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DISOPYRAMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Disopyramide is a quinidine-like Type 1 antidysrhythmic, cardiac depressant drug. It has negative inotropic and anticholinergic properties and is effective in the treatment of documented life-threatening ventricular dysrhythmias, such as sustained ventricular tachycardia. It depresses myocardial excitability and conduction velocity.

Specific Substances

    1) SC-7031
    2) CAS 3737-09-5 (disopyramide)
    3) CAS 22059-60-5 (disopyramide phosphate)

Available Forms Sources

    A) FORMS
    1) Disopyramide is available as 100 mg and 150 mg capsules and extended-release capsules (Prod Info disopyramide phosphate oral capsules, 2015; Prod Info NORPACE(R), NORPACE(R) CR oral capsules, extended-release capsules, 2006).
    B) USES
    1) Disopyramide is a Type 1 antidysrhythmic agent indicated in the treatment of documented life-threatening ventricular dysrhythmias, such as sustained ventricular tachycardia (Prod Info disopyramide phosphate oral capsules, 2015).

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) In overdose, cardiovascular and anti-muscarinic effects are pronounced. Severe effects include apnea, loss of consciousness, loss of spontaneous respiration, and cardiac arrest.
    2) Similar cardiovascular toxicities occur as with quinidine and procainamide; depression of atrial, atrioventricular and ventricular conduction, dysrhythmias, hypotension, heart failure, syncope, cinchonism, paresthesia, and coma; but anticholinergic effects are more pronounced, and heart failure is more frequent.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Blurred vision, dry mouth, and angle-closure glaucoma (in those predisposed) are anticholinergic toxicities (Sathyavagiswaran, 1987; JEF Reynolds , 2000).
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Depressed myocardial contractility is a significant feature of disopyramide poisoning which shares similar toxic effects with quinidine. Sinoatrial, atrioventricular, and his-ventricular depression of conduction may occur along with ventricular tachycardia and ventricular fibrillation. Disopyramide has a strong negative inotropic effect.
    2) Syncope is usually related to transient torsade de pointes ventricular tachycardia. Hypotension occurs from alpha receptor blockade and depressed myocardial contractility. Heart failure may result.
    3) Toxic ECG manifestations, in addition to the aforementioned dysrhythmias, include significant QRS and QT interval prolongation (greater than 50% prolongation suggests toxicity), PR prolongation, ST depression, and T inversion.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Apnea and pulmonary edema may result following overdoses.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Paresthesias, psychosis, and coma may occur.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Paralytic ileus has been reported.
    B) WITH POISONING/EXPOSURE
    1) Dry mouth, decreased bowel activity, and constipation may occur.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Disopyramide may cause urinary retention.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Disopyramide may cause a generalized rash and a lupus-like syndrome.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) Cases of severe hypoglycemia following therapeutic disopyramide have been reported.
    0.2.20) REPRODUCTIVE
    A) There were no adverse effects in an infant born to a woman treated with disopyramide for the last 14 weeks of pregnancy.
    B) Disopyramide is excreted into human milk.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of disopyramide in humans.

Laboratory Monitoring

    A) Obtain serial ECG's and institute continuous cardiac monitoring following overdoses. ECG should be monitored for cardiac dysrhythmias, including torsade de pointes, QRS widening, QT prolongation, and AV dissociation.
    B) Monitor vital signs, especially blood pressure and heart rate.
    C) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.
    D) Monitor oxygen saturation and respiratory function in all disopyramide overdose cases. Severe overdoses may result in respiratory failure.
    E) Monitor lab work (liver function tests, CBC, electrolytes, urinalysis) as clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) 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.
    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) Monitor plasma levels (if available), and serum potassium. If refractory dysrhythmia develops, assess calcium and magnesium levels.
    D) VENTRICULAR DYSRHYTHMIAS
    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.
    2) LIDOCAINE: ADULT: LOADING DOSE: 1 to 1.5 milligram/kilogram via IV 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. Only bolus therapy is recommended during cardiac arrest. INFUSION: Once circulation is restored begin an infusion of 1 to 4 mg/min. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute). PEDIATRIC: LOADING DOSE: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute. Monitor ECG continuously.
    3) 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.
    a) 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.
    b) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    c) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    E) BRADYCARDIA
    1) 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.
    F) HYPOTENSION: Theoretically, pure or predominant alpha agonists such as norepinephrine or phenylephrine may be more effective than dopamine.
    G) 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.

