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PHENYLPROPANOLAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Phenylpropanolamine is a sympathomimetic agent with primarily direct alpha-adrenergic agonist effects, but also indirect stimulation of norepinephrine release. It also has weak beta-1 agonist effects but lacks beta-2 agonist properties. It is used as an oral and topical decongestant and an anorexiant.

Specific Substances

    A) Phenylpropanolamine
    1) Phenylpropanolamine (racemic)
    2) d,l-norephedrine
    3) PPA
    4) PPA (abbreviation for phenylpropanolamine)
    L-norephedrine
    1) L-norephedrine
    D-norephedrine
    1) D-norephedrine
    L-norpseudoephedrine
    1) L-norpseudoephedrine
    D-norpseudoephedrine (this isomer is used in European products)
    1) D-norpseudoephedrine (this isomer is used in European products)

Available Forms Sources

    A) FORMS
    1) COMBINATION PRODUCTS/"LOOK ALIKES": Caffeine was formerly available in combination with phenylpropanolamine and ephedrine in formulations designed to mimic controlled stimulants. This combination was declared irrational by the FDA in August, 1982 and removed from the market. Combinations of caffeine with phenylpropanolamine are illegal regardless of labeling.
    B) USES
    1) FDA ADVISORY - The FDA has requested the discontinuation of phenylpropanolamine from all pharmaceutical products and has issued a public health warning concerning the risk of hemorrhagic stroke associated with phenylpropanolamine use, particularly among women ((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 POISONING/EXPOSURE
    1) Signs and symptoms of phenylpropanolamine overdoses may include hypertension, mydriasis, arrhythmias, anxiety, chest pain, auditory and visual hallucinations, paranoid ideation, occasionally delirium and psychosis, seizures, hemorrhagic and non-hemorrhagic cerebral infarctions, rhabdomyolysis, and renal failure.
    2) Most overdoses require only observation for a period of 4 to 8 hours; sustained-release preparations may require a longer period of observation. Pharmacologic intervention is required only in severely symptomatic patients.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypertension may occur, accompanied by tachycardia (usually seen in combination overdose with beta stimulants or anticholinergics) or bradycardia (more commonly with single-ingredient products).
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Mydriasis has been reported.
    B) WITH THERAPEUTIC USE
    1) Blurred vision has been reported.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Tachycardia or bradycardia, precordial pain, and increased blood pressure may be noted. Hypertensive crisis and resultant cerebral hemorrhage or myocardial ischemia may occur following acute ingestion.
    B) WITH POISONING/EXPOSURE
    1) Cardiac arrhythmias may be noted. Tachycardia, precordial pain, and increased blood pressure may be noted. Hypertensive crisis and resultant cerebral hemorrhage or myocardial ischemia may occur following acute ingestion. Cardiomyopathy has been reported.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Adult respiratory distress syndrome has occurred in fatal overdose cases.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Anxiety, confusion, dizziness, headache, nervousness, insomnia, dyskinesia, muscle tremor, seizures, altered mental status, and cerebral hemorrhage may develop.
    B) WITH POISONING/EXPOSURE
    1) Anxiety, confusion, dizziness, headache, nervousness, insomnia, aggressiveness and loss of impulse control, dyskinesia, muscle tremor, seizures, altered mental status, auditory and visual hallucinations, and cerebral hemorrhage may develop.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Anorexia, nausea, and vomiting may be noted.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Interstitial nephritis, acute tubular necrosis, and renal failure, usually secondary to rhabdomyolysis, may occur.
    2) Urinary retention has occurred following PPA ingestion.
    0.2.15) MUSCULOSKELETAL
    A) WITH POISONING/EXPOSURE
    1) Rhabdomyolysis has been reported after overdose.
    0.2.16) ENDOCRINE
    A) WITH POISONING/EXPOSURE
    1) Hypoglycemia was reported in one mixed overdose of unknown amount.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Psychiatric disturbances, particularly in children, have been reported after ingestion of phenylpropanolamine including restlessness, irritability, aggressiveness, sleep disturbances, psychotic episodes, confusion, acute mania, and hallucinations.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) PPA can cause allergic and anaphylactoid reactions.
    0.2.20) REPRODUCTIVE
    A) PPA is a FDA Pregnancy Category C. An association between 1st trimester use and fetal malformations has been found.

Laboratory Monitoring

    A) Monitor CPK, renal function and urine output in severely symptomatic patients and those with prolonged seizures or coma.
    B) Monitor ECG and vital signs in all patients.

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.
    B) MONITOR ECG AND VITAL SIGNS (especially blood pressure and pulse) in symptomatic patients.
    C) MONITOR URINARY OUTPUT and renal function in symptomatic patients.
    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) AGITATION, DISORIENTATION, increased motor activity, and tachypnea require only conservative supportive care.
    F) TACHYDYSRHYTHMIAS: Usually do not require treatment unless hemodynamic compromise develops. Propranolol (0.01 to 0.1 mg/kg IV slowly up to 2 mg per dose) may be useful to relieve palpitations and associated anxiety, especially in combination overdoses with other sympathomimetics. Propranolol may exacerbate hypertension in patients with single-ingredient PPA overdose.
    G) VENTRICULAR TACHYCARDIA or PVC's following phenylpropanolamine ingestion may respond to lidocaine (1 mg/kg IV, repeat 0.5 mg/kg if necessary and follow with 20 to 40 mcg/kg/min infusion).
    H) BRADYCARDIA: Bradycardia has generally not required treatment unless hemodynamic compromise develops. Since the bradycardia is a reflex response, atropine should theoretically be avoided as it may worsen hypertension.
    I) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.

