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PROPYLHEXEDRINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Specific Substances

    1) 1-cyclohexyl-2-methylaminopropane
    2) hexahydrodesoxyephedrine
    3) CHP-Depot
    4) CAS 3595-11-7

Available Forms Sources

    A) FORMS
    1) Propylhexedrine (Benzedrex(R)) is available as a nasal inhaler with propylhexedrine 250 mg as the active ingredient, delivering in each 800 mL of air 0.4 to 0.5 mg of propylhexedrine (Prod Info BENZEDREX nasal inhaler, 2014).
    B) USES
    1) Propylhexedrine is used to provide temporary relief of nasal congestion, promote nasal and sinus drainage, and to relieve sinus pressure (Prod Info BENZEDREX nasal inhaler, 2014; Prod Info Benzedrex(R) Inhaler, propylhexedrine, 1990).
    2) OBESITY: Propylhexedrine has been given in usual doses of 50 to 150 mg daily in divided doses by mouth as an anorectic agent for the short-term management of moderate to severe obesity (JEF Reynolds , 1990; Wesson, 1986).

Therapeutic Toxic Class

    A) Propylhexedrine is a central stimulant and indirect-acting sympathomimetic with actions similar to those of dexamfetamine.
    B) Propylhexedrine was developed as a substitute for the amphetamine which was formerly contained in Benzedrine(R) inhalers.
    C) Due to the abuse of Benzedrine(R) inhalers, the manufacturer reformulated the product to include propylhexedrine as the active ingredient and now the product is known as Benzedrex(R). Although propylhexedrine replaced the amphetamine in the inhaler, propylhexedrine abuse has occurred.

