4360-12-7

Available Forms Sources

    A) FORMS
    1) Ajmaline is available in oral and intravenous forms (S Sweetman , 2002).
    2) Prajmaline (Neo-Gilurytmal(R)) is a chemical modification of ajmaline and available in oral form (Somberg, 1985).
    B) USES
    1) Ajmaline is used to treat dysrhythmias, including supraventricular and ventricular, and discovering latent conduction system disorders (Kaul et al, 1985; S Sweetman , 2002).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) EFFECTS include ventricular dysrhythmias, heart block, hypotension, apnea, ataxia, seizures, and coma. Cardiac arrest and cardiogenic shock have been reported in some cases of exposure. Deaths have also occurred. Other effects include vomiting, diarrhea, oliguria, flushing, and skin mottling.
    2) ONSET can be precipitous; within seconds when given IV, and within 30 to 60 minutes when ingested.
    3) DURATION: ECG changes resolved in 8 to 30 hours.
    4) RISK FACTORS: Toxicity is increased by rapid intravenous administration, renal or hepatic insufficiency, digitalization, and hypokalemia.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Severe intoxications are associated with dysrhythmias, often with sudden onset, including intraventricular block, left bundle branch block, bradycardia, tachycardia, prolonged QT and QRS intervals, extrasystoles, ventricular dysrhythmias, and asystole. Cardiogenic shock has been reported in up to 36% of cases.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Apnea and cyanosis have been reported.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Confusion, disorientation, and restlessness have occurred with therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) CNS manifestations occur as a complication of cardiogenic shock, or in patients with coingestants with CNS properties. Ataxia, seizures, and coma have been reported after overdose.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, diarrhea, and abdominal pain have been reported in a few toxic ingestions.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Ajmaline has caused hepatitis and intrahepatic cholestasis.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Oliguria may occur in patients with severe hypotension.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Agranulocytosis has been reported as a rare side effect.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Flushing is a minor sign of toxicity. Cyanosis and skin mottling may develop in patients with cardiogenic shock.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Monitor serum electrolytes. Obtain an ECG and institute continuous cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Because of the potential for seizures and coma within 30 to 60 minutes, emesis is contraindicated.
    B) 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.
    C) 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.
    D) Continuous electrocardiographic monitoring is required. Ventricular dysrhythmias have been reported in overdose.
    1) Manage airway aggressively.
    2) High degree atrioventricular block may require the use of a cardiac demand pacemaker.
    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) 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.
    G) VENTRICULAR DYSRHYTHMIAS: Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine. Because this agent can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution.
    H) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    I) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.