Range Of Toxicity

    A) Greater than 10 mg/kg PPA has been reported as a minimum toxic dose in children; 3 mg/kg in infants. 17.5 mg/kg PPA alone generally results in symptoms.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Signs and symptoms of phenylpropanolamine overdoses may include hypertension, mydriasis, arrhythmias, anxiety, chest pain, auditory and visual hallucinations, paranoid ideation, occasionally delirium and psychosis, seizures, hemorrhagic and non-hemorrhagic cerebral infarctions, rhabdomyolysis, and renal failure.
    2) Most overdoses require only observation for a period of 4 to 8 hours; sustained-release preparations may require a longer period of observation. Pharmacologic intervention is required only in severely symptomatic patients.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypertension may occur, accompanied by tachycardia (usually seen in combination overdose with beta stimulants or anticholinergics) or bradycardia (more commonly with single-ingredient products).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Severe hypertension has been reported following phenylpropanolamine overdose (Larson & Rogers, 1986; Gibson et al, 1987) with peak blood pressure effects occurring approximately 2.5 hours after ingestion (Lake et al, 1989).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Tachycardia usually occurs in combination products containing phenylpropanolamine and either an anticholinergic agent or a beta- sympathomimetic agent (Weesner et al, 1982) Logie & Smith, 1984; (Lake et al, 1990).
    B) WITH POISONING/EXPOSURE
    1) Tachycardia usually occurs in combination products containing phenylpropanolamine and either an anticholinergic agent or a beta- sympathomimetic agent (Weesner et al, 1982) Logie & Smith, 1984; (Lake et al, 1990).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Mydriasis has been reported.
    B) WITH THERAPEUTIC USE
    1) Blurred vision has been reported.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision was among the mild symptoms reported as adverse drug reactions to phenylpropanolamine (Lake et al, 1990).
    B) WITH POISONING/EXPOSURE
    1) Mydriasis may be noted (King et al, 1988).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Tachycardia or bradycardia, precordial pain, and increased blood pressure may be noted. Hypertensive crisis and resultant cerebral hemorrhage or myocardial ischemia may occur following acute ingestion.
    B) WITH POISONING/EXPOSURE
    1) Cardiac arrhythmias may be noted. Tachycardia, precordial pain, and increased blood pressure may be noted. Hypertensive crisis and resultant cerebral hemorrhage or myocardial ischemia may occur following acute ingestion. Cardiomyopathy has been reported.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Phenylpropanolamine has a propensity to produce significant hypertension (Cantu et al, 2003; Howrie & Wolfson, 1983; Horowitz et al, 1979; Lake et al, 1990), and may result in reflex bradycardia (Fredriksen, 1982), extensive myocardial ischemia, cerebral hemorrhage, or renal toxicity.
    b) The hypertension seen with phenylpropanolamine is more severe when the patient is supine (Horowitz et al, 1980; Lake et al, 1990).
    c) Of the 45 hypertensive crises reported with phenylpropanolamine use, intracranial hemorrhages occurred in 24 and 6 resulted in death (Lake et al, 1990). Another 15 had hypertensive encephalopathy or seizures.
    d) Peak blood pressure effects of phenylpropanolamine occur at about 2.5 hours after PPA ingestion with individual times ranging from 0.5 to 4.5 hours (Lake et al, 1989).
    e) The effect of therapeutic doses of PPA on blood pressure is subject to individual variation that may not be predictable from dose or serum concentrations of the drug.
    1) In a study of 10 normotensive subjects, 2 exhibited an extreme hypertensive response after administration of 0.31 and 0.23 mg/kg IV, whereas the other 8 subjects had only minor pressor effects after 0.44 mg/kg IV. Peak serum PPA levels were lower in the hyperresponders (O'Connell et al, 1989).
    2) Ingestion of 75 mg sustained-release capsule or 25 mg immediate-release capsule three times daily in 881 normotensive volunteers resulted in an increase of blood pressure of 2 to 4 mmHg (Blackburn et al, 1989).
    f) Systolic blood pressures exceeding 180 mmHg were reported in 8 of 15 subjects three hours after ingestion of 150 mg sustained-release PPA (twice the usual therapeutic dose) (Lake et al, 1989).
    g) Clinically significant, transient hypertension was reported following 150 mg of sustained-release phenylpropanolamine (peak at 2.25 to 2.5 hours post-ingestion) and following 75 mg of sustained-release phenylpropanolamine plus 400 mg caffeine (peak at 2 to 3 hours post-ingestion) in a double- blind, randomized cross-over design trial in 6 patients (Lake et al, 1988).
    h) PPA usually only minimally increases the blood pressure when a 50 mg dose is administered to normotensive adults. However, a dose of approximately 3 times the maximum recommended OTC dose (37.5 mg) increased pressure a mean of 24 mmHg in 10 subjects (Pentel, 1984).
    i) A slight but significant increase in diastolic blood pressure was reported in subjects given 25 mg PPA and alkalinization of the urine with sodium bicarbonate, compared to subjects given PPA alone (Zimmerman et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) Sustained-release phenylpropanolamine preparations were more likely to produce severe hypertension requiring hospital care (Larson & Rogers, 1986).
    b) Most severe complications of PPA toxicity are secondary to hypertension (King et al, 1988).
    c) Ingestion of 12.5 to 25 mg phenylpropanolamine increased systolic blood pressure by 21 +/- 14 mm Hg after 90 minutes in patients with impaired baroreflex function and autonomic impairment (eg; diabetic neuropathy). When the same dose of phenylpropanolamine was ingested with 16 oz water, systolic blood pressure increased by 82 +/- 2 mm Hg (Jordan et al, 2004).
    d) CASE REPORT - A 17-year-old pregnant female, at 35 weeks gestation, developed severe hypertension (205/132 mmHg) 5 hours after ingestion of approximately 1500 mg phenylpropanolamine, with or without pseudoephedrine. A Cesarean section was performed after a fetal monitor indicated persistent fetal distress. The patient's hypertension resolved following supportive care (Hantsch et al, 1997).
    1) The authors speculate that an undiagnosed pre-eclampsia may have contributed to the patient's sympathomimetic intoxication.
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) The primary expected effect of PPA on the heart rate is reflex bradycardia (Lake et al, 1990).
    b) Phenylpropanolamine has been reported to cause bradycardia with atrioventricular block (Wenckebach type) in three patients (Woo et al, 1985) Burton et al, 1985).
    C) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT (INFANT) - Supraventricular tachycardia (270 beats/minute) was reported in a 6-week-old infant after administration of PPA 4.5 mg every 6 hours for 3 doses (Conway et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia was reported in 22% of 92 overdose cases, however combination products were included (Larson & Rogers, 1986).
    b) Tachycardia usually occurs with combination overdoses with anticholinergics or beta sympathomimetic agents, such as ephedrine or caffeine, or in the presence of ischemia or myocarditis (Lake et al, 1990; Woo et al, 1985).
    c) CASE REPORT - Tachycardia (130 to 140 bpm) was reported in a 17-year-old female following an overdose ingestion of approximately 1500 mg PPA. The patient recovered with supportive care (Hantsch et al, 1997).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 14-year-old girl who ingested 700 to 900 mg of PPA, along with ephedrine and caffeine, developed PVCs, junctional ectopic beats, PACs, and short periods of ventricular tachycardia. The dysrhythmias were unresponsive to lidocaine and resolved after administration of propranolol (Weesner et al, 1982).
    b) CASE REPORT - A 14-year-old girl developed bigeminy followed by atrial fibrillation with a rapid ventricular response (160 beats/minute) after ingesting 225 milligrams of PPA and 36 milligrams of brompheniramine (Chin & Choy, 1993). Her course was complicated by the development severe left ventricular dysfunction and pulmonary edema.
    E) CARDIOMYOPATHY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 14-year-old girl presented with acute cardiomyopathy after a minimal overdose of PPA and brompheniramine. Symptoms included myocardial dysfunction, ventricular dysrhythmia and secondary pulmonary edema without any systemic hypertension (Chin & Chow, 1993).
    1) The total creatine kinase and the MB isozyme were significantly elevated within the first 24 hours, but returned to normal by the third day.
    b) CASE REPORT - A 22-year-old woman presented to the ED after intentionally ingesting of an unknown amount of phenylpropanolamine. An ECG revealed sinus tachycardia (125 bpm) and a chest x-ray showed cardiomegaly and pulmonary congestion. An echocardiography indicated severe left ventricular systolic dysfunction with an ejection fraction of 20%. Laboratory studies revealed an initial serum creatine kinase level of 262 international units/L that peaked at 446 international units/L 18 hours post-admission. The patient was hypoxic, necessitating mechanical ventilation. Following treatment with direct hemoperfusion, the patient's condition gradually improved and she was removed from the ventilator 3 days post-admission. A repeat chest x-ray and echocardiography, performed 9 days post-admission, revealed normal images and the patient was discharged 10 days later without sequelae (Nozoe et al, 2005).
    F) VENTRICULAR ARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) A 14-year-old girl ingested 15 to 18 capsules of RJ8(R) (ephedrine 25 mg, caffeine 200 mg, phenylpropanolamine 50 mg) and presented with PVC's, functional ectopic beats, PAC's and short period of ventricular tachycardia which were unresponsive to lidocaine, but converted to a normal sinus rhythm following the administration of 1 mg IV propranolol (Weesner et al, 1982).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Adult respiratory distress syndrome has occurred in fatal overdose cases.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Late onset (30 hours or more post-ingestion) adult respiratory distress syndrome has been described after PPA overdose in fatal cases (Logie & Scott, 1984; Patterson, 1980).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 14-year-old girl developed severe left ventricular dysfunction and pulmonary edema after ingesting 225 milligrams of PPA and 36 milligrams of brompheniramine (Chin & Choy, 1993).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anxiety, confusion, dizziness, headache, nervousness, insomnia, dyskinesia, muscle tremor, seizures, altered mental status, and cerebral hemorrhage may develop.