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) Chronic use or misuse may result in left ventricular hypertrophy, nystagmus, ophthalmoplegia, hypertension, ischemic necrosis of injection sites, pulmonary edema, and various forms of CNS stimulation.
    2) Other systemic effects reported with chronic use include headache, nervousness, and tachycardia.
    3) Fatalities have occurred following oral and IV use due to myocardial infarction, heart failure or pulmonary hypertension.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Vital sign changes may include tachypnea, hyperthermia, hypertension and tachycardia.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Transient diplopia, permanent ophthalmoplegia and horizontal nystagmus have been reported as sequelae of IV abuse. Excessive inhalation of propylhexedrine may cause stinging, bleeding, chronic rhinitis, rebound nasal congestion, and temporary enlargement of the nasal turbinates.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Chronic IV abuse of propylhexedrine has resulted in severe left ventricular hypertrophy consistent with congestive cardiomyopathy and hypertension. Myocardial infarction, severe hypotension, PVCs, and pericardial effusions were reported after a large ingestion. Sudden death may occur secondary to cardiac arrhythmias associated with pulmonary hypertension and cor pulmonale.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Pulmonary foreign body granulomas, pulmonary hypertension, pulmonary edema, and diffuse fibrosis have been reported following oral or IV abuse of propylhexedrine.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Propylhexedrine abuse is reported to produce a short rush at the moment of initial ingestion; prolonged stimulation or excitement has also been reported with heavy use. Ingestion or chewing of inhaler contents has been reported to produce agitation, headache, shaking, anxiety, and toxic psychosis. Brainstem dysfunction, necrotizing vasculitis, and intracranial hemorrhage have been reported after IV abuse.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) GI bleeding may occur following abuse.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Thrombocytopenia has been reported following abuse.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Several cases of tissue injury, including cellulitis and ischemic necrosis, were reported following parenteral propylhexedrine abuse.
    0.2.18) PSYCHIATRIC
    A) WITH POISONING/EXPOSURE
    1) A schizophrenia-like reaction has been reported following misuse.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor patient's EKG, blood pressure, and electrolytes (specifically potassium).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) 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.
    0.4.3) INHALATION EXPOSURE
    A) There is no specific antidote. Treatment is directed at supportive care and treatment of pulmonary edema, hypertension, hyperthermia, and CNS excitation.
    B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    C) Tachycardia and hypertension in agitated patients will often respond to sedation with benzodiazepines. Consider esmolol in patients with hemodynamically significant tachycardia.
    1) PRECAUTIONS: Beta blockers should be administered cautiously to patients with reactive airway disease (asthma) or congestive heart failure.
    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 place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Propylhexedrine amounts of 250 mg (contents of one propylhexedrine inhaler) in an adult, and 375 mg in a 3-year-old child orally have caused serious symptoms including pulmonary edema and myocardial infarction.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Chronic use or misuse may result in left ventricular hypertrophy, nystagmus, ophthalmoplegia, hypertension, ischemic necrosis of injection sites, pulmonary edema, and various forms of CNS stimulation.
    2) Other systemic effects reported with chronic use include headache, nervousness, and tachycardia.
    3) Fatalities have occurred following oral and IV use due to myocardial infarction, heart failure or pulmonary hypertension.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Vital sign changes may include tachypnea, hyperthermia, hypertension and tachycardia.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respirations may be increased if pulmonary complications have occurred.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: Heat stroke and death were reported in an 11-year-old girl taking propylhexedrine 50 mg twice daily in combination with phentermine 30 mg/day and a diuretic. The child was participating in a hike with 107 other children who developed no significant problems. The authors proposed that sympathomimetics produced heat intolerance by increasing endogenous heat production via central effects and by impeding heat dissipation by producing peripheral vasoconstriction (Kew et al, 1982).
    B) WITH POISONING/EXPOSURE
    1) Hyperthermia was reported in an abuse case (Liggett, 1982).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypertension may occur; severe hypotension was reported following myocardial infarction in one case.
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Increased heart rate may occur.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Transient diplopia, permanent ophthalmoplegia and horizontal nystagmus have been reported as sequelae of IV abuse. Excessive inhalation of propylhexedrine may cause stinging, bleeding, chronic rhinitis, rebound nasal congestion, and temporary enlargement of the nasal turbinates.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) One report described 7 cases of transient diplopia secondary to IV abuse of propylhexedrine, particularly after injection into the neck vein. Onset was immediate in most cases, and lasted several minutes to several hours (Fornazzari et al, 1986).
    2) Right-internuclear ophthalmoplegia, depressed right gag reflex with paralysis of the right half of the tongue, and horizontal nystagmus have been reported as permanent neurologic dysfunction from abuse of IV propylhexedrine (Fornazzari et al, 1986).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Excessive inhalation of propylhexedrine may cause stinging, rebound nasal congestion, and temporary enlargement of the nasal turbinates. Prolonged use can cause rebound congestion, redness, swelling and chronic rhinitis (JEF Reynolds , 2000).
    B) WITH POISONING/EXPOSURE
    1) Massive nasal bleeding, resulting in death, was seen in one overdose case in a drug-dependent patient (Raudonat & Schmidt, 1989).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Chronic IV abuse of propylhexedrine has resulted in severe left ventricular hypertrophy consistent with congestive cardiomyopathy and hypertension. Myocardial infarction, severe hypotension, PVCs, and pericardial effusions were reported after a large ingestion. Sudden death may occur secondary to cardiac arrhythmias associated with pulmonary hypertension and cor pulmonale.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) WITH POISONING/EXPOSURE
    a) Chronic IV abuse of propylhexedrine has been reported to result in severe left ventricular hypertrophy consistent with congestive cardiomyopathy, and cor pulmonale (Croft et al, 1982; Anderson et al, 1979).
    b) CASE SERIES: One report described 4 patients 26 to 36 years of age who presented with evidence of severe left ventricular failure, characterized by left ventricular dilatation, increased left ventricular end-diastolic and end-systolic volume indices, depressed left-ventricular ejection fractions, mild mitral regurgitation, severe global hypokinesis, and some degree of pulmonary hypertension. All patients were chronic abusers of IV propylhexedrine (Croft et al, 1982a).
