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BRETYLIUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bretylium is a quaternary ammonium compound classified as a Vaughan Williams Class III antiarrhythmic agent (Frumin et al, 1989). Like guanethidine, it blocks adrenergic transmission by inhibiting norepinephrine release from adrenergic nerve endings (Gilman et al, 1985; Prod Info Bretylium Tosylate injection, 1998).

Specific Substances

    1) Bretylan
    2) Bretylate
    3) Bretylium-p-toluenesulfonate
    4) Bretylium tosilate
    5) Bretylol
    6) (2-Bromobenzyl)ethyldimethylammonium
    7) toluene-4-sulphonate
    8) Darenthin
    9) Darentin
    10) N-Ethyl-N-o-bromobenzyl-N,N-dimethyl-
    11) ammonium tosylate
    12) Ornid
    13) CAS 59-41-6 (bretylium)
    14) CAS 61-75-6 (bretylium tosylate)

Available Forms Sources

    A) FORMS
    1) Bretylium is available as a 50 mg/mL injectable solution in 10 mL vials and ampules for intramuscular or intravenous use and in prediluted, premixed bags of 5 percent dextrose for intravenous infusion (Prod Info Bretylium Tosylate injection, 1998).
    B) USES
    1) Bretylium is used in the treatment of resistant VT and VF unresponsive to defibrillation or other pharmacologic agents (Anon, 2000). Its use is limited to immediately life-threatening ventricular arrhythmias (S Sweetman , 2000).
    2) In 2000, bretylium was removed from advanced cardiac life support (ACLS) guidelines and algorithms based on a high occurrence of side effects, other safer agents, and limited supply by the manufacturer (Anon, 2000).

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 THERAPEUTIC USE
    1) Severe hypotension appears to be the most serious manifestation of bretylium toxicity. Paradoxical ventricular dysrhythmias, as well as bradycardia, may also occur. Initial hypertension may occur due to early norepinephrine release.
    2) During 1999 bretylium was unavailable from the manufacturer, which prompted a review of its use during cardiopulmonary resuscitation. Based on that review, the guidelines established for advanced cardiac life support (ACLS) no longer include bretylium due to a high occurrence of side effects, the use of other safer agents and limited supply by the manufacturer.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Initial hypertension and tachycardia may be observed, followed by pronounced hypotension and bradycardia.
    2) Increases in PVCs may occur initially due to catecholamine release.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Mild conjunctivitis, nasal congestion, and parotid pain have been reported as adverse reactions to bretylium.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Hypotension is common with therapeutic use. Orthostatic hypotension is also common.
    2) Transient hypertension and aggravation of dysrhythmias may be observed due to initial catecholamine release.
    3) Tachydysrhythmias, bradycardia and ECG changes have been reported.
    B) WITH POISONING/EXPOSURE
    1) Severe hypotension may be seen with overdose.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Shortness of breath has been reported with therapeutic use.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Dizziness, vertigo, faintness, or lethargy may associated with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) A flaccid state of paralysis has been described with massive overdose.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea and vomiting may be noted, especially with rapid IV administration. Diarrhea and abdominal pain have also been reported.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Renal insufficiency has been reported infrequently with therapeutic use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Flushing, diaphoresis, and erythematous macular rashes have been reported with therapy.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Anxiety, confusion, emotional lability, or psychosis may occur with therapy.
    0.2.20) REPRODUCTIVE
    A) Safety during pregnancy has not been established, but in an emergent situation the potential benefits probably outweigh the risks.
    B) It is not known whether bretylium is secreted into breast milk; problems in humans have not been reported.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.
    0.2.22) OTHER
    A) Bretylium may exacerbate digitalis toxicity.
    B) Procainamide and quinidine may counteract the inotropic effects, and enhance the hypotensive effects, of bretylium.

Laboratory Monitoring

    A) Determination of plasma bretylium levels is not clinically useful; however, quantitation can be performed via gas-liquid chromatography (GLC) with electron capture detection.