    B) WITH POISONING/EXPOSURE
    1) Anxiety, confusion, dizziness, headache, nervousness, insomnia, aggressiveness and loss of impulse control, dyskinesia, muscle tremor, seizures, altered mental status, auditory and visual hallucinations, and cerebral hemorrhage may develop.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness was the most common effect reported after overdose, observed in 36% of 92 cases; however, combination products were included (Larson & Rogers, 1986).
    B) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Anxiety, nervousness, insomnia, dizziness, confusion, psychotic reactions, and muscle tremor (most notably of the hands) may occur following ingestion (Lake et al, 1990; Mueller, 1983).
    2) WITH POISONING/EXPOSURE
    a) Anxiety, nervousness, insomnia, dizziness, confusion, psychotic reactions, and muscle tremor (most notably of the hands) may occur following ingestion (Lake et al, 1990; Mueller, 1983).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures, cerebral hemorrhage (and resultant altered mental status), and hallucinations have been reported following phenylpropanolamine ingestion (Lake et al, 1990; Hantsch et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Seizures, cerebral hemorrhage (and resultant altered mental status), and hallucinations have been reported following phenylpropanolamine ingestion (Lake et al, 1990; Hantsch et al, 1997).
    b) CASE REPORT (PPA-ALONE) - Ingestion of 900 mg on one occasion and 50 mg on rechallenge resulted in a seizure in a 28-year-old woman (Cornelius et al, 1984).
    c) CASE REPORT (PPA-CAFFEINE COMBINATION) - A 13-year-old female who had been ingesting a time-released diet capsule (75 mg PPA and 200 mg caffeine) daily for two weeks developed hypertension (BP 210/100 mmHg) and seizures on the morning following the ingestion of two time-released diet capsules (Howrie & Wolfson, 1983).
    d) CASE REPORT (PPA-ANTIHISTAMINE COMBINATION) - Seizures were reported in a 4-year-old child following ingestion of PPA 50 mg and brompheniramine (Norvenius et al, 1979).
    3) ANIMAL STUDIES
    a) PPA-CAFFEINE COMBINATION - Animal studies have shown that the co-ingestion of PPA decreases the threshold for caffeine-induced seizures (Walker, 1989).
    D) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Intracerebral hemorrhage and angiographic evidence of carotid and vertebral artery vasculitis or vasospasm ("beading") have been reported in several patients taking only one 25 to 75 mg dose of phenylpropanolamine (Cantu et al, 2003; Kase et al, 1987; McDowell & LeBlanc, 1985; Fallis & Fisher, 1985; Traynelis & Brick, 1986; Glick et al, 1987; Maher, 1987).
    b) Six stroke cases which occurred after first use of phenylpropanolamine products in therapeutic doses were labelled as idiosyncratic effects (Lake et al, 1990).
    c) Two cases of intracerebral hemorrhage and subarachnoid hemorrhage after ingestions of therapeutic doses of PPA are described (Sloan et al, 1991).
    d) CASE REPORT (INFANT) - A 7-week-old ex-32 week premature infant was given 2.5 mL of an OTC cold preparation (PPA 6.25 mg and brompheniramine 1 mg) and, within 30 minutes, was stiff and unresponsive with her head turned to the right side. A brain CT scan showed a right cerebellar and midbrain hemorrhage extending into the ventricular system, consistent with a ruptured arteriovenous malformation (AVM). The AVM rupture was believed to have been caused by a sudden increase in intracranial pressure secondary to the administration of PPA. The patient recovered following supportive treatment with dopamine and epinephrine (Hamilton & Sharieff, 2000).
    e) A case-control study was conducted to determine the association between therapeutic use of phenylpropanolamine and the occurrence of hemorrhagic stroke. For the association between hemorrhagic stroke and PPA use within three days in all patients, the adjusted odds ratio was 1.49; in women, the adjusted odds ratio was 1.98, suggesting that PPA increases the risk for hemorrhagic stroke ((Horwitz, 2000)). The investigators of the study were unable to determine if the risk for hemorrhagic stroke (with the use of PPA) in men was different from that of women due to the low number of PPA exposed men included in this study (n=19).
    f) Kernan et al (2000) conducted a case control study of patients 18 to 49 years of age with subarachnoid or intracerebral hemorrhage without previously diagnosed brain lesion (Kernan et al, 2000). For women the adjusted odds ration was 16.58 (95% CI 1.51 to 182.21) for the association between using appetite suppressants containing PPA and the risk of a hemorrhagic stroke. The dose of PPA used for appetite suppression is greater than the dose used in cough and cold preparations. The association between use of PPA in cough and cold preparations and increased risk of hemorrhagic stroke is less clear (Ernst & Hartz, 2001; Wolowich et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS - Intracerebral hemorrhage and angiographic evidence of carotid and vertebral artery vasculitis or vasospasm ("beading") were reported in a 17-year-old obese girl who ingested 375 mg of PPA (Forman et al, 1989), in a 27-year-old man who ingested 585 mg of PPA (Maertens et al, 1987), and in a 25-year-old man who took 5 times the therapeutic dose (Mesnard & Ginn, 1984).
    E) VASCULITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS - Intracerebral hemorrhage and angiographic evidence of carotid and vertebral artery vasculitis or vasospasm ("beading") were reported in a 17-year-old obese girl who ingested 375 mg of PPA (Forman et al, 1989), in a 27-year-old man who ingested 585 mg of PPA (Maertens et al, 1987), and in a 25-year-old man who took 5 times the therapeutic dose (Mesnard & Ginn, 1984).
    b) CASE SERIES - Cerebral vasculitis was described in a 39-year-old man who ingested 180 mg of PPA and a 61-year-old woman who ingested 120 mg of PPA (Le Coz et al, 1988).
    c) CASE REPORT - An 8-year-old boy on chronic peritoneal dialysis developed occipital infarcts after ingesting unknown amounts of PPA-containing product for an upper respiratory tract infection. CT scan of the head revealed bilateral watershed infarcts in the parieto-occipital areas with edema, though without mass effect. The presence of a focal vasculitis was confirmed by an MRI/MRA. An initial serum PPA concentration was 300 ng/mL (normal range 90 ng/mL after a 50-mg dose; suggested adult dose). Following supportive therapy, he recovered without further sequelae (Delorio, 2004).
    F) CEREBRAL ARTERY OCCLUSION
    1) WITH THERAPEUTIC USE
    a) Cerebral infarct has been reported in patients taking phenylpropanolamine (Cantu et al, 2003; Edwards et al, 1987; Johnson et al, 1983).
    b) CASE REPORT - Cerebral infarct was also reported in a woman taking an over-the-counter diet preparation containing 75 mg phenylpropanolamine daily for several months, she discontinued them for 6 months and then took one single dose on the night prior to admission (Edwards et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - Non-hemorrhagic cerebral infarction was reported following prolonged excessive use of a phenylpropanolamine/caffeine combination by a 24-year-old man (Johnson et al, 1983).
    b) CASE REPORT - Cerebral infarction was reported in a 34-year-old man who had been taking PPA 112.5 to 300 mg/day for 4 months. He was not hypertensive (Johnson et al, 1983).
    G) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Acute, persistent, severe headache was the most common chief complaint noted in 32 (39%) of severe adverse drug reactions to phenylpropanolamine (Lake et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) Headache, vomiting, chest pain, and shortness of breath were reported after an overdose ingestion of approximately 1500 mg phenylpropanolamine (Hantsch et al, 1997).
    H) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Two patients have been described who developed persistent dyskinetic syndromes (spasmodic torticollis and cranial dystonia) when PPA was withdrawn after chronic use (Theil & Dressler, 1994).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Anorexia, nausea, and vomiting may be noted.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal symptoms may include anorexia, nausea, and vomiting (Larson & Rogers, 1986; Hantsch et al, 1997).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Seven patients developed acute hepatitis, characterized by abdominal pain, jaundice, and elevated liver enzyme levels, within 2 to 12 weeks after beginning daily use of LipoKinetix(R), a dietary supplement containing 25 mg norephedrine (phenylpropanolamine), 100 mg sodium usniate, 100 mcg 3,5-diiodothyronine, 3 mg yohimbine, and 100 mg caffeine. One of the seven patients developed fulminant hepatic failure with cerebral edema despite discontinuation of LipoKinetix(R). With supportive care, all seven patients gradually recovered without sequelae (Favreau et al, 2002). LipoKinetix(R) was the only dietary ingested by three of the seven patients, including the patient who developed fulminant hepatic failure.
    b) The FDA issued an immediate recall of LipoKinetix(R) due to several reports of the occurrence of hepatotoxicity in association with the consumption of LipoKinetix(R) ((Anon, 2001)).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Interstitial nephritis, acute tubular necrosis, and renal failure, usually secondary to rhabdomyolysis, may occur.
    2) Urinary retention has occurred following PPA ingestion.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute interstitial nephritis (Lee et al, 1979), acute tubular necrosis (Duffy et al, 1981; Lake et al, 1990), and acute renal failure accompanied by rhabdomyolysis (Swenson et al, 1982; Rumpf et al, 1983) have been reported in patients ingesting phenylpropanolamine or the isomer d-norpseudoephedrine (Hampel et al, 1983).
    1) In one of these patients renal failure developed after 3 weeks of ingesting therapeutic doses; whereas signs and symptoms of renal failure were noted 5 days after ingesting 1.5 to 2.5 grams of PPA in another case (Swenson et al, 1982).
    B) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 37-year-old woman was reported to have acute urinary retention after ingestion of PPA 50 mg/day for 2 weeks (Napolez & Lauth, 1988).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - Proteinuria and oliguria was reported in a 17-year-old female following an overdose ingestion of approximately 1500 mg PPA. The patient recovered following administration of crystalloids and low-dose dopamine (Hantsch et al, 1997).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Rhabdomyolysis has been reported after overdose.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis, accompanied by acute renal failure, has been reported after overdose with phenylpropanolamine (Swenson et al, 1982; Hampel et al, 1983; Rumpf et al, 1983).