Range Of Toxicity

    A) Disopyramide doses up to 1600 mg/day (given in divided doses) were tolerated in a limited number of patients with severe refractory ventricular tachycardia. In one case series, doses of 1.5 g were toxic in young adults following intentional misuse. Based on a small number of cases, doses of 2.5 g have caused severe toxicity. A teenage female survived an intentional overdose of 2.0 grams following intensive therapy for sustained electromechanical dissociation.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) In overdose, cardiovascular and anti-muscarinic effects are pronounced. Severe effects include apnea, loss of consciousness, loss of spontaneous respiration, and cardiac arrest.
    2) Similar cardiovascular toxicities occur as with quinidine and procainamide; depression of atrial, atrioventricular and ventricular conduction, dysrhythmias, hypotension, heart failure, syncope, cinchonism, paresthesia, and coma; but anticholinergic effects are more pronounced, and heart failure is more frequent.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Blurred vision, dry mouth, and angle-closure glaucoma (in those predisposed) are anticholinergic toxicities (Sathyavagiswaran, 1987; JEF Reynolds , 2000).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Blurred vision, dilated pupils, and angle-closure glaucoma (in those predisposed) are anticholinergic toxicities (Sathyavagiswaran, 1987; JEF Reynolds , 2000).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Depressed myocardial contractility is a significant feature of disopyramide poisoning which shares similar toxic effects with quinidine. Sinoatrial, atrioventricular, and his-ventricular depression of conduction may occur along with ventricular tachycardia and ventricular fibrillation. Disopyramide has a strong negative inotropic effect.
    2) Syncope is usually related to transient torsade de pointes ventricular tachycardia. Hypotension occurs from alpha receptor blockade and depressed myocardial contractility. Heart failure may result.
    3) Toxic ECG manifestations, in addition to the aforementioned dysrhythmias, include significant QRS and QT interval prolongation (greater than 50% prolongation suggests toxicity), PR prolongation, ST depression, and T inversion.
    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) Toxicity is similar to quinidine and quinine. However, depressed myocardial contractility with congestive heart failure (especially in those with left ventricular dysfunction) is more prominent.
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Sudden development of cardiogenic shock occurs early in severe overdose, within 1 to 4 hours (Silberschmidt, 1981). Cardiogenic shock was reported in 24 of 106 cases reported to a French poison center (Jaeger et al, 1981). Disopyramide-induced cardiovascular collapse may be unresponsive to standard therapy (Kim & Benowitz, 1990).
    C) DECREASED CARDIAC OUTPUT
    1) WITH POISONING/EXPOSURE
    a) Increased peripheral vascular resistance has occurred that is a reflex to decreased cardiac output as a result of negative inotropic effects. Decreased stroke volume will cause a reflex increase in systemic vascular resistance (Kim & Benowitz, 1990).
    D) ATRIOVENTRICULAR BLOCK
    1) WITH POISONING/EXPOSURE
    a) Atrioventricular block may occur (Sathyavagiswaran, 1987). This was reported in 21 of 106 cases reported to a French poison center, with intraventricular block in 24 cases (Jaeger et al, 1981).
    E) VENTRICULAR ARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Toxic serum levels of disopyramide may result in ventricular tachycardias and QT prolongation. Severe dysrhythmias were reported in 12 of 106 cases of disopyramide overdose (Jaeger et al, 1981).
    2) CASE REPORT - Following an interaction between azithromycin and disopyramide, toxic serum levels of disopyramide occurred, with resultant ventricular tachycardia accompanied by hypotension in a 35-year-old woman. The patient became pulseless and was cardioverted to a junctional rhythm. Markedly prolonged QT interval and T wave inversions were noted as well as persistent hypotension. The patient recovered following symptomatic therapy (Granowitz et al, 2000).
    F) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Makkar et al (1993) have retrospectively determined that women, irrespective of the presence or absence of other underlying heart conditions, are more at risk than men of developing torsades de pointes with disopyramide therapy (in the setting of prolonged QT interval).
    2) WITH POISONING/EXPOSURE
    a) Overdoses may result in significant QRS interval widening, with bundle branch blocks. Therapeutic doses have caused QT prolongation, many times with prominent U waves (greater than 50% prolongation suggests toxicity), as an adverse or toxic effect. PR prolongation, ST depression, and T inversion have also been reported. Syncopal episodes may accompany ECG changes (Kim & Benowitz, 1990).
    G) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Early loss of consciousness with subsequent respiratory arrest, tachy- or bradydysrhythmias and cardiac arrest is characteristic of severe disopyramide overdoses. Malignant dysrhythmias and death may follow initial responses to CPR and antidysrhythmic therapy (Accornero et al, 1993; Kim & Benowitz, 1990).
    b) CASE REPORT - Accornero et al (1993) report a case of a 16-year-old female who presented to the ED approximately 2 hours following an overdose of 2 grams. She was unconsciousness, cyanotic and in cardiopulmonary arrest. Prolonged CPR (75 minutes) with isoproterenol infusion and epinephrine IV boluses was maintained. During this time ECG revealed wide QRS complexes, prolonged electromechanical dissociation occasionally merging into torsade de pointes pattern.
    1) Two hours later, ECG showed complete right bundle branch block and a short QT interval and hypotension. A dopamine drip was started. Ten hours later she was conscious with stable blood pressure. She was discharged 7 days later with normal ECG and EEG.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) FIBRILLATION VENTRICULAR
    a) ANIMAL STUDIES - Murakawa et al (1995) determined, in a study of class I antidysrhythmic agents, that therapeutic disopyramide doses did not appear to significantly alter defibrillation efficiency in dogs. No apparent influence on defibrillation threshold was noted with disopyramide.

