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GANGLIONIC BLOCKERS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ganglionic blocking agents interfere with neurotransmission in sympathetic and parasympathetic ganglia. These agents are unfrequently used in hypertensive emergencies and to induce controlled hypotension during surgery.

Specific Substances

    A) HEXAMETHONIUM (SYNONYM)
    1) Hexamethonii
    2) Hexonium
    3) CAS 60-26-4
    4) CAS 55-97-0 (dibromide)
    5) CAS 2079-78-9 (tartrate)
    MECAMYLAMINE (SYNONYM)
    1) Mecamylamini
    2) CAS 60-40-2
    3) CAS 826-39-1 (hydrochloride)
    PEMPIDINE (SYNONYM)
    1) CAS 79-55-0
    2) CAS 546-48-5 (tartrate)
    PENTOLINIUM (SYNONYM)
    1) Pentapyrrolidinium
    2) Pentolinio
    3) CAS 144-44-5
    4) CAS 52-62-0 (tartrate)
    TRIMETHAPHAN (SYNONYM)
    1) Methioplegium
    2) Trimetaphani
    3) Trimethaphan
    4) CAS 68-91-7 (camsylate)
    5) CAS 7187-66-8

Available Forms Sources

    A) FORMS
    1) TRIMETHAPHAN: 50 mg/mL (Arfonad(R))
    2) MECAMYLAMINE: 2.5 mg tablets (Enversine(R))

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) General effects of ganglionic blockade include postural hypotension, tachycardia, blurred vision, dry mouth, constipation, urinary retention, drowsiness, and impotence.
    0.2.4) HEENT
    A) Mydriasis, blurred vision may occur.
    0.2.5) CARDIOVASCULAR
    A) Postural hypotension, tachycardia, and syncope are common. Various arrhythmias (AV block, left bundle branch block, ventricular fibrillation) have been reported with trimethaphan therapy.
    0.2.6) RESPIRATORY
    A) Respiratory arrest has resulted from high-dose trimethaphan therapy.
    0.2.7) NEUROLOGIC
    A) Seizures may occur, especially following large doses of mecamylamine. Tremor, hallucinations, and confusion may also follow high dose mecamylamine.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, diarrhea, constipation, and paralytic ileus may occur.
    0.2.15) MUSCULOSKELETAL
    A) Prolonged neuromuscular blockade may occur after trimethaphan therapy.
    0.2.20) REPRODUCTIVE
    A) Hexamethonium and trimethaphan are both classified in pregnancy category C.

Laboratory Monitoring

    A) Blood levels of these agents are not clinically useful.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    C) Monitor blood pressure closely, as well as the EKG.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) 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.
    E) 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.
    F) MONITOR ECG and vital signs carefully.
    G) PHYSOSTIGMINE OR NEOSTIGMINE (0.5 to 1 mg/IV slowly) have reversed many of the effects of ganglionic blocking agents. Urecholine may be useful in the treatment of urinary retention.

Range Of Toxicity

    A) Insufficient data in the literature to assess the range of toxicity following acute exposure.

Clinical Effects

Summary Of Exposure

    A) General effects of ganglionic blockade include postural hypotension, tachycardia, blurred vision, dry mouth, constipation, urinary retention, drowsiness, and impotence.

Heent

    3.4.1) SUMMARY
    A) Mydriasis, blurred vision may occur.
    3.4.3) EYES
    A) MYDRIASIS - Blurring of vision and mydriasis have been reported (Prod Info Inversine(R), mecamylamine hydrochloride, 1998).

Cardiovascular

    3.5.1) SUMMARY
    A) Postural hypotension, tachycardia, and syncope are common. Various arrhythmias (AV block, left bundle branch block, ventricular fibrillation) have been reported with trimethaphan therapy.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Postural hypotension may be severe and difficult to regulate. Orthostatic dizziness or syncope may develop (Prod Info Inversine(R), mecamylamine hydrochloride, 1998).
    2) CASE REPORT - A 7.5-month-old infant with severe hypertension (220/150) and pneumococcal meningitis inadvertently received trimethaphan 20 milligrams/kilogram IV instead of 20 micrograms/kilogram. Within 30 seconds there were no palpable pulses and blood pressure could not be obtained. Pupils were dilated 5 to 6 mm and unreactive to light (the child had previously manifested a left 6th nerve palsy). Systolic blood pressure was 70 mm Hg within one minute after IV fluid bolus. Over the next two hours 75/ml/kg of IV fluid and dopamine infusion of 10 mcg/kg/min were administered to maintain a systolic blood pressure of 80 to 100 mm Hg. Dopamine was weaned over the next six hours and the pupils became normal sized and reactive to light. The patient recovered (Hammer, 1996).
    B) CARDIOVASCULAR FINDING
    1) CARDIAC OUTPUT may increase in the failing heart due to lowered peripheral vascular resistance or may decrease in the normal heart due to a decrease in venous return.
    C) TACHYARRHYTHMIA
    1) Tachycardia is frequently an associated phenomenon and syncope may occur.
    D) CONDUCTION DISORDER OF THE HEART
    1) CASE REPORT - Severe reversible EKG changes, consisting of first-degree AV block, left bundle branch block, and ventricular fibrillation, were reported in a patient treated with trimethaphan for acute aortic dissection (DiLeo et al, 1984).
    2) CASE REPORT - Left bundle branch block was associated with the use of trimethaphan in a patient with pre-existing sinus bradycardia, intraventricular condition delay, and left ventricular hypertrophy (Young et al, 1989).