    B) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Systemic effects have included hypertension following abuse (Liggett, 1982; JEF Reynolds , 2000).
    C) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) Fatalities following oral or IV propylhexedrine use have been reported secondary to myocardial infarction and heart failure (JEF Reynolds , 2000).
    b) CASE REPORT: A 22-year-old man ingested 250 mg of propylhexedrine. The following symptoms developed: headache, palpitations, severe chest pain and hypotension, multiple premature ventricular contractions, pulmonary edema, myocardial infarction, and pericardial effusion (Marsden & Sheldon, 1972).
    D) DEAD - SUDDEN DEATH
    1) WITH POISONING/EXPOSURE
    a) Sudden death has been reported in IV users of propylhexedrine. Findings on autopsy have included pulmonary foreign-body granulomas, pulmonary fibrosis with vascular changes, and cardiomegaly.
    b) The possible mechanism is cardiac dysrhythmias that are associated with pulmonary hypertension and cor pulmonale (White & DiMaio, 1977; Sturner et al, 1974; DiMaio & Garriott, 1977; Anderson et al, 1979).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Pulmonary foreign body granulomas, pulmonary hypertension, pulmonary edema, and diffuse fibrosis have been reported following oral or IV abuse of propylhexedrine.
    3.6.2) CLINICAL EFFECTS
    A) PULMONARY HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Fatalities following oral or IV use have been reported secondary to pulmonary hypertension during therapeutic use (JEF Reynolds , 2000).
    b) CASE REPORT: Pulmonary hypertension was reported in a 39-year-old woman who had taken propylhexedrine orally for 8 years for control of obesity. Clinical examination and ECG studies returned to normal 12 months following discontinuation of the drug (Cameron et al, 1984).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema, adult respiratory distress syndrome, and pulmonary granulomas have been reported with propylhexedrine abuse (Anderson et al, 1982).
    C) DRUG DEPENDENCE
    1) WITH POISONING/EXPOSURE
    a) Pulmonary foreign body granulomas, pulmonary hypertension, pulmonary edema, and diffuse fibrosis have been reported following oral or IV abuse of propylhexedrine (Garriott, 1975; White & DiMaio, 1977; Robertson et al, 1976; Riddick & Reisch, 1981; Croft et al, 1982).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Propylhexedrine abuse is reported to produce a short rush at the moment of initial ingestion; prolonged stimulation or excitement has also been reported with heavy use. Ingestion or chewing of inhaler contents has been reported to produce agitation, headache, shaking, anxiety, and toxic psychosis. Brainstem dysfunction, necrotizing vasculitis, and intracranial hemorrhage have been reported after IV abuse.
    3.7.2) CLINICAL EFFECTS
    A) DISORDER OF BRAIN STEM
    1) WITH POISONING/EXPOSURE
    a) One report described 2 cases of confirmed brainstem dysfunction and 5 cases of transient diplopia secondary to IV abuse of propylhexedrine. All patients experienced transient diplopia. One patient had right-internuclear ophthalmoplegia and another had depressed right gag reflex and paralysis of the right half of the tongue; deficits persisted for months. The mechanism was postulated to be biochemical or ischemic brainstem dysfunction (Fornazzari et al, 1986)
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Excessive use of propylhexedrine has been associated with headache (JEF Reynolds , 2000).
    C) CENTRAL STIMULANT ADVERSE REACTION
    1) WITH POISONING/EXPOSURE
    a) Abuse of propylhexedrine is reported to produce a short rush at the moment of initial ingestion; prolonged stimulation or excitement have also been reported with heavy use (Smith et al, 1988).
    b) CASE REPORT: Over a period of months, a 33-year-old man with amphetamine dependence ingested up to 8 cotton inserts daily, each containing 250 mg of propylhexedrine. He removed the inserts from Benzedrex(R) nasal inhalers, soaked them in a beverage, and then swallowed them whole. He reported effects that included feeling a heightened mood, sense of focus, and productivity accompanied by an elevated heart rate. The effects occurred within 2 to 3 minutes of ingestion and persisted for approximately 3 hours. In an attempt to support this habit he resorted to stealing the inhalers and was incarcerated for theft. Eventually he was admitted to a residential outpatient treatment program (Fernandez Julia & Francis, 2012).
    c) CASE REPORT: Ingestion of a propylhexedrine inhaler was reported to produce agitation, shaking, and anxiety in a 29-year-old man with a history of amphetamine abuse. Euphoria was not described (Liggett, 1982).
    D) PSYCHOTIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Psychosis may occur following abuse (JEF Reynolds , 2000).
    b) CASE REPORT: A schizophrenia-like reaction was reported in a 24-year-old woman who chewed the contents of 1 or 2, 250 mg propylhexedrine inhalers daily for 2 years. Symptoms resolved over a 2-week period following discontinuation of the drug (McIntyre, 1976).
    c) CASE REPORT: A 30-year-old man developed transient worsening of schizophrenic symptoms including delusional thoughts and paranoia following chewing propylhexedrine inhalers (Johnson et al, 1972).
    E) INTRACRANIAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Chronic IV abuse has been reported to result in necrotizing vasculitis and intracranial hemorrhage (Croft et al, 1982).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) GI bleeding may occur following abuse.
    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal bleeding was reported in a case of propylhexedrine abuse (Marsden & Sheldon, 1972).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Thrombocytopenia has been reported following abuse.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Thrombocytopenia was reported in a 22-year-old man who abused propylhexedrine (Marsden & Sheldon, 1972).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Several cases of tissue injury, including cellulitis and ischemic necrosis, were reported following parenteral propylhexedrine abuse.
    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Six cases of tissue injury including cellulitis and ischemic necrosis were reported following parenteral propylhexedrine abuse. The mechanism was thought to be intense local vasospasm, and not due to fiber from the inhaler wicks (Mancusi-Ungaro et al, 1984).
    b) CASE REPORT: Attempted injection of a propylhexedrine solution into neck veins resulted in paracervical swelling containing extensive necrotic tissue (Perez et al, 1991).
    c) CASE REPORT: Distal necrosis in the index finger and thumb occurred in a 22-year-old following intra-arterial injection of propylhexedrine into the radial aspect of his left wrist. Digital cyanosis progressed to gangrene and amputation (Covey et al, 1988).
    B) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Flushing was reported by a 33-year-old man with amphetamine dependence who ingested up to 8 cotton inserts daily, each containing 250 mg of propylhexedrine. The inserts were removed from Benzedrex(R) nasal inhalers. Effects occurred within minutes of ingestion and persisted for approximately 3 hours (Fernandez Julia & Francis, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) AKATHISIA
    1) WITH POISONING/EXPOSURE
    1) CASE REPORT: Motor restlessness and muscle tension were reported by a 33-year-old man with amphetamine dependence who ingested up to 8 cotton inserts daily, each containing 250 mg of propylhexedrine. The inserts were removed from Benzedrex(R) nasal inhalers. Effects occurred within minutes of ingestion and persisted for approximately 3 hours (Fernandez Julia & Francis, 2012).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) 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) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