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) 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.
    D) Hypertension is generally transient and may be followed by profound hypotension, it should generally NOT be treated.
    E) BRADYCARDIA - Initial treatment of bradycardia should include the use of atropine and isoproterenol.
    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) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    G) Hemodialysis has not shown to be of significant benefit in removing bretylium. Other elimination methods have not been evaluated.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.
    0.4.6) PARENTERAL EXPOSURE
    A) 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.
    B) HYPERTENSION is usually transient and may be followed by profound hypotension; it should generally NOT be treated.
    C) BRADYCARDIA - Initial treatment of bradycardia should include the use of atropine and isoproterenol.
    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.
    D) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    E) Hemodialysis has not shown to be of significant benefit in removing bretylium. Other elimination methods have not been evaluated.

Range Of Toxicity

    A) Death has occurred following a 30 mg/kg bolus; the serum level was 8,800 ng/mL.
    B) A 12 mg/kg/hour dose was survived by a 3-day-old infant, although with significant (but reversible) toxicity. The serum level was 17 mcg/mL 12 hours after the infusion was stopped.
    C) A 74-year-old female with a significant history of arteriosclerosis and cardiovascular disease, survived an inadvertent bolus of 81.5 mg/kg (4 grams) of bretylium over 10 to 15 minutes. Six hours after overdose the patient developed neurological depression which slowly cleared over a 24-hour period.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Severe hypotension appears to be the most serious manifestation of bretylium toxicity. Paradoxical ventricular dysrhythmias, as well as bradycardia, may also occur. Initial hypertension may occur due to early norepinephrine release.
    2) During 1999 bretylium was unavailable from the manufacturer, which prompted a review of its use during cardiopulmonary resuscitation. Based on that review, the guidelines established for advanced cardiac life support (ACLS) no longer include bretylium due to a high occurrence of side effects, the use of other safer agents and limited supply by the manufacturer.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Initial hypertension and tachycardia may be observed, followed by pronounced hypotension and bradycardia.
    2) Increases in PVCs may occur initially due to catecholamine release.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CASE REPORT - HYPERTHERMIA was reported in one patient given therapeutic doses of bretylium for refractory ventricular fibrillation secondary to myocardial infarction.
    a) Approximately 12 hours after bretylium was started, a maximum rectal temperature of 42.3 degrees C (108.2 degrees F) was measured. Other potential causes were ruled out. Bretylium was discontinued, and the patient's temperature normalized within four hours. Rechallenge was not attempted (Perlman et al, 1989).
    b) A similar case was reported in a 59-year-old male after respiratory arrest in which bretylium 120 mg/hr was given for persistent dysrhythmias (Thibault, 1989). Maximum temperature was 108 degrees F. Other source of fever were ruled out, and the patient's temperature decreased following the withdrawal of bretylium and ranitidine. The patient died on hospital day 7 of cardiac failure.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Transient hypertension may occur with the first dose due to initial norepinephrine release (Prod Info Bretylium Tosylate injection, 1998).
    2) HYPOTENSION is common in therapeutic use (Bodnar, 1980).
    a) INCIDENCE - Orthostatic hypotension is common; hypotension and may occur in up to 50% of patients while supine (Gilman et al, 1985; Prod Info Bretylium Tosylate injection, 1998).
    B) WITH POISONING/EXPOSURE
    1) Hypotension may be severe in overdose (Bodnar, 1980).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) The initial release of catecholamines induced by bretylium may exacerbate dysrhythmias, and an increase in premature ventricular contractions may occur in some patients (Prod Info Bretylium Tosylate injection, 1998).
    a) Bradycardia has been reported as a side effect of bretylium (Prod Info Bretylium Tosylate injection, 1998).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mild conjunctivitis, nasal congestion, and parotid pain have been reported as adverse reactions to bretylium.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CONJUNCTIVITIS is a rare adverse event occurring in approximately 0.1% of patients (Prod Info Bretylium Tosylate injection, 1998).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASAL CONGESTION has been reported as a rare side effect during therapeutic use which occurs in approximately 0.1% of patients (Prod Info Bretylium Tosylate injection, 1998).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) PAROTID PAIN and tenderness have been reported as side effects of bretylium therapy (Singh et al, 1981).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypotension is common with therapeutic use. Orthostatic hypotension is also common.
    2) Transient hypertension and aggravation of dysrhythmias may be observed due to initial catecholamine release.
    3) Tachydysrhythmias, bradycardia and ECG changes have been reported.
    B) WITH POISONING/EXPOSURE
    1) Severe hypotension may be seen with overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension is the principal limiting side effect of bretylium (Gilman et al, 1985; Prod Info Bretylium Tosylate injection, 1998); orthostatic hypotension of may occur in up to 50% of patients (Prod Info Bretylium Tosylate injection, 1998). Severe hypotension occurs with therapeutic doses (Kron & Nolan, 1983; Narang et al, 1980).
    2) WITH POISONING/EXPOSURE
    a) In overdose, profound, intractable hypotension may be seen (Bodnar et al, 1980).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Transient hypertension may be seen, especially after the first dose, due to an initial release of norepinephrine from adrenergic nerve endings (Gilman et al, 1985; Prod Info Bretylium Tosylate injection, 1998).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) The initial release of catecholamines induced by bretylium may exacerbate arrhythmias in some patients (Prod Info Bretylium Tosylate injection, 1998).