Endocrine

    3.16.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypoglycemia was reported in one mixed overdose of unknown amount.
    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - An 11-month-old boy was given an unknown amount of PPA- antihistamine combination preparation. Blood sugar level upon admission was 51 mg/dl and the patient was unable to be awakened. Urine ketones were 4+ (Barness, 1993).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) PPA can cause allergic and anaphylactoid reactions.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Two cases of an allergic response to phenylpropanolamine have been described. The first case was a 17-year-old girl who had hay fever and asthma (Speer, 1978). She reported having severe reactions, including dyspnea, wheezing, coughing, hives, and facial swelling to Triaminic(R) tablets, Contac(R), Listerine(R) cold tablets and Dimetapp(R). The only ingredient all 4 medications have in common is phenylpropanolamine. She had no history of any other drug reaction.
    b) CASE REPORT - The second case involved a 41-year-old female diagnosed as having urticaria and anaphylactoid purpura. She reported developing a similar reaction in 1975 and 1976 about 10 days after beginning a course of Triaminic(R) tablets. She also reported having developed chest tightness, wheezing, and fatigue after 1 dose of Sineoff(R), Sinutab(R), and Sinutab II(R). Phenylpropanolamine is the common ingredient in these items. When evaluated 2 months later she reported that her skin was clear (Speer, 1978).