Respiratory

    3.6.1) SUMMARY
    A) Respiratory arrest has resulted from high-dose trimethaphan therapy.
    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) Respiratory arrest has been reported following high doses of trimethaphan (6 to 16 mg/min) (Dale & Schroeder, 1976).
    B) FIBROSIS OF LUNG
    1) Chronic therapy has led to coughing, dyspnea, and intraalveolar and interstitial pulmonary fibrosis (Doniach et al, 1954; Perry et al, 1957; Heard, 1962; Rokseth & Storstein, 1960; Petersen et al, 1959; Hildeen et al, 1958).
    C) RESPIRATORY FAILURE
    1) A 24-year-old woman developed pulmonary inflammation 3 days after inhaling hexamethonium as part of a clinical research trial. Minimal clinical details are available, but she died of respiratory failure despite intensive care (McCarthy, 2001).

Neurologic

    3.7.1) SUMMARY
    A) Seizures may occur, especially following large doses of mecamylamine. Tremor, hallucinations, and confusion may also follow high dose mecamylamine.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) Mydriasis, urinary retention, and impotence may occur. Seizures may occur and are frequent with large doses of mecamylamine (Prod Info Inversine(R), mecamylamine hydrochloride, 1998).
    B) PSYCHOTIC DISORDER
    1) Psychosis, tremor, hallucinations, confusion, depression, and anxiety have been reported with mecamylamine in doses of 60 to 65 mg/day (Harington & Kincaid-Smith, 1958).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, diarrhea, constipation, and paralytic ileus may occur.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) Nausea, vomiting, and diarrhea may occur with therapeutic doses (Prod Info Inversine(R), mecamylamine hydrochloride, 1998).
    B) DRUG-INDUCED ILEUS
    1) Paralytic ileus and constipation may occur with therapeutic doses (Prod Info Inversine(R), mecamylamine hydrochloride, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) Urinary retention, impotence and decreased libido may occur with therapeutic doses (Prod Info Inversine(R), mecamylamine hydrochloride, 1998).

Musculoskeletal

    3.15.1) SUMMARY
    A) Prolonged neuromuscular blockade may occur after trimethaphan therapy.
    3.15.2) CLINICAL EFFECTS
    A) FLACCID PARALYSIS
    1) TRIMETHAPHAN - Cases of prolonged neuromuscular blockade and apnea lasting 17 hours (Nakamura et al, 1980) and 5.5 hours (Wilson et al, 1976) have been reported when trimethaphan was used in combination with non-depolarizing blocking agents.

Reproductive

    3.20.1) SUMMARY
    A) Hexamethonium and trimethaphan are both classified in pregnancy category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    HEXAMETHONIUMC
    TRIMETHAPHANC
    Reference: Briggs et al, 1998

Genotoxicity

    A) Mecamylamine was not mutagenic in a S typhimurium assay and not clastogenic in Chinese hamster ovary cells or the mouse micronucleus test (reviewed in Young et al, 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Blood levels of these agents are not clinically useful.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    C) Monitor blood pressure closely, as well as the EKG.

Methods

    A) OTHER
    1) Serum levels are not clinically useful.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Blood levels of these agents are not clinically useful.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    C) Monitor blood pressure closely, as well as the EKG.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    B) MONITORING OF PATIENT
    1) Expansion of the vascular volume with measurement of CVP and central arterial blood pressure will assist in management.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) PHYSOSTIGMINE
    1) Physostigmine or neostigmine (0.5 to 1 milligram intravenously, slowly) have reversed many of the effects of ganglionic blocking agents (Nakamura et al, 1980).
    2) Gastrointestinal function may be restored with cholinergic agents such as BETHANECHOL.