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Apnea and pulmonary edema may result following overdoses.
    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Apnea may occur just prior to loss of consciousness (Sathyavagiswaran, 1987). An early loss of consciousness following an episode of respiratory arrest was the most common clinical finding reported in 5 cases of fatal disopyramide overdosage (JEF Reynolds , 2000).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema, probably secondary to compromised cardiac function, may occur following overdoses. This is a common finding at necropsy (Kim & Benowitz, 1990; JEF Reynolds , 2000).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Paresthesias, psychosis, and coma may occur.
    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) A severe sensory-motor neuropathy, unresponsive to corticosteroids, was described in a 71-year-old patient during therapy with disopyramide (500 mg/day for 4 years). It improved following discontinuation of disopyramide. The mechanism of drug-induced neuropathy is unknown (Briani et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) Paresthesias and neuropathy have been reported after overdose, but are uncommon.
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma may occur (Hayler et al, 1978; Michaelek, 1982; Anderson et al, 1980). Sedation and blurred vision may occur and are related anticholinergic effects. Lethargy leading to early loss of consciousness, usually within 90 minutes of an overdose, may occur (Kim & Benowitz, 1990).
    C) PSYCHOTIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Psychosis with agitation and distress leading to paranoia and hallucinations has been reported (Prod Info Norpace(R), disopyramide, 1996), with complete recovery following withdrawal of disopyramide.
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Following ingestion of 600 mg disopyramide, a 2-year-old boy experienced seizures as well as hypotension and cardiac dysrhythmias and died 28 hours after the ingestion (Hutchison & Kilham, 1978).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Paralytic ileus has been reported.
    B) WITH POISONING/EXPOSURE
    1) Dry mouth, decreased bowel activity, and constipation may occur.
    3.8.2) CLINICAL EFFECTS
    A) APTYALISM
    1) WITH POISONING/EXPOSURE
    a) Dry mouth, an anticholinergic effect, may occur (Sathyavagiswaran, 1987; JEF Reynolds , 2000).
    B) CONSTIPATION
    1) WITH POISONING/EXPOSURE
    a) Constipation and decreased bowel sounds, anticholinergic effects, may occur (Sathyavagiswaran, 1987; JEF Reynolds , 2000).
    C) NAUSEA, VOMITING AND DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Vomiting and diarrhea has been reported (Sathyavagiswaran, 1987).
    D) DRUG-INDUCED ILEUS
    1) WITH THERAPEUTIC USE
    a) A case of paralytic ileus is reported in a 74-year-old male following therapeutic usage of disopyramide. He presented to the ED with nausea, vomiting, abdominal pain and severe constipation. He was taking no other medication and there was no evidence of ischemic bowel disease. On withdrawal of the drug, symptoms quickly resolved (Ahmad, 1991).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses have occasionally been associated with cholestatic jaundice with elevated serum liver enzyme levels. Laboratory values generally return to normal following discontinuance of the drug, but may remain elevated for several months (JEF Reynolds , 2000).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Disopyramide may cause urinary retention.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) Urinary retention, an anticholinergic effect, may occur (Sathyavagiswaran, 1987).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Disopyramide may cause a generalized rash and a lupus-like syndrome.
    3.14.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Disopyramide has been reported to cause generalized rashes, pruritus, and a lupus-like syndrome as adverse effects (Prod Info Norpace, 1996).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Cases of severe hypoglycemia following therapeutic disopyramide have been reported.
    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Therapeutic usage of disopyramide has resulted in severe hypoglycemia with inappropriately high endogenous serum insulin levels in some cases (Nappi et al, 1983; Goldberg et al, 1980; Smith et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) There were no adverse effects in an infant born to a woman treated with disopyramide for the last 14 weeks of pregnancy.
    B) Disopyramide is excreted into human milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) LABOR ABNORMAL
    1) In one report, uterine contractions were repeatedly precipitated by disopyramide at 32 weeks gestation. These subsided with discontinuation of the drug (Leonard et al, 1978). A precise association with disopyramide therapy was unclear.
    B) PREGNANCY CATEGORY
    DISOPYRAMIDEC
    Reference: Briggs et al, 1998
    C) LACK OF EFFECT
    1) There were no adverse effects in an infant born to a woman treated with disopyramide for the last 14 weeks of pregnancy. At birth the fetal blood level was only 39% of the maternal level (Shaxted & Milton, 1979).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Disopyramide is excreted into human milk. In two cases, women taking chronic disopyramide were reported to have milk concentrations of disopyramide and its metabolite ranging from 2.6 to 4.4 mcg/mL and from 9.6 to 12.3 mcg/mL, respectively (Briggs et al, 1998).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of disopyramide in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) No evidence of possible carcinogenicity was found during 18 months of disopyramide use in rats. Oral doses as high as 400 mg/kg/day (approximately 30 times the usual daily human dose of 600 mg/day) were studied (Prod Info NORPACE(R), NORPACE(R) CR oral capsules, extended-release capsules, 2006).