    1) Two cases have been reported in which bretylium was associated with the development of ventricular tachycardia and fibrillation. In both cases, ectopy was controlled with propranolol, suggesting an adrenergic mechanism (Anderson et al, 1981).
    D) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia has been reported as a side effect of bretylium (Prod Info Bretylium Tosylate injection, 1998).
    E) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Bretylium slows A-V node conduction and sinus rate. P-R and Q-T intervals may be increased, while the QRS interval is usually not affected. Conduction in the His-Purkinje system is not altered (Gilman et al, 1985).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Shortness of breath has been reported with therapeutic use.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported as a side effect of bretylium (Prod Info Bretylium Tosylate injection, 1998).
    b) INCIDENCE - 0.1% of patients have experienced symptoms during therapeutic use (Prod Info Bretylium Tosylate injection, 1998).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dizziness, vertigo, faintness, or lethargy may associated with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) A flaccid state of paralysis has been described with massive overdose.
    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness and vertigo or faintness may be seen secondary to the hypotensive effects of bretylium. Lethargy may also be seen (Prod Info Bretylium Tosylate injection, 1998).
    b) INCIDENCE - 0.7% of patients have experienced symptoms during therapeutic use (Prod Info Bretylium Tosylate injection, 1998).
    B) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A flaccid state of paralysis resembling brain death has been described after a massive overdose (12 mg/kg/hour). Pupils were fixed and dilated, and reflexes were absent. After discontinuing the infusion, the patient recovered within 26 hours (Thompson & Sussmane, 1989).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 74-year-old woman with previous myocardial infarction, hypertension, severe peripheral vascular disease, hyperlipidemia, previous cerebrovascular accident, and right lung lobectomy for adenocarcinoma received 3.5 milligrams/kilogram boluses of bretylium tosylate and a 2 milligram/minute infusion for resistant ventricular tachycardia. She inadvertently received an additional 4 gram bolus (81.5 milligrams/kilogram) over 15 minutes and developed hypotension requiring a balloon pump, and coma (GCS 3). She became progressively more responsive over the next 24 hours (GCS 9 to 10 intubated) and further improved over the next 4 weeks to the point where she could hold conversations. She ultimately died 50 days after admission of a cardiac arrest (Gibson & Munter, 1995).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea and vomiting may be noted, especially with rapid IV administration. Diarrhea and abdominal pain have also been reported.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common side effects of bretylium, and occur most often with rapid IV administration (Gilman et al, 1985; Prod Info Bretylium Tosylate injection, 1998).
    b) INCIDENCE - Approximately 3% of patients have reported symptoms during administration (Prod Info Bretylium Tosylate injection, 1998).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea and abdominal pain occur infrequently with therapeutic use (Prod Info Bretylium Tosylate injection, 1998).
    b) INCIDENCE - 0.1% of patients have reported symptoms after therapeutic use (Prod Info Bretylium Tosylate injection, 1998).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Renal insufficiency has been reported infrequently with therapeutic use.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Renal dysfunction may be observed, but is a rare event of therapy (Prod Info Bretylium Tosylate injection, 1998).
    b) INCIDENCE - Observed in approximately 0.1% of patients following therapy (Prod Info Bretylium Tosylate injection, 1998).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Flushing, diaphoresis, and erythematous macular rashes have been reported with therapy.
    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing and erythematous macular rashes have been reported with therapeutic use (Prod Info Bretylium Tosylate injection, 1998).
    b) INCIDENCE - 0.1% of patients have reported symptoms after therapeutic use (Prod Info Bretylium Tosylate injection, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Safety during pregnancy has not been established, but in an emergent situation the potential benefits probably outweigh the risks.
    B) It is not known whether bretylium is secreted into breast milk; problems in humans have not been reported.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    BRETYLIUMC
    Reference: Briggs et al, 1998
    1) The safety of bretylium during human pregnancy has not been established. However, as the drug is intended for use only in life-threatening situations, it may be used in pregnant women when its benefits outweigh the potential risk to the fetus (Prod Info Bretylium Tosylate injection, 1998).
    2) A potential risk of reduced uterine blood flow and fetal hypoxia (bradycardia) exists; however, problems in humans have not been documented (USPDI, 1989; (Briggs et al, 1998).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether bretylium is expressed in breast milk; problems in humans have not been documented (USPDI, 1989; (Briggs et al, 1998).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Determination of plasma bretylium levels is not clinically useful; however, quantitation can be performed via gas-liquid chromatography (GLC) with electron capture detection.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Plasma bretylium concentrations are not useful in overdose management (Ellenhorn & Barceloux, 1988).
    2) Therapeutic determination of serum bretylium levels is not useful; in dogs, antifibrillatory actions are correlated with myocardial tissue concentrations, but not with plasma concentrations (Anderson et al, 1980).