Range Of Toxicity

Summary

    A) Insufficient data in the literature to assess the range of toxicity following acute exposure.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Historical data has been included for this review. Many of these medications are not widely available for therapeutic use.
    2) Reported therapeutic doses:
    a) PENTOLINIUM: Up to 100 mg/day in divided doses
    b) MECAMYLAMINE: Up to 25 mg/day in divided doses
    c) TRIMETHAPHAN: Infusion may be initiated at a rate of 0.5 to 1 mg/min when using a 0.1% solution (1 mg/mL) and titrate to the desired therapeutic response. Individual response is extremely variable and dosing has ranged from 0.3 to 6 mg/min. Dosages should not exceed 5 mg/min. Close monitoring and caution should be exercised (Prod Info Arfonad(R), 1996).
    d) PEMPIDINE: 10 to 75 mg/day
    7.2.2) PEDIATRIC
    A) A therapeutic dose for the pediatric population has not been established for these agents.

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) MECAMYLAMINE - Doses of 60 to 65 milligrams/day produced severe tremors and hallucinations in 4 patients (Harington & Kincaid-Smith, 1958).
    2) TRIMETHAPHAN - Respiratory arrest has been reported following high doses of trimethaphan (6 to 16 milligrams/min) (Dale & Schroeder, 1976).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) MECAMYLAMINE
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 40 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 90 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Toxicologic Mechanism

    A) All agents of this class produce a post-synaptic membrane stabilization which results in an antagonism of acetylcholine neurotransmission. This effect is associated with a variety of altered physiologic functions.
    B) In the control of hypertension, ganglionic blockade effectively destroys adrenergic control of the vascular bed with resultant vasodilation and a fall in systolic and diastolic pressures.

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    4) Caravati EM, Knight HH, & Linscott MS: Esophageal laceration and charcoal mediastinum complicating gastric lavage. J Emerg Med 2001; 20:273-276.
    5) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    6) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    7) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    8) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    9) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    10) Dale RC & Schroeder ET: Respiratory paralysis during treatment of hypertension with trimethaphan camsylate. Arch Intern Med 1976; 136:816-818.
    11) DiLeo M, Dalmasso M, & Libero L: Severe electrocardiographic abnormalities during Arfonad administration. G Ital Cardiol 1984; 14:931-934.
    12) Doniach I, Morrison B, & Steiner RE: Lung changes during hexamethonium therapy for hypertension. Br Heart J 1954; 16:101-108.
    13) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    14) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    15) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    16) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    17) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    18) Hammer GB: Ultra-high dose trimethaphan in an infant with severe hypertension. J Toxicol Clin Toxicol 1996; 34:227-229.
    19) Harington M & Kincaid-Smith P: Psychosis and tremor due to mecamylamine. Lancet 1958; 1:499-501.
    20) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    21) Heard BE: Fibrous healing of old iatrogenic pulmonary oedema ("hexamethonium lung"). J Pathol 1962; 83:159-164.
    22) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    23) Hildeen T, Krogsgaard AR, & Vimptrup BJ: Fatal pulmonary changes during medical treatment of malignant hypertension. Lancet 1958; 2:830-832.
    24) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    25) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    26) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    27) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    28) McCarthy M: Healthy volunteer dies in US physiology study. Lancet 2001; 357:2114.
    29) Nakamura K, Koide M, & Imanaga T: Prolonged neuromuscular blockade following trimetaphan infusion. Anaesthesia 1980; 35:1202-1207.
    30) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    31) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    32) Perry HM Jr, O'Neal RM, & Thomas WA: Pulmonary disease following chronic chemical ganglionic blockade: a clinical and pathologic study. Am J Med 1957; 22:37-50.
    33) Petersen AG, Dodge M, & Helwig FC: Pulmonary changes associated with hexamethonium therapy. Arch Intern Med 1959; 103:285-288.
    34) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    35) Product Information: Arfonad(R), trimethaphan camsylate. Roche Laboratories, Nutley, NJ, 1996.
    36) Product Information: Inversine(R), mecamylamine hydrochloride. Layton Bioscience, Inc, Sunnyvale, CA, 1998.
    37) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    38) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    39) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    40) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    41) RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    42) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    43) Rokseth R & Storstein O: Pulmonary complications during mecamylamine therapy. Acta Med Scand 1960; 167:23-27.
    44) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    45) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    46) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2010; 14(2):162-168.
    47) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    48) Vale JA, Kulig K, American Academy of Clinical Toxicology, et al: Position paper: Gastric lavage. J Toxicol Clin Toxicol 2004; 42:933-943.
    49) Vale JA: Position Statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:711-719.
    50) Wilson SL, Miller RN, & Wright C: Prolonged neuromuscular blockade associated with trimethaphan: a case report. Anesth Analg 1976; 55:353-356.
    51) Young WL, Gitelman DR, & Tatemichi TK: Acute left bundle branch block precipitated by trimethaphan (letter). Anesth Analg 1989; 69:413-414.