Genotoxicity

    A) In the Ames test, no evidence of possible mutagenicity was found (Prod Info NORPACE(R), NORPACE(R) CR oral capsules, extended-release capsules, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain serial ECG's and institute continuous cardiac monitoring following overdoses. ECG should be monitored for cardiac dysrhythmias, including torsade de pointes, QRS widening, QT prolongation, and AV dissociation.
    B) Monitor vital signs, especially blood pressure and heart rate.
    C) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.
    D) Monitor oxygen saturation and respiratory function in all disopyramide overdose cases. Severe overdoses may result in respiratory failure.
    E) Monitor lab work (liver function tests, CBC, electrolytes, urinalysis) as clinically indicated.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray should be obtained in any patient with significant toxicity or pulmonary symptoms.

Methods

    A) IMMUNOASSAY
    1) An EMIT(R) homogeneous enzyme immunoassay is available for quantitation of disopyramide in serum or plasma. The assay's range of quantitation is 0.5 to 8.0 mcg/mL disopyramide. Clinical studies show excellent correlation between this method and HPLC or GLC.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Obtain serial ECG's and institute continuous cardiac monitoring following overdoses. ECG should be monitored for cardiac dysrhythmias, including torsade de pointes, QRS widening, QT prolongation, and AV dissociation.
    B) Monitor vital signs, especially blood pressure and heart rate.
    C) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.
    D) Monitor oxygen saturation and respiratory function in all disopyramide overdose cases. Severe overdoses may result in respiratory failure.
    E) Monitor lab work (liver function tests, CBC, electrolytes, urinalysis) as clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) 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) Administration of 50 grams of activated charcoal reduced absorption of a 200 mg dose of disopyramide to 3 to 4 percent that of controls. Saturation of the adsorptive capacity occurred at ratios of less than 7.5 of charcoal-to-drug in vitro (Neuvonen & Olkkola, 1984).
    2) 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.
    3) 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) 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.
    2) DO NOT use procainamide, quinidine, or disopyramide.
    3) 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).
    B) 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.
    C) BRADYCARDIA
    1) 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).
    2) ISOPROTERENOL
    a) ISOPROTERENOL INDICATIONS
    1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    3) Refractory bradycardia or heart block that compromises blood pressure requires temporary pacemaker insertion. Markedly prolonged conduction, Mobitz II block, or third degree heart block should be considered indications for prophylactic pacemaker insertion.
    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) Pure or predominant alpha agonists may be more effective in managing hypotension. These include norepinephrine or phenylephrine. However, isoproterenol, a pure beta agonist, was effective in maintaining blood pressure in a patient who ingested 20 grams of disopyramide (Holt, 1980).