Range Of Toxicity

    A) An estimated lethal dose for adults is 100 to 500 mg/kg, but a death was reported in a child after ingestion of 53 mg/kg.
    B) Death has also occurred in an adult who ingested 2500 mg.
    C) One mg/kg is therapeutic, 4 mg/kg significantly prolongs atrioventricular conduction, and 8 mg/kg IV may produce hypotension.
    D) Based on its pharmacologic effects, ajmaline depresses the conductivity of the heart. High doses can produce a negative inotropic effect, cardiac dysrhythmias, coma and death.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) EFFECTS include ventricular dysrhythmias, heart block, hypotension, apnea, ataxia, seizures, and coma. Cardiac arrest and cardiogenic shock have been reported in some cases of exposure. Deaths have also occurred. Other effects include vomiting, diarrhea, oliguria, flushing, and skin mottling.
    2) ONSET can be precipitous; within seconds when given IV, and within 30 to 60 minutes when ingested.
    3) DURATION: ECG changes resolved in 8 to 30 hours.
    4) RISK FACTORS: Toxicity is increased by rapid intravenous administration, renal or hepatic insufficiency, digitalization, and hypokalemia.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Eye twitching or blinking has been reported as an adverse effect or sign of minor toxicity (Somberg, 1985; Almog et al, 1979).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Severe intoxications are associated with dysrhythmias, often with sudden onset, including intraventricular block, left bundle branch block, bradycardia, tachycardia, prolonged QT and QRS intervals, extrasystoles, ventricular dysrhythmias, and asystole. Cardiogenic shock has been reported in up to 36% of cases.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Ajmaline may trigger atrial or ventricular dysrhythmias (eg, sinus bradycardia, sinoatrial or atrioventricular node block, or block at the bundle of His) that can progress to cardiac arrest, coma, and death. Ventricular dysrhythmias have been reported with therapeutic use, especially in patients with preexisting cardiac disease; effects include ventricular tachycardia, ventricular flutter, and ventricular fibrillation (S Sweetman , 2002; Fachinformation, 1998)Talwar et al, 1987; Suarex et al, 1984 (Wellens et al, 1980; Nielsen, 1979; Batalow & Apostolow, 1968; Hanusch, 1966; Kaltenbach & Klepzig, 1961). Fatalities have been reported in some cases following therapeutic use (Hanusch, 1966).
    2) WITH POISONING/EXPOSURE
    a) Severe intoxications are associated with dysrhythmias, often with a sudden onset. The following dysrhythmias can occur: intraventricular heart block, left bundle branch block, bradycardia, tachycardia, prolonged QT and QRS intervals, extrasystoles, ventricular dysrhythmias (ie, ventricular flutter supraventricular tachycardia, ventricular tachycardia), and asystole Mobis & Minz, 1999; (Almog et al, 1979)Ben-Shacher & Kishon, 1979; (Riboulet et al, 1979; Binder & Widmer, 1972; Larbig et al, 1970). Cardiac arrest was reported in 22.5% of hospitalized patients with ajmaline overdose (Riboulet et al, 1979).
    b) CASE REPORTS
    1) TODDLER: A 20-month-old child ingested 200 to 400 mg (4 to 8 tablets) of ajmaline and became pale, limp, and unresponsive within 3 hours postingestion. Peripheral pulses and blood pressure were not measurable. The ECG indicated lengthened ventricular complexes with ventricular flutter and supraventricular tachycardia reported. Following symptomatic care, the ECG normalized within 48 hours of exposure (Binder & Widmer, 1972).
    2) ADOLESCENT: A 16-year-old girl intentionally ingested 30 tablets of a combination preparation that contained 30 mg ajmaline, 25 mg spartein sulfate, 50 mg antazoline HCl, and 5 mg phenobarbital. Within 30 minutes the patient was somnolent, cyanotic, hypotensive (bpm 80/60) with a weak pulse, which progressed to an absent pulse and no measurable blood pressure. Cardiac monitoring indicated intermittent lengthening of the QRS complex, marked ST depression, and ventricular flutter. Following intensive supportive care (ie, cardiac massage, artificial respiration), the patient recovered, and normal sinus rhythm was established 19.5 hours postingestion (Larbig et al, 1970).
    3) ADULT: A 58-year-old man with a history of cold- and exercise-induced angina developed ventricular fibrillation progressing to asystole after unintentional intracoronary administration of ajmaline during a percutaneous coronary intervention. Intravenous lipid emulsion (250 mL) was administered, although it did not result in immediate improvement. After the patient had received 130 minutes of CPR, and was treated with overdrive pacing, he had return of sinus rhythm. He was treated with therapeutic hypothermia for 24 hours, and was discharged neurologically intact approximately 6 days later (Gillis, 2011).
    c) CASE SERIES
    1) Seven cases of acute ajmaline overdose (doses ranged from 10 to 40 mg/kg) were reported during a 3-year period. Cardiac effects could be observed within 1 hour of ingestion. Three cardiac arrests and 1 case of hypovolemic shock were reported. Dysrhythmias included the following: atrioventricular blocks (3), intraventricular blocks (6), ventricular tachycardia (3), and prolongation of the QT interval (6). Supportive treatment was based on sodium replacement, temporary cardiac pacing, cardiac massage and defibrillation, sympathomimetics and artificial ventilation as indicated. Of the 7 patients, 1 died (Bouffard et al, 1983).
    B) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Although rare, QT prolongation and torsade de pointes have been reported following intravenous administration of ajmaline (total bolus doses 50 to 90 milligrams; infusion 1 gram/24 hours) (Haverkamp et al, 2001; Kaul et al, 1985).
    b) CASE REPORT: Torsade de pointes was reported after a 1 mg/kg bolus dose in a patient with primary myocardial disease and left bundle branch block (Kaul et al, 1985).
    c) CASE REPORTS: Two cases of QT prolongation and torsade de pointes (TDP) have been reported following intravenous administration of ajmaline (total bolus doses 50 to 90 mg; infusion 1 g/24 hours). In one case, the duration of the QTc interval increased from 430 ms before administration of ajmaline to 600 ms at the time of TDP (Haverkamp et al, 2001).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Systolic hypotension has been reported, especially following rapid intravenous injection. Intravenous bolus injection of 50 mg over 2 minutes (recommended time course is 10 mg/minute, or 5 minutes in this case) in 11 patients resulted in a significant decrease in systolic brachial artery blood pressure for at least 5 minutes, while having no effect on diastolic pressure. No differences were noted between patients with or without heart disease (Saetre et al, 1974).