Methods

    A) CHROMATOGRAPHY
    1) Gas-liquid chromatography (GLC) with an electron capture detector has been used to measure plasma bretylium concentrations. This assay has a sensitivity of 5 to 10 ng/mL, and thus is sufficiently sensitive to quantitate plasma levels in patients receivng bretylium (Rapeport, 1985).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Monitoring

    A) Determination of plasma bretylium levels is not clinically useful; however, quantitation can be performed via gas-liquid chromatography (GLC) with electron capture detection.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) Since bretylium is used parenterally, oral exposures are probably extremely rare.
    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) SUMMARY
    1) Since bretylium is used parenterally, oral exposures are probably extremely rare.
    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.
    C) 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).
    6.5.3) TREATMENT
    A) HYPOTENSIVE EPISODE
    1) Because bretylium administration results in depletion of norepinephrine, a direct-acting pressor such as norepinephrine may theoretically be more effective than an indirect-acting agent such as dopamine, whose efficacy depends partially on intrinsic norepinephrine stores.
    2) 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.
    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).
    4) 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).
    5) PHENYLEPHRINE
    a) MILD OR MODERATE HYPOTENSION
    1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    b) CONTINUOUS INFUSION
    1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    c) ADVERSE EFFECTS
    1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    6) The antiarrhythmic efficacy of bretylium is due to its effects on the myocardium, while its hypotensive properties are mediated through autonomic neuronal blockade (Gilman et al, 1985). This has led to speculation that the use of agents that block amine transport at the adrenergic nerve terminal membrane (reuptake 1) such as imipramine would inhibit the uptake of bretylium into autonomic neurons and reduce or eliminate its hypotensive side effects. Woosley et al (1982) showed that protriptyline is able to antagonize hypotension to some degree without reducing antiarrhythmic efficacy. However, further study is needed to determine the safety and efficacy of this treatment.
    B) HYPERTENSIVE EPISODE
    1) Hypertension is generally transient and may be followed by profound hypotension, it should generally NOT be treated.
    C) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) Propranolol has been used successfully to terminate the paradoxical ectopy that may occur with bretylium (Anderson et al, 1981), and may be a useful adjunct to therapy. A short acting, cardioselective agent such as esmolol may be preferred
    3) PROPRANOLOL/ADULT DOSE
    a) INTRAVENOUS: 0.5 mg to 1 mg per dose IV over 1 minute. May repeat dose up to a total of 0.1 mg/kg, if needed (Neumar et al, 2010). A second dose may be repeated in 2 minutes, if necessary; however, any additional drug administration should be given at least 4 hours later (Prod Info propranolol HCl IV injection, 2008).
    b) The maximum dose is 3 mg; the rate should not exceed 1 mg/min (Prod Info propranolol HCl IV injection, 2008).
    4) PROPRANOLOL/PEDIATRIC DOSE
    a) INTRAVENOUS: 0.01 to 0.15 mg/kg IV every 6 to 8 hours (Luedtke et al, 1997).
    5) MONITORING
    a) The drug should be administered with cardiac monitoring or central venous pressure monitoring. Monitor for bradycardia, hypotension and congestive heart failure (Prod Info propranolol HCl IV injection, 2008).
    6) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a; 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, 2010a). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010a).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    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, 2010a).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    7) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010a; Vanden Hoek,TL,et al).
    b) PROCAINAMIDE/ADULT LOADING DOSE
    1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010a).
    2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010a).
    3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010a).
    c) PROCAINAMIDE/CONTROLLED INFUSION
    1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010a).
    e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    h) MONITORING PARAMETERS
    1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    i) AVOID
    1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010a).
    D) 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, 2010a).
    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, 2010a).
    2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010a).
    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).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.