Reproductive

    3.20.1) SUMMARY
    A) PPA is a FDA Pregnancy Category C. An association between 1st trimester use and fetal malformations has been found.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) An association between 1st trimester use and fetal malformations has been found: Hypospadias, eye and ear, polydactyly, cataract, and pectus escavatum. Statistical significance of these associations is not known (Briggs et al, 1998)
    2) An association between PPA use anytime during pregnancy and a congenital dislocation of the hip has been reported in 12 cases out of 2489 (Briggs et al, 1998).
    3) A case-controlled surveillance of first trimester medication use revealed an association between ingestion of PPA and gastroschisis (Werler et al, 1992).
    3.20.3) EFFECTS IN PREGNANCY
    A) ADVERSE EFFECTS
    1) Post-partum women may be more susceptible to adverse neurologic and psychiatric effects of PPA (Maher, 1977; (Lake et al, 1988a).
    B) PREGNANCY CATEGORY
    PHENYLPROPANOLAMINEC
    Reference: Briggs et al, 1998
    C) HYPOXIA
    1) The use of PPA during pregnancy may constrict uterine vessels and reduce blood flow thereby producing fetal hypoxia (Briggs et al, 1998).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) There is no data available regarding breastfeeding, according to Briggs et al, (1998). Nice (1995) reports that PPA should be avoided if at all possible when breastfeeding.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CPK, renal function and urine output in severely symptomatic patients and those with prolonged seizures or coma.
    B) Monitor ECG and vital signs in all patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum CPK and renal function in severely symptomatic patients and those with prolonged seizures or coma.
    2) Monitor serum electrolytes in patients with dysrhythmias or rhabdomyolysis.
    4.1.3) URINE
    A) OTHER
    1) Monitor urinary output and examine urine for myoglobin in symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) MONITOR EKG AND VITAL SIGNS (especially blood pressure and pulse) in all patients. Prolonged observation (at least 24 hours) may be necessary in patients ingesting sustained-release formulations of PPA.

Radiographic Studies

    A) CT RADIOGRAPH
    1) A CT scan is indicated in patients with severe headache, neurologic deficits, or abnormal mental status.

Methods

    A) CHROMATOGRAPHY
    1) Urine screen by thin layer chromatography is available in some labs for qualitative identification. The TLC method cannot distinguish between PPA and the congener d-norpseudoephedrine (Gal & Lichtenstein, 1987).
    2) Thin layer chromatography followed by gas chromatography can differentiate between amphetamine and phenylpropanolamine (Mueller, 1983).
    B) IMMUNOASSAY
    1) EMIT - The enzyme-multiplied-immunoassay homogeneous or monoclonal amphetamine assay (EMIT) does not differentiate between amphetamine and phenylpropanolamine (Grinstead, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children with a minor ingestion may be monitored at home with adequate adult supervision and telephone support and follow-up. Based on a prospective study of 92 cases, refer children ingesting 10 mg/kg or more and adults or adolescents with deliberate ingestions to a health care facility for observation (Larson & Rogers, 1986).
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Based on a prospective study of 92 cases, refer children ingesting 10 mg/kg or more and adults or adolescents with deliberate ingestions to a health care facility for observation (Larson & Rogers, 1986).
    B) SUSTAINED-RELEASE PRODUCTS: Prolonged observation (at least 24 hours) may be necessary in patients ingesting sustained-release formulations of PPA.

Monitoring

    A) Monitor CPK, renal function and urine output in severely symptomatic patients and those with prolonged seizures or coma.
    B) Monitor ECG and vital signs in all patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Activated charcoal has been shown to be effective in reducing the bioavailability of PPA (Tsuchiya & Levy, 1972 a,b).
    2) 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).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal has been shown to be effective in reducing the bioavailability of phenylpropanolamine (Tsuchiya & Levy, 1972 a,b).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) MONITOR ECG AND VITAL SIGNS (especially blood pressure and pulse) in all patients. Prolonged observation (at least 24 hours) may be necessary in patients ingesting sustained-release formulations of PPA.
    2) MONITOR URINARY OUTPUT and renal function in symptomatic patients.
    B) PSYCHOMOTOR AGITATION
    1) AGITATION, DISORIENTATION, increased motor activity, hallucinations, hyperventilation, and tachypnea generally requires only conservative supportive therapy and benzodiazepines.
    C) 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).
    D) 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) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    E) TACHYARRHYTHMIA
    1) 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).
    F) BRADYCARDIA
    1) Bradycardia does not generally require treatment (Burton et al, 1985) (Woo et al, 1985). Since the bradycardia is a reflex response, atropine should theoretically be avoided as it may worsen hypertension (King et al, 1988).
    G) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    H) EXPERIMENTAL THERAPY
    1) In a rat model for severe phenylpropanolamine poisoning pretreatment with phentolamine 3 milligrams/kilogram reduced mortality (mortality 2/14 in the phentolamine group compared with 10/14 controls) and the degree of myocardial injury (Burns et al, 2001).

Enhanced Elimination

    A) PERITONEAL DIALYSIS
    1) Phenylpropanolamine was shown to be eliminated by peritoneal dialysis in a 10-year-old with chronic renal failure who developed hypertension, seizures, and bilateral occipital infarcts as well as parietal, frontal and temporal lesions on MRI. When serum PPA levels were 300 ng/ml in the serum, dialysate contained 98 ng/ml PPA; when serum contained 190 ng/ml PPA, dialysate contained 120 ng/ml. Half life of PPA in this patient was 46 hours (compared with 4 to 7 hours in patients with normal renal function) (Lewis-Younger et al, 2001).