    D) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Circulatory collapse was reported in 36% of acute ajmaline poisonings admitted to a hospital in a retrospective study of 38 cases (Riboulet et al, 1979).
    b) CASE REPORTS: A pressure of 75/50 mmHg was measured in an adult after ingestion of 32 mg/kg (Jornod & Barrelet, 1965), and 80/60 mmHg was observed in another adult who took 1000 mg (Almog et al, 1979).
    E) CARDIOGENIC SHOCK
    1) WITH THERAPEUTIC USE
    a) PRAJMALINE
    1) CASE REPORT: A young man was receiving metoprolol for the treatment of parasystole and was given 120 mg prajmaline and 600 mg (normal dose between 50 to 400 mg/day) of metoprolol and developed cardiogenic shock, ventricular tachycardia, and ventricular fibrillation. The patient was successfully resuscitated, and required temporary pacing. The patient was monitored for approximately 1 week with only minor ventricular ectopic beats; therapy was not restarted (Almasi et al, 1996).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Apnea and cyanosis have been reported.
    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH THERAPEUTIC USE
    a) Respiratory arrest and/or depression have been reported in rare cases of ajmaline therapy (S Sweetman , 2002; Fachinformation, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Apnea and cyanosis were reported after the ingestion of 250 mg (23 mg/kg) in a 17-month-old (Ben-Shachar & Kishon, 1979).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Confusion, disorientation, and restlessness have occurred with therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) CNS manifestations occur as a complication of cardiogenic shock, or in patients with coingestants with CNS properties. Ataxia, seizures, and coma have been reported after overdose.
    3.7.2) CLINICAL EFFECTS
    A) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Ataxia developed within 30 minutes after ingestion of 250 mg by a 17-month-old child (Ben-Shachar & Kishon, 1979).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Epileptiform convulsions have been reported in rare cases during therapy (Fachinformation, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Seizures occurred within 50 minutes in a 17-month-old who ingested 250 mg (Ben-Shachar & Kishon, 1979). They have been reported in other overdoses where the dose ingested was about 30 mg/kg (Ben-Shachar & Kishon, 1979; Jornod & Barrelet, 1965) Kallfelz & Rottauwe, 1964.
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Coma occurred within 2 hours in a 17-month-old who ingested 250 mg (Ben-Shachar & Kishon, 1979), and within 30 minutes in an adult who ingested 32 mg/kg (Jornod & Barrelet, 1965). CNS depression has been reported in other cases, and usually results from cardiogenic shock or concomitant overdose with CNS depressant drugs (Riboulet et al, 1979)Kallfelz & Rottauwe, 1964.
    D) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Disorientation, restlessness, and inability to understand commands were observed in a 67-year-old patient taking prajmalium bitartrate (Lessing & Copperman, 1977).
    E) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesias have been reported with ajmaline therapy (Fachinformation, 1998).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, diarrhea, and abdominal pain have been reported in a few toxic ingestions.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, diarrhea, appetite loss, and constipation have been reported during therapy with parenteral (injection or infusion) ajmaline therapy (Grenadier et al, 1983).
    2) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, abdominal pain, and diarrhea have been reported in a few toxic ingestions (Ikeda et al, 1988; Mikhov et al, 1982).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Ajmaline has caused hepatitis and intrahepatic cholestasis.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Ajmaline and similar compounds such as N-propyl-ajmalium bitartrate have caused drug-induced hepatitis and intrahepatic cholestasis (Larrey et al, 1986; Borsch et al, 1984) Homberg et al, 1985; (Somberg, 1985).
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) The cholestasis seen after administration is thought to be due to an immune response (Rotmensch et al, 1981; Rotmensch et al, 1980; Beermann et al, 1971).
    C) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transaminase increases (up to 3 times normal) have been reported with ajmaline therapy (Fachinformation, 1998).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Oliguria may occur in patients with severe hypotension.
    3.10.2) CLINICAL EFFECTS
    A) OLIGURIA
    1) WITH POISONING/EXPOSURE
    a) Oliguria may occur in overdose, and is associated with cardiovascular collapse (Riboulet et al, 1979).
    B) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Glomerulonephritis and renal insufficiency have been reported, and are probably due to immunologic changes induced by ajmaline therapy (Fachinformation, 1998).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Agranulocytosis has been reported as a rare side effect.
    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis has been reported as a rare side effect (Wilson et al, 1971).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Flushing is a minor sign of toxicity. Cyanosis and skin mottling may develop in patients with cardiogenic shock.
    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) Flushing is a sign of minor toxicity (Almog et al, 1979).
    B) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Cyanosis and skin mottling may be observed in patients with decreased perfusion due to cardiogenic shock (Riboulet et al, 1979).
    C) XANTHOMATOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Xanthoma has been reported in a woman following oral ajmaline therapy. Symptoms persisted for over 2 years following ajmaline withdrawal (Beerman et al, 1971).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) GENERAL
    1) Ajmaline should not be used in the first trimester of pregnancy, as there are no data from animal or human studies. Use later in pregnancy should only take place in strongly compelling circumstances in the presence of physician monitoring. A reduced dose of ajmaline during pregnancy is suggested (Fachinformation, 1998).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes. Obtain an ECG and institute continuous cardiac monitoring.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes as hypokalemia may increase toxicity.