    a) NOREPINEPHRINE
    1) 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).
    2) DOSE
    a) 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).
    b) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    c) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) 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).
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Enhanced Elimination

    A) DIURESIS
    1) Forced diuresis is potentially dangerous, has not been shown to increase disopyramide excretion or improve outcome after overdose, and is not recommended. Attempt to maintain normal urine output, since 40% to 70% is excreted unchanged in the urine irrespective of pH.
    B) HEMODIALYSIS
    1) Hemodialysis and peritoneal dialysis are not expected to be effective in the removal of disopyramide.
    a) The half-life of disopyramide was not changed during dialysis and no more than 2.4% of the dose was removed during a 2-hour procedure in 6 chronic hemodialysis patients receiving therapeutic doses (Sevka et al, 1981).
    C) HEMOPERFUSION
    1) There is no evidence that hemoperfusion provides significant drug removal or affects outcome. In two overdose reports, charcoal and resin hemoperfusion removed only small amounts of total drug (4.5% of ingested dose in 5 hours of resin hemoperfusion, 0.5% of ingested dose during 7 hours of charcoal hemoperfusion) (Gosselin, 1980; Holt 1980). In one patient clearance by charcoal hemoperfusion was calculated at 26.4 to 35.5 milliliters/minute (Holt, 1980).

Range Of Toxicity

Summary

    A) Disopyramide doses up to 1600 mg/day (given in divided doses) were tolerated in a limited number of patients with severe refractory ventricular tachycardia. In one case series, doses of 1.5 g were toxic in young adults following intentional misuse. Based on a small number of cases, doses of 2.5 g have caused severe toxicity. A teenage female survived an intentional overdose of 2.0 grams following intensive therapy for sustained electromechanical dissociation.

Therapeutic Dose

    7.2.1) ADULT
    A) 400 to 800 mg/day in divided doses (Prod Info disopyramide phosphate oral capsules, 2015)
    1) Doses up to 1600 mg/day in divided doses were tolerated in a limited number of patients with severe refractory ventricular tachycardia (Prod Info disopyramide phosphate oral capsules, 2015).
    2) A 300-mg loading dose of immediate-release disopyramide may be used when rapid control of ventricular arrhythmia is required (Prod Info disopyramide phosphate oral capsules, 2015).
    7.2.2) PEDIATRIC
    A) 11 MONTHS AND YOUNGER: 10 to 30 mg/kg/day in divided doses (Prod Info disopyramide phosphate oral capsules, 2015)
    B) 1 to 4 YEARS: 10 to 20 mg/kg/day in divided doses (Prod Info disopyramide phosphate oral capsules, 2015)
    C) 4 to 12 YEARS: 10 to 15 mg/kg/day in divided doses (Prod Info disopyramide phosphate oral capsules, 2015)
    D) 12 to 18 YEARS: 6 to 15 mg/kg/day in divided doses (Prod Info disopyramide phosphate oral capsules, 2015)

Minimum Lethal Exposure

    A) The mortality rate was 12.2% in a series of 106 overdoses, 90% of which were deliberate intoxication in young adults (Jaeger et al, 1981).