Range Of Toxicity

Summary

    A) Greater than 10 mg/kg PPA has been reported as a minimum toxic dose in children; 3 mg/kg in infants. 17.5 mg/kg PPA alone generally results in symptoms.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) NASAL DECONGESTION - 25 milligrams every 4 hours as needed for nasal decongestion; up to a maximum daily dose of 150 milligrams (USPDI, 1999).
    2) APPETITE SUPPRESSION - 25 milligrams immediate release form 3 times a day; not to exceed 75 milligrams in a 24 hour period or 75 milligrams sustained- release form once a day (USPDI, 1999).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) NASAL DECONGESTION (6 TO 12 YEARS) - 12.5 milligrams every 4 hours, up to a maximum daily dose of 75 milligrams (USPDI, 1999).
    2) NASAL DECONGESTION (2 TO 6 YEARS) - 6.25 milligrams every 4 hours, up to a maximum daily dose of 37.5 milligrams (USPDI, 1999).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) ADULT
    a) A 15-year-old girl died after ingestion of PPA 400 to 450 milligrams; death was attributed to ARDS (Logie & Scott, 1984).
    b) Death in a 19-year-old woman after ingestion of 500 to 600 milligrams of PPA in a sustained-release formulation was also attributed to ARDS, occurring 2 days post-ingestion (Patterson, 1980).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) USUAL TOLERATED DOSE - 2 to 3 times the therapeutic dose is usually tolerated, especially in children.
    B) CASE REPORTS
    1) ADULT
    a) Ingestion of 3.6 milligrams/kilogram of PPA in a 22-year-old woman resulted in bradycardia, hypertension, headache, drowsiness, nausea, and vomiting (Larson & Rogers, 1986).
    b) MILD HYPERTENSION (140 to 150 mmHg systolic and 90 to 108 mmHG diastolic) was reported in 4 adolescent or adult patients who ingested 1.7 to 6.3 milligrams/kilogram (Larson & Rogers, 1986).
    c) Sustained-release phenylpropanolamine preparations are more likely to produce severe hypertension requiring hospital care (Larson & Rogers, 1986).
    2) PEDIATRIC
    a) MINIMUM TOXIC DOSE - A 5 month study of 70 patients reports that a toxic dose of PPA in children is 8 to 10 milligrams/kilogram; that symptoms will generally develop in patients following the ingestion of 17.5 milligram/kilogram PPA alone within 2 hours and persist for 6 to 13 hours; and that the combination of caffeine and PPA results in additive pharmacologic effects of both drugs (Ekins & Spoerke, 1983).
    b) In a study of 92 patients with PPA overdose children ingesting less than 10 milligrams/kilogram did not develop significant toxicity (Larson & Rogers, 1986).
    c) Moderate or severe hypertension was reported in children ingesting 10.3 to 50 milligrams/kilogram (Larson & Rogers, 1986).
    d) Sustained-release phenylpropanolamine preparations are more likely to produce severe hypertension requiring hospital care (Larson & Rogers, 1986).
    e) CASE REPORT - Severe hypertension (205/132 mmHg), possibly complicated by undiagnosed pre-eclampsia, was reported in a 17-year-old female, at 35 weeks gestation, following an overdose ingestion of approximately 1500 milligrams PPA. The hypertension resolved following magnesium sulfate, a Cesarean section and post-operative care (Hantsch et al, 1997).
    f) CASE REPORT - An 8-year-old boy on chronic peritoneal dialysis developed occipital infarcts after ingesting unknown amounts of PPA-containing product for an upper respiratory tract infection. An initial serum PPA concentration was 300 ng/mL (normal range 90 ng/mL after a 50-mg dose; suggested adult dose). Following supportive therapy, he recovered without further sequelae (Delorio, 2004).
    g) Infants may develop toxicity at doses greater than 3 milligrams/kilogram (Frejaville PJ, Bismuth C & Conso F, 1981).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Serum levels of 380 +/- 262 nanograms/milliliter were observed 2 hours after administration of phenylpropanolamine doses of 2.1 to 3.7 milligrams/ kilogram to test the effectiveness in incontinence in children. With single daily doses of 100 to 200 milligrams, the serum levels ranged from 139 to 469 nanograms/milliliter (Hanzlick, 1993).
    b) Therapeutic blood concentrations are believed to range from 30 to 200 nanograms/milliliter (Hanzlik & Davis, 1993).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT - An 8-year-old boy on chronic peritoneal dialysis developed occipital infarcts after ingesting unknown amounts of PPA-containing product for an upper respiratory tract infection. An initial serum PPA concentration was 300 ng/mL (normal range 90 ng/mL after a 50-mg dose; suggested adult dose). Following supportive therapy, he recovered without further sequelae (Delorio, 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Phenylpropanolamine is used predominately as an oral nasal decongestant, or as an anorexiant. The sympathomimetic effects of PPA result from its ability to release norepinephrine from nerve terminals and stimulate alpha-1 and beta-1 adrenoreceptors.

Toxicologic Mechanism

    A) Phenylpropanolamine acts primarily on the peripheral alpha adrenergic receptors, with only a weak effect on beta receptors. The most common toxicity is hypertension due to vasoconstriction of peripheral vasculature. Reflex bradycardia may be seen.
    B) CARDIAC EFFECTS - Catecholamines and sympathetic amines can cause myocardial necrosis in animals and humans (Pentel et al, 1982).
    C) CEREBROVASCULAR EFFECTS - Vascular beading, a pattern of uneven cerebrovascular spasm attributed to PPA and other sympathomimetic drugs, has been demonstrated in 12 North American adverse drug reactions to PPA (Lake et al, 1990). Ten of these cases had intracranial hemorrhage and significant neurologic deficits.
    1) Cantu et al (2003) described several mechanisms by which phenylpropanolamine causes cerebrovascular complications: the development of hypertensive crisis as a consequence of a direct vasoconstrictive action of the drugs, or the development of angiitis (Cantu et al, 2003).
    D) CAFFEINE COMBINATIONS -
    1) Rats pretreated either acutely or chronically with PPA (30 mg/kg as a single dose or BID for 6 days) had a lower threshold for caffeine-induced seizures (Walker, 1989).
    E) DRUG INTERACTIONS -
    1) Indomethacin inhibits production of vasodilator prostaglandins, thus enhancing PPA's vasoconstrictor action (Lake et al, 1990).
    2) MAO-inhibitors block the catabolism of catecholamines, thereby prolonging the catecholamine effect (Lake et al, 1990).
    3) Propranolol and other beta blockers can block cardiac beta receptors and vasodilator beta receptors thereby producing unopposed alpha constriction which can worsen acute hypertension due to elevated catecholamine levels (Blum & Atsmon, 1975; McLaren, 1976).
    4) TCAs inhibit neuronal reuptake inactivation of norepinephrine and block presynaptic alpha-2 receptors, resulting in increased synaptic concentrations of norepinephrine that may increase blood pressure and alter mood and behavior (Crews & Smith, 1978).

Physicochemical

Physical Characteristics

    A) PPA hydrochloride is a white crystalline powder with a slight aromatic odor.

Molecular Weight

    A) 151.21

Animal Toxicology

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) DOG
    1) 1.5 milligrams/kilogram orally three times daily has been used for treating primary sphincter incompetence (Richter & Ling, 1985).
    11.3.2) MINIMAL TOXIC DOSE
    A) LACK OF INFORMATION
    1) No specific information on a minimal toxic dose was available at the time of this review.