Methods

    A) CHROMATOGRAPHY
    1) Thin-layer chromatography can be used for qualitative analysis; high performance liquid chromatography can be used for quantitative analysis (Ikeda et al, 1988).
    2) Gelbke & Schlicht (1977) developed a gas chromatography method for analyzing N-propylajmalinium bitartrate in postmortem specimens.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor serum electrolytes. Obtain an ECG and institute continuous cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) Because of the potential for seizures and coma within 30 to 60 minutes, emesis is contraindicated.
    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) EMESIS/NOT RECOMMENDED
    1) Because of the potential for seizures and coma within 30 to 60 minutes, emesis is contraindicated.
    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.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Continuous electrocardiographic monitoring is required.
    2) Manage airway aggressively. Artificial ventilation may be required.
    3) High degree atrioventricular block may require the use of a cardiac demand pacemaker (Ben-Shacher & Kishon, 1979) (Bouffard et al, 1983).
    4) Cardiopulmonary bypass has been suggested for use following overdose (Bouffard et al, 1983).
    B) 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).
    C) 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).
    D) BRADYCARDIA
    1) ATROPINE/DOSE
    a) 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).
    b) 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.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    E) VENTRICULAR ARRHYTHMIA
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine. Because this agent can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution.
    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).
    F) 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, 2010; 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, 2010). 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, 2010). 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, 2010). 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, 2010).
    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, 2010). 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, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    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.
    G) MYELOSUPPRESSION
    1) AGRANULOCYTOSIS: No specific treatment was necessary, patients responded well to withdrawal of ajmaline (Wilson et al, 1971). Consider use of filgrastim in select patients; usual dose is 5 micrograms/kilogram/day subcutaneously.

Enhanced Elimination

    A) DIURESIS
    1) Forced diuresis has not been shown to reliable increase excretion or affect outcome, and it may cause complications such as congestive heart failure. Routine use is NOT recommended.
    2) Forced diuresis with a saline infusion resulted in elimination of 31 milligrams of ajmaline within 24 hours. The initial ingestion was 250 milligrams in a 17-month-old (Ben-Shachar & Kishon, 1979). Thus about 12.4% was eliminated.
    3) In one case where 1000 milligrams was ingested by an adult, the urinary excretion under forced diuresis was 35.28 milligrams during the first 24 hours, 6 milligrams during the second, and nothing subsequently. This amounts to only 4% of the dose taken.
    4) Other patients have recovered without forced diuresis (Hager et al, 1968; JEF Reynolds , 1991).
    B) HEMODIALYSIS
    1) Hemodialysis was not found to be dialyzable (Padrini et al, 1991; Koeppel et al, 1989).
    a) Hemodialysis in 4 patients with renal failure resulted in removal of 13% of the original ajmaline dose of 50 mg IV bolus infusion (Koeppel et al, 1989). Hemodialysis in one patient with chronic renal failure resulted in no change of the final elimination phase of the drug (Padrini et al, 1991).
    C) HEMOFILTRATION
    1) Hemofiltration was not found to be clinically effective (Koeppel et al, 1989).
    a) Hemofiltration following an initial dose of 50 mg IV bolus infusion removed only 9% of ajmaline in the plasma compartment, corresponding to less than 3% of the total dose (Koeppel et al, 1989).