Enhanced Elimination

    A) HEMODIALYSIS
    1) While bretylium is dialyzable (Reynolds, 1990), use of hemodialysis has never been reported after bretylium overdose. Its large volume of distribution and high degree of tissue binding suggest that hemodialysis is probably of limited value (Rapeport, 1985). In two studies of bretylium elimination in patients with renal failure, hemodialysis did not significantly reduce the body burden of the drug (Josselson et al, 1983) Yacobi et al, 1983).

Abstracts

Case Reports

    A) INFANT
    1) A syndrome resembling clinical brain death was reported in a 3-day-old infant who inadvertently received bretylium 12 mg/kg/hour instead of the 1 mg/kg/hour intended. Pupils were fixed and dilated, and reflexes were absent. Neurological evaluation revealed "no evidence" of brain function, but an EEG showed only mildly attenuated activity. Bretylium was withdrawn, and the patient recovered completely over the next 26 hours. Serum bretylium level was 17 mcg/mL 12 hours after the drug was discontinued (Thompson & Sussmane, 1989).
    B) ADULT
    1) A 58-year-old man inadvertently received a 30 mg/kg bolus of bretylium. Intially, severe hypertension was seen, followed by severe, unrelenting hypotension. Dopamine, albumin, and fluid challenge were initially successful. However, intractable renal failure ensued, and the patient expired due to non-responsive ventricular asystole (Bodnar et al, 1980).