Maximum Tolerated Exposure

    A) Disopyramide doses up to 1600 mg/day (given in divided doses) were tolerated in a limited number of patients with severe refractory ventricular tachycardia (Prod Info NORPACE(R), NORPACE(R) CR oral capsules, extended-release capsules, 2006).
    B) Toxic dose for disopyramide has not been established; greater than therapeutic doses may cause toxic symptoms.
    C) Ingestions of greater than 2.5 grams have caused severe toxicity in 5 of 14 cases (Gosselin, 1980).
    D) CASE REPORTS
    1) The toxic dose was reported to be 1.5 grams in healthy adults in a series of 106 overdoses (Jaeger et al, 1981).
    2) A 16-year-old female survived an intentional overdose of 2.0 grams following intensive therapy for sustained electromechanical dissociation (Accornero et al, 1993).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Therapeutic plasma range is reported to be 2 to 6 mcg/mL (Prod Info disopyramide phosphate oral capsules, 2015).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Disopyramide plasma concentrations up to 9 mcg/mL were reported in a limited number of patients who tolerated disopyramide doses up to 1600 mg/day (Prod Info disopyramide phosphate oral capsules, 2015).
    b) Adverse effects have been reported with plasma levels of 3.6 and 10 micrograms/milliliter (Drug Therapy, 1984), and deaths reported with levels of 16 micrograms/milliliter (Wayne, 1980).
    c) A patient with a serum level of 16.5 mcg/mL demonstrated impaired cardiac conduction and hypotension (Holt, 1980).
    2) CASE REPORTS
    a) Plasma level of 11.0 micrograms/milliliter was reported 4 hours following an overdose of 2 grams in a 16-year-old girl. The level decreased to 4.6 micrograms/milliliter 12 hours following ingestion (Accornero et al, 1993).
    b) Disopyramide plasma level was 15.5 micrograms/milliliter in an 11-year-old girl who died following probable overdoses of lidocaine and disopyramide during surgery (Sakata et al, 1988).
    c) Disopyramide blood concentrations of 146 and 63 micrograms/milliliter were found at autopsy (Sathyavagiswaran, 1987).
    d) Disopyramide concentrations in fatal cases have ranged from 4.3 to 146 milligrams/liter (Sathyavagiswaran, 1987).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 114 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) 352 mg/kg (RTECS , 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 305 mg/kg (RTECS , 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 170 mg/kg (RTECS , 2002)
    5) LD50- (ORAL)RAT:
    a) 333 mg/kg (RTECS , 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 800 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although chemically unrelated to quinidine, disopyramide has similar electrophysiologic effects as other type I antiarrhythmics (Prod Info disopyramide phosphate oral capsules, 2015).
    B) Therapeutic dosing decreases automaticity in the sinus node and Purkinje fibers. Its vagolytic action may, however, increase heart rate. Although disopyramide mildly prolongs intranodal conduction in patients with bundle branch block, it does not precipitate atrioventricular block.
    C) As with quinidine, the probable mechanism of disopyramide-induced ventricular tachycardia or ventricular fibrillation is temporal dispersion of refractoriness resulting from prolonged repolarization. This predisposes to reenty circuits.
    D) Disopyramide has antimuscarinic activity. It has no effect on alpha or beta-adrenergic receptors (Prod Info disopyramide phosphate oral capsules, 2015).

Physicochemical

Physical Characteristics

    A) Disopyramide is a white to off-white powder which is odorless or almost odorless. Disopyramide phosphate 1.3 grams is approximately equal to 1 gram of disopyramide. Solubility in water is good; it is slightly soluble in alcohol and practically insoluble in chloroform, in dichloromethane, and in ether (JEF Reynolds , 2000).

Ph

    A) The pH of a 5% solution ranges from 4.0 to 5.0 (JEF Reynolds , 2000).

Molecular Weight

    A) 339.5 (disopyramide)
    B) 437.5 (disopyramide phosphate)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Accornero F, Pellanda A, & Ruffini C: Prolonged cardiopulmonary resuscitation during acute disopyramide poisoning. Vet Hum Toxicol 1993; 35:231-232.
    3) Ahmad S: Disopyramide-related paralytic ileus: case report (letter). JAGS 1991; 39:317-318.
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