Abstracts

Case Reports

    A) INFANT
    1) A 17-month-old girl ingested 5 tablets (250 mg of ajmaline, or 23 mg/kg). She developed an ataxic gait within 30 minutes, and clonic-tonic seizures within 50 minutes. At 2 hours postingestion she became comatose, apneic, and cyanotic.
    a) She was lavaged, given cardiac monitoring, and forced diuresis. During the first 24 hours she excreted 31 mg of ajmaline. Eight hours postingestion she converted to a sinus rhythm without left bundle-branch block. She was released from intensive care the day after the ingestion (Ben-Shachar & Kishon, 1979).
    B) ADULT
    1) A 24-year-old man was found unconscious and in shock 30 minutes after ingestion of 32 mg/kg of ajmaline. Complications included seizures, apnea, and arrhythmias (ventricular fibrillation, left bundle branch block); EKG normalized within 30 hours of ingestion (Jornod & Barrelet, 1965).

Range Of Toxicity

Summary

    A) An estimated lethal dose for adults is 100 to 500 mg/kg, but a death was reported in a child after ingestion of 53 mg/kg.
    B) Death has also occurred in an adult who ingested 2500 mg.
    C) One mg/kg is therapeutic, 4 mg/kg significantly prolongs atrioventricular conduction, and 8 mg/kg IV may produce hypotension.
    D) Based on its pharmacologic effects, ajmaline depresses the conductivity of the heart. High doses can produce a negative inotropic effect, cardiac dysrhythmias, coma and death.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AJMALINE -
    a) INTRAVENOUS - Intravenous (IV) bolus injections should not exceed 50 milligrams or 1 milligram/kilogram. The rate of injection should not exceed 10 milligrams/minute, and should be slowed in patients with significant pre-existing coronary dysfunction. Exact dosage should be determined by the physician. If absolutely necessary, bolus IV injection may be repeated in 30 minutes. Numerous IV injections should be avoided, and changed to continual IV drip infusion if necessary (Fachinformation, 1998).
    b) SLOW DRIP INFUSION - Standard intravenous infusion dose ranges from 0.5 to 1 milligram per kilogram per hour (mg/kg/h). Doses up to 2000 milligrams in 24 hours may be administered with careful monitoring of administered drug, serum drug concentrations, and excreted metabolites (Fachinformation, 1998).
    1) Slow drip infusion of ajmaline is recommended for tachycardias in conjunction with myocardial infarction, for stabilization effect on electroconversion of coronary infarction, as well as in intravenous (IV) bolus injection therapy-resistant cases. (Fachinformation, 1998).
    2) PRAJMALIUM -
    a) One hundred milligrams/day is given orally in divided doses (Lessing & Copperman, 1977).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Pediatric use has not been proven completely safe and is not recommended (Fachinformation, 1998).