Range Of Toxicity

Summary

    A) Death has occurred following a 30 mg/kg bolus; the serum level was 8,800 ng/mL.
    B) A 12 mg/kg/hour dose was survived by a 3-day-old infant, although with significant (but reversible) toxicity. The serum level was 17 mcg/mL 12 hours after the infusion was stopped.
    C) A 74-year-old female with a significant history of arteriosclerosis and cardiovascular disease, survived an inadvertent bolus of 81.5 mg/kg (4 grams) of bretylium over 10 to 15 minutes. Six hours after overdose the patient developed neurological depression which slowly cleared over a 24-hour period.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL/SUMMARY
    1) During 1999 bretylium was unavailable from the manufacturer, which prompted a review of its use during cardiopulmonary resuscitation. Based on that review, the guidelines established for advanced cardiac life support (ACLS) no longer include bretylium due to a high occurrence of side effects, the use of other safer agents, and limited supply by the manufacturer (Anon, 2000).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal dose of bretylium in man has not been defined. However, a patient receiving 30 milligrams/kilogram via intravenous bolus died from renal failure, hypotension, and ventricular fibrillation (Bodnar et al, 1980).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) NEONATE
    a) A 3-day-old infant survived after receiving 12 milligrams/kilogram/hour. Although initial presentation was a clinical picture resembling brain death and inotropic support was required, recovery ensued. Serum bretylium concentration was 17 micrograms/milliliter 12 hours after withdrawal of the drug (Thompson & Sussmane, 1989).
    2) ADULT
    a) A 74-year-old female with a significant history of arteriosclerosis and cardiovascular disease, survived an inadvertent bolus of 81.5 mg/kg (4 grams) of bretylium over 10 to 15 minutes (Gibson & Munter, 1995). The patient was admitted in cardiac arrest and had an inferior myocardial infarction which required a temporary intraaortic balloon pump for cardiac stabilization.
    1) Six hours after overdose the patient developed neurological depression which slowly cleared over a 24-hour period. Despite normal mentation throughout the remainder of her hospitalization, the patient developed multiorgan failure and ARDS and died on the fiftieth day of hospitalization.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) SUMMARY: The toxic effects of bretylium are not correlated with plasma concentrations (Anderson et al, 1980a; Josselson et al, 1983; Romhilt et al, 1972).
    b) Severe toxicity was observed after a 2 gram (30 mg/kg) intravenous bolus of bretylium was accidentally administered to a 58-year-old man. A plasma bretylium level of 8,800 ng/mL was measured 3 hours after the dose; after the patient became anuric, no further decrease in drug level was seen, even 15 hours later (Bodnar et al, 1980).
    c) A plasma level of 17 mcg/mL was survived by a 3-day-old infant, but was associated with severe (but temporary) neurologic and cardiovascular toxicity (Thompson & Sussmane, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAMUSCULAR)MOUSE:
    1) 64 mg/kg (RTECS, 2000)
    B) LD50- (INTRAPERITONEAL)MOUSE:
    1) 39 mg/kg (RTECS, 2000)
    C) LD50- (ORAL)MOUSE:
    1) 400 mg/kg (RTECS, 2000)
    D) LD50- (SUBCUTANEOUS)MOUSE:
    1) 72 mg/kg (RTECS, 2000)
    E) LD50- (INTRAMUSCULAR)RAT:
    1) 84 mg/kg (RTECS, 2000)
    F) LD50- (INTRAPERITONEAL)RAT:
    1) 57 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bretylium selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons. After causing an initial release of norepinephrine, it blocks subsequent norepinephrine release in response to sympathetic stimulation by depressing adrenergic nerve terminal excitability. It also blocks the reuptake of norepinephrine and epinephrine (reuptake 1) at adrenergic nerve terminals. Although catecholamine stores are not depleted by bretylium, catecholamine effects are observed on the myocardium shortly after administration, and result in a chemical sympathectomy-like state which resembles that of a surgical sympathectomy (Prod Info Bretylium Tosylate injection, 1998).
    B) Bretylium is a quaternary ammonium agent with both class II and class III antiarrhythmic activity (Prod Info bretylium tosylate injection, 1997). It prolongs repolarization (increases the effective refractory period) and increases action potential duration. The resultant elevation of the ventricular fibrillation threshold is thought to be the major mechanism of antifibrillatory action of the drug (Anderson et al, 1980).

Toxicologic Mechanism

    A) The adrenergic blockade induced by bretylium leads to vasodilation, so there is little or no change in cardiac output or left ventricular filling pressure after the effects caused by initial norepinephrine release have ceased. This results in hypotension, which may be severe (Gilman et al, 1985).
    B) The early arrhythmogenic and hypertensive properties of bretylium may be related to initial catecholamine release, or it may be due to increased sensitivity to circulating catecholamines (a manifestation of denervation hypersensitivity) (Gokhale & Gulati, 1961). In addition, because bretylium inhibits reuptake 1 in adrenergic nerve endings, it is able to potentiate the actions of circulating catecholamines (Gilman et al, 1985).

Physicochemical

Physical Characteristics

    A) TASTE: Bretylium tosylate has an extremely bitter taste (Budavari, 1989).

Molecular Weight

    A) BRETYLIUM TOSYLATE: 414.37 (Budavari, 1989)

References

General Bibliography

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    40) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    41) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    42) Product Information: bretylium tosylate injection, bretylium tosylate injection. Abbott Laboratories, North Chicago, IL, 1997.
    43) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    44) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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    47) Product Information: propranolol HCl IV injection, propranolol HCl IV injection. Bedford Laboratories (per DailyMed), Bedford, OH, 2008.
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