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

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor patient's EKG, blood pressure, and electrolytes (specifically potassium).

Methods

    A) CHROMATOGRAPHY
    1) Propylhexedrine may be analyzed by techniques similar to amphetamines including plasma ionization gas chromatography (Baselt, 1982).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor patient's EKG, blood pressure, and electrolytes (specifically potassium).

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) 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) GENERAL TREATMENT
    1) Follow recommendations under inhalation exposure when appropriate.

Inhalation Exposure

    6.7.2) TREATMENT
    A) RECOMMENDATION TO STOP TREATMENT
    1) Discontinue all sympathomimetic agents.
    B) MONITORING OF PATIENT
    1) Monitor patient's ECG and blood pressure.
    C) TACHYARRHYTHMIA
    1) Tachycardia and hypertension in agitated patients will often respond to sedation with benzodiazepines.
    2) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).
    3) PRECAUTIONS: Beta blockers should be administered cautiously to patients with reactive airway disease (asthma) or congestive heart failure.
    D) 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).
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: 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, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

    A) ADULT
    1) Ingestion of a propylhexedrine inhaler has been reported to produce agitation, shaking, nausea, and anxiety in a 29-year-old man with a history of amphetamine abuse. Euphoria was not noted. Hypertension, tremor and hyperthermia disappeared within 4 hours after ingestion and the patient experienced no sequelae (Liggett, 1982).