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) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    4) Anon : FDA issues public health warning on phenylpropanolamine. U.S. Food and Drug Administration. Rockville, MD, USA. 2000. Available from URL: http://www.fda.gov/bbs/topics/ANSWERS/ANS01051.html. As accessed Accessed November 13, 2000.
    5) Anon: FDA warns consumers not to use the dietary supplement LipoKinetix.. U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition. College Park, MD, USA. 2001. Available from URL: http://www.cfsan.fda.gov. As accessed Accessed December 3, 2001.
    6) Barness LA: Unforgettable patients. J Pediatrics 1993; 122:320.
    7) Blackburn GL, Morgan JP, & Lavin PT: Determinants of the pressor effect of phenylpropanolamine in healthy subjects. JAMA 1989; 261:3267-3272.
    8) Blum I & Atsmon A: A paradoxical rise in blood pressure during propranolol treatment (letter). Br Med J 1975; 4:623.
    9) Briggs GG, Freeman RK, & Yaffe SJ: Drugs in Pregnancy and Lactation. 5th ed, Williams & Wilkins, Baltimore, MD, 1998.
    10) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    11) Brown NJ, Ryder D, & Branch RA: A pharmacodynamic interaction between caffeine and phenylpropanolamine. Clin Pharmacol Ther 1991; 50:363-371.
    12) Burns MJ, Dickson EW, & Sivilotti MLA: Phentolamine reduces myocardial injury and mortality in a rat model of phenylpropanolamine poisoning. Clin Toxicol 2001; 39:129-134.
    13) Cantu C, Arauz A, Murillo-Bonilla LM, et al: Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003; 34:1667-1673.
    14) Castellani S: Catatonia associated with phenylpropanolamine overdose and fluphenazine treatment: Case report. J Clin Psychiatr 1985; 46:288-289.
    15) 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.
    16) Chin C & Choy M: Cardiomyopathy induced by phenylpropanolamine. J Pediatrics 1993; 123:825-827.
    17) 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.
    18) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    19) Chouinard G, Ghadirian AM, & Jones BD: Death attributed to ventricular arrhythmia induced by thioridazine in combination with a single Contac C capsule. Can Med Assoc J 1978; 119:729-731.
    20) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    21) Conway EE, Walsh CA, & Palomba AL: Supraventricular tachycardia following the administration of phenylpropanolamine in an infant. Pediatr Emerg Care 1989; 5:173-174.
    22) Cornelius JR, Soloff PH, & Reynolds CF: Paranoia, homicidal behavior, and seizures associated with phenylpropanolamine. Am J Psychiatr 1984; 141:120-121.
    23) Crews F & Smith C: Presynaptic alpha receptor subsensitivity after long-term antidepressant treatment. Science 1978; 202:322-324.
    24) Cuthbert MF, Greenberg MP, & Morley SW: Cough and cold remedies: a potential danger to patients on monoamine oxidase inhibitors. Br Med J 1969; 1:404-405.
    25) 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.
    26) Delorio NM: Cerebral infarcts in a pediatric patient secondary to phenylpropanolamine, a recalled medication. J Emerg Med 2004; 26(3):305-307.
    27) Dewsnap P & Libby G: A case of affective psychosis after routine use of proprietary cold remedy containing phenylpropanolamine (letter). Hum Exp Tox 1992; 11:295-297.
    28) Duffy WB, Senekjian HO, & Knight TF: Acute renal failure due to phenylpropanolamine. South Med J 1981; 74:1548-1549.
    29) Edwards M, Russo L, & Harwood-Nuss A: Cerebral infarction with a single oral dose of phenylpropanolamine. Am J Emerg med 1987; 5:163-164.
    30) Ekins BR & Spoerke DG: An estimation of the toxicity of non-prescription diet aids from seventy exposure cases. Vet Hum Toxicol 1983; 25:81-85.
    31) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    32) Ernst ME & Hartz A: Phenlypropanolamine and hemorrhagic stroke (letter). N Eng J Med 2001; 344:1094.
    33) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    34) Fallis RJ & Fisher M: Cerebral vasculitis and hemorrhage associated with phenylpropanolamine. Neurology 1985; 35:405-407.
    35) Favreau JT, Ryu ML, & Braunstein G: Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136:590-595.
    36) Forman HP, Levin S, & Stewart B: Cerebral vasculitis and hemorrhage in an adolescent taking diet pills containing phenylpropanolamine: case report and review of literature. Pediatrics 1989; 83:737-741.
    37) Frejaville PJ, Bismuth C & Conso F: Toxicologie Clinique, 3rd ed. Flamarrion Medecine-Sciences, 1981.
    38) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
    39) Gibson GJ & Warrel DA: Hypertensive crisis and phenylpropanolamine. Lancet 1972; 2:492-493.
    40) Gibson RG, Oliver JA, & Leak D: Nifedipine therapy of phenylpropanolamine-induced hypertension. Am Heart J 1987; 113:406-407.
    41) Glick R, Hoying J, & Cerullo L: Phenylpropanolamine: an over-the-counter drug causing central nervous system vasculitis and intracerebral hemorrhage. Neurosurgery 1987; 20:969-974.
    42) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    43) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    44) Grinstead GF: Ranitidine and high concentrations of phenylpropanolamine cross react in the EMIT/monoclonal amphetamine/methamphetamine assay. Clin Chem 1989; 35:1998-1999.
    45) 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.
    46) Hamilton RS & Sharieff G: Phenylpropanolamine-associated intracranial hemorrhage in an infant (letter). Amer J Emerg Med 2000; 18:343-345.
    47) Hampel G, Horstkotte H, & Rumpf KW: Myoglobinuric renal failure due to drug-induced rhabdomyolysis. Human Toxicol 1983; 2:197-203.
    48) Hantsch C, Meredith T, & Seger D: Sympathomimetic overdose and pregnancy-related hypertension (abstract). J Toxicol Clin Toxicol 1997; 35:499-500.
    49) Hanzlick R: National association of medical examiners pediatric toxicology registry report 2: phenylpropanolamine update. Am J Forens Med Pathol 1993; 14:268-269.
    50) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    51) Harrison WM, McGrath PJ, & Stewart JW: MAOIs and hypertensive crises: the role of OTC drugs. J Clin Psychiatry 1989; 50:64-65.
    52) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    53) Horowitz JD, Lang WJ, Howes LG, et al: Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lancet 1980; 1(8159):60-61.
    54) Horowitz JD, McNeil JJ, & Sweet B: Hypertension and postural hypotension induced by phenylpropanolamine (Trimolets). Med J Aust 1979; 1:175-176.
    55) Howrie DL & Wolfson JH: Phenylpropanolamine-induced hypertensive seizures. J Pediatr 1983; 102:143-145.
    56) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    57) Ilbawi MN, Idriss FS, DeLeon SY, et al: Hemodynamic effects of intravenous nitroglycerin in pediatric patients after heart surgery. Circulation 1985; 72(3 Pt 2):II101-II107.
    58) Johnson DA, Etter HS, & Reeves DM: Stroke and phenylpropanolamine use (letter). Lancet 1983; 2:970.
    59) Jordan J, Shannon JR, Diedrich A, et al: Water potentiates the pressor effect of ephedra alkaloids. Circulation 2004; 109:1823-1825.
    60) Kase CS, Foster TE, & Reed JE: Intracerebral hemorrhage and phenylpropanolamine use. Neurology 1987; 37:399-404.
    61) Kernan WN, Viscoli CM, & Brass LM: Phenylpropanolamine and the risk of hemorrhagic stroke. N Eng J Med 2000; 343:1826-1832.
    62) Khurana V, de la Fuente M, & Bradley TP: Hypertensive crisis secondary to phenylpropanolamine interacting with triple-drug therapy for HIV prophylaxis. Am J Med 1999; 106:118-119.
    63) King WD, Kohaut EC, & Palmisano PA: Phenylpropanolamine toxicity. The Children's Hospital of Alabama Poison Information Bulletin 1988; 17:1-2.
    64) 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.
    65) Koch-Weser J: Hypertensive emergencies. N Engl J Med 1974; 290:211.
    66) Laitinen P, Happonen JM, Sairanen H, et al: Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth 1997; 11(7):870-874.
    67) Lake CR, Caloga G, & Clymer R: A double dose of phenylpropanolamine causes transient hypertension. Am J Med 1988; 85:339-343.
    68) Lake CR, Gallant S, & Masson E: Adverse drug effects attributed to phenylpropanolamine: a review of 142 case reports. Am J Med 1990; 89:195-208.
    69) Lake CR, Masson EB, & Quirk RS: Psychiatric side effects attributed to phenylpropanolamine. Pharmacopsychiatry 1988a; 21:171-181.
    70) Lake CR, Zaloga G, & Bray J: Transient hypertension after two phenylpropanolamine diet aids and the effects of caffeine: a placebo-controlled followup study. Am J Med 1989; 86:427-432.
    71) Larson WL & Rogers A: Overdosage from phenylpropanolamine: Experience of the Hennepin Regional Poison Center. Vet Hum Toxicol 1986; 28:546-548.
    72) Le Coz P, Woimant F, & Rougemont D: Angiopathies cerebrales benignes et phenylpropanolamine. Rev Neurol 1988; 144:295-300.
    73) Lee KY, Vandongen R, & Beilin LJ: Severe hypertension after ingestion of an appetite supressant (phenylpropanolamine) with indomethacin. Lancet 1979; 2:1110-1111.
    74) Lewis-Younger C, Horowitz Z, & Mak R: Elimination of pnehylpropanolamine in peritoneal dialysis (abstract). J Toxicol Clin Toxicol 2001; 39:509-510.
    75) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    76) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    77) Logie AW & Scott CM: Fatal overdosage of phenylpropanolamine. Br Med J 1984; 289:591.
    78) Maertens P, Lum G, & Williams JP: Intracranial hemorrhage and cerebral angiopathic changes in a suicidal phenylpropanolamine poisoning. South Med J 1987; 80:1584-1586.
    79) Maher LM: Postpartum intracranial hemorrhage and phenylpropanolamine use. Neurology 1987; 37:1686.
    80) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    81) Marshall RD & Douglas CJ: Phenylpropanolamine-induced psychosis. Potential predisposing factors. Gen Hosp Psychiatry 1994; 16:358-360.
    82) McDowell JR & LeBlanc HJ: Phenylpropanolamine and cerebral hemorrhage. West J Med 1985; 142:688-691.
    83) McLaren EH: Severe hypertension produced by interaction of phenylpropanolamine with methyldopa and oxprenolol. Br Med J 1976; 2:283-284.
    84) McMillian WD, Trombley BJ, Charash WE, et al: Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm 2011; 68(2):130-134.
    85) Mesnard B & Ginn DR: Excessive phenylpropanolamine ingestion followed by subarachnoid hemorrhage (letter). South Med J 1984; 77:939.
    86) Mueller SM: Phenylpropanolamine, a non-prescription drug with potentially fatal side effects. N Engl J Med 1983; 308:653.
    87) Nam YT, Shin T, & Yoshitake J: Induced hypotension for surgical repair of congenital dislocation of the hip in children. J Anesth 1989; 3(1):58-64.
    88) Napolez A & Lauth W: Drug-induced urinary retention (letter). Ann Emerg Med 1988; 17:1367.
    89) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    90) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    91) Norvenius G, Widerlov E, & Lonnerholm G: Phenylpropanolamine and mental disturbances (letter). Lancet 1979; 2:1367-1368.
    92) Nozoe M, Namera A, Kohriyama K, et al: Over-the-counter medication and acute life-threatening myocardial damage. Int J Cardiol 2005; 102(3):545-547.
    93) O'Connell MB, Pentel PR, & Zimmerman CL: Individual variability in the blood pressure response to intravenous phenylpropanolamine: A pharmacokinetic and pharmacodynamic investigation. Clin Pharmacol Ther 1989; 45:252-259.
    94) Orson J & Bassow L: Over-the-counter cough formulas. Clin Pediatr 1987; 287.
    95) Patterson FK: Delayed fatal outcome after possible Ru-Tuss(R) overdose. J Forensic Sci 1980; 25:349-352.
    96) Pentel P: Toxicity of over-the-counter stimulants. JAMA 1984; 2:1898-1903.
    97) Pentel PR, Asinger RW, & Benowitz NL: Propranolol antagonism of phenylpropanolamine-induced hypertension. Clin Pharmacol Ther 1985; 37:488-494.
    98) Pentel PR, Mikell FL, & Zavoral JH: Myocardial injury after phenylpropanolamine ingestion. Br Heart J 1982; 47:51-54.
    99) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    100) Product Information: BREVIBLOC(TM) intravenous injection, esmolol HCl intravenous injection. Baxter Healthcare Corporation (per FDA), Deerfield, IL, 2012.
    101) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    102) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    103) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    104) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    105) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    106) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    107) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    108) RI Horwitz: Phenylpropanolamine & risk of hemorrhagic stroke: final report of the Hemorrhagic Stroke Project. U.S. Food and Drug Administration. Rockville, MD, USA. 2000. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3647b1_tab19.doc. As accessed Accessed November 13, 2000.
    109) Rasch DK & Lancaster L: Successful use of nitroglycerin to treat postoperative pulmonary hypertension. Crit Care Med 1987; 15(6):616-617.
    110) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    111) Rhoney D & Peacock WF: Intravenous therapy for hypertensive emergencies, part 1. Am J Health Syst Pharm 2009; 66(15):1343-1352.
    112) Richter KP & Ling GV: Clinical response and urethral pressure profile changes after phenylpropanolamine in dogs with primary sphincter incompetence. J