Minimum Lethal Exposure

    A) ADULT
    1) An estimated lethal dose for adults is 100 to 500 milligrams/kilogram (Ikeda et al, 1988).
    2) Death has also occurred in an adult who ingested 2500 milligrams (Ikeda et al, 1988).
    B) PEDIATRIC
    1) A death was reported in a 4-year-old child after ingestion of 53 milligrams/kilogram (Ikeda et al, 1988).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) AJMALINE -
    a) SUMMARY - Based on its pharmacologic effects, ajmaline depresses the conductivity of the heart. High doses can produce a negative inotropic effect, cardiac dysrhythmias, coma, and death (S Sweetman , 2002).
    1) One milligram/kilogram is therapeutic, 4 milligrams/kilogram significantly prolongs atrioventricular conduction, and 8 milligrams/kilogram intravenously may produce hypotension (Almog et al, 1979).
    b) Doses of 23 to 30 milligrams/kilogram have caused coma, seizures, cyanosis, and ventricular fibrillation (Ben-Shachar & Kishon, 1979; Jornod & Barrelet, 1965) Kallfelz & Rottauwe, 1964).
    c) CASE REPORTS -
    1) TODDLER - A 20-month-old ingested between 200 to 400 milligrams of ajmaline and became unresponsive, limp with no measurable blood pressure and later developed ventricular dysrhythmias (ventricular flutter and supraventricular tachycardia). The child recovered completely following supportive care (Binder & Widmer, 1972).
    2) TODDLER - A 17-month-old ingested 23 milligrams/kilogram and developed ataxia, coma, seizures, and bundle-branch block (Ben-Shachar & Kishon, 1979).
    3) TEENAGER - A 16-year-old female ingested 30 tablets of a combination product (that contained 30 milligrams ajmaline, 25 milligrams spartein sulfate, 500 milligrams antazoline HCl and 5 milligrams phenobarbital) and developed somnolence, cyanosis, and hypotension, within 30 minutes of the ingestion. Symptoms progressed to an absent pulse and no measurable blood pressure along with ventricular dysrhythmias. Following intensive supportive care the patient was in normal sinus rhythm 19.5 hours after the ingestion (Larbig et al, 1970).
    4) ADULT - An adult who ingested 32 milligrams/kilogram was asymptomatic 15 minutes postingestion, but was found comatose, cyanotic, and hypotensive 30 minutes postingestion (Jornod & Barrelet, 1965).
    2) PRAJMALINE -
    a) GENERAL
    1) N-propyl ajmaline bitartrate is several times more effective as an antiarrhythmic than is ajmaline in animals tested (Nakayama et al, 1973).
    2) Weidner & Philipsborn (1971) found that 0.2 milligram per kilogram of prajmalium was approximately equivalent to 1 milligram of ajmaline in both therapeutic and toxic effect.
    b) CASE REPORT
    1) A young adult ingested 120 milligrams of prajmaline and 600 milligrams metoprolol and developed cardiogenic shock and ventricular dysrhythmias. The patient was treated symptomatically and recovered without sequelae (Almasi et al, 1996).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) THERAPEUTIC LEVEL - Therapeutic blood level of ajmaline is 1 to 3 micrograms per deciliter (Almog et al, 1979).
    b) TOXIC LEVEL - The toxic concentration of ajmaline is estimated to be 15 micrograms per deciliter (Almog et al, 1979).
    1) An adult patient who ingested 1000 milligrams had a blood level of 300 micrograms/deciliter 150 minutes postingestion. This patient survived (Almog et al, 1979).
    2) A child who was thought to have ingested 53 milligrams/kilogram had a blood level of 5.5 micrograms/milliliter. The time when the sample was taken was not specified, but is assumed to be after death (Ikeda et al, 1988).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Ajmaline prolongs ventricular repolarization, refractoriness and prolongs QT intervals in both therapeutic and toxic doses (Chiale et al, 1982; Ben-Shachar & Kishon, 1979).
    B) Ajmaline alters the permeability of cellular membranes to sodium and potassium, slowing depolarization, repolarization, and the rate of conduction. In overdose, there is a negative inotropic effect with both atrioventricular and intraventricular blocks (Ben-Shachar & Kishon, 1979).
    C) HYPOTENSION - is caused by reduced cardiovascular performance and decreased coronary flow (Almog et al, 1979).

Physicochemical

Physical Characteristics

    A) This compound is a yellow to white crystalline powder without odor (JEF Reynolds , 1991).

Molecular Weight

    A) 326.4

References

General Bibliography

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    3) Almasi R, Magel F, & Kosik G: Cardiogenic shock and ventricular fibrillation induced by prajmalium and metoprolol poisoning (abstract). Orv Hetil 1996; 137(13):695-700.
    4) Almog C, Maidan A, & Pik A: Acute intoxication with ajmaline. Isr J Med Sci 1979; 15:570-572.
    5) 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.
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    7) Beermann B, Ericsson JLE, & Hellstrom K: Transient cholestasis during treatment with ajmaline, and chronic xanthomatous cholestasis after administration of ajmaline, methyltestosterone and ethinylestradiol. Acta Med Scand 1971; 190:241-250.
    8) Ben-Shachar G & Kishon Y: Intoxication with ajmaline in an infant. Chest 1979; 76:97-98.
    9) Binder C & Widmer M: Ein fall von ajmalin-intoxikation in kleinkindesalter (German). Wien Klin Wochenschr 1972; 84(4):67-69.
    10) Borsch G, Schmidt G, & Hopmann G: Prajmaliumbitartrate-associated liver damage. Klin Wochenschr 1984; 62:998-1000.
    11) Bouffard Y, Roux H, & Perrot D: Acute ajmaline poisoning. Study of 7 cases (abstract) (French). Arch Mal Coeur Vaiss 1983; 76(7):771-777.
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