Range Of Toxicity

Summary

    A) Propylhexedrine amounts of 250 mg (contents of one propylhexedrine inhaler) in an adult, and 375 mg in a 3-year-old child orally have caused serious symptoms including pulmonary edema and myocardial infarction.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRANASAL
    1) The recommended dose is 2 inhalations per nostril no more than once every 2 hours. Each inhalation delivers 0.4 mg to 0.5 mg of propylhexedrine in each 800 mL of air (Prod Info BENZEDREX nasal inhaler, 2014).
    B) ORAL
    1) Propylhexedrine has been given in doses of 50 to 150 mg/day in divided doses in the short-term management of moderate to severe obesity (JEF Reynolds , 1990).
    7.2.2) PEDIATRIC
    A) INTRANASAL
    1) CHILDREN AGED 6 TO 12 YEARS: The recommended dose is 2 inhalations per nostril no more than once every 2 hours. Each inhalation delivers 0.4 mg to 0.5 mg of propylhexedrine in each 800 mL of air (Prod Info BENZEDREX nasal inhaler, 2014).
    2) CHILDREN UNDER AGE 6: Propylhexedrine safety and efficacy have not been established (Prod Info BENZEDREX nasal inhaler, 2014).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) Riddick & Reisch (1981) reported a case of fatal propylhexedrine intoxication from ingestion of multiple cotton pledgets obtained from Benzedrex(R) inhalers. On autopsy, 10 pledgets were found. Microscopically, all organs were acutely edematous and scattered granulomas were identified in the lungs; there was no evidence of pulmonary hypertension.

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) Propylhexedrine amounts of 250 milligrams (contents of one propylhexedrine inhaler) in an adult, and 375 milligrams in a 3-year-old child orally have caused serious symptoms including pulmonary edema and myocardial infarction (Baselt, 1982).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Therapeutic Blood Concentrations (Propylhexedrine) - After normal therapeutic usage are 0.01 milligram/liter (DiMaio & Garriott, 1977).
    b) CASE REPORTS
    1) The blood concentration in a lethal case of intoxication was determined to be 3.75 milligrams/liter. However, the cause of death was due to a massive blood aspiration from nasal bleeding (Raudonat & Schmidt, 1989).
    2) Riddick & Reisch (1981) reported a case of fatal propylhexedrine intoxication from ingestion of multiple cotton pledgets obtained from Benzedrex(R) inhalers. The propylhexedrine blood level was 3.6 milligrams/deciliter, and urine level was 6 milligrams/deciliter. No other drugs were found on toxicology screening.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 83 mg/kg ((RTECS, 2000))
    B) LD50- (ORAL)MOUSE:
    1) 190 mg/kg ((RTECS, 2000))
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 92 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Propylhexedrine is a sympathomimetic specific for alpha-adrenergic receptors (Gilman et al, 1990). Propylhexedrine is structurally related to amphetamine and is used as a local nasal decongestant.
    1) The mechanism of action of propylhexedrine-induced vasoconstriction has not been fully determined, but is expected to be similar to that of amphetamine.
    B) Propylhexedrine has approximately one-twelfth the central nervous system activity and one-eighth the pressor activity of dl-amphetamine (Garriott, 1975; White & DiMaio, 1977).

Physicochemical

Physical Characteristics

    A) A clean colorless liquid with a characteristic amine odor; it volatilizes at room temperature and absorbs carbon dioxide from the air (JEF Reynolds , 2000).

Ph

    A) Solutions in water are alkaline to litmus (JEF Reynolds , 2000)

Molecular Weight

    A) 155.28 (JEF Reynolds , 2000)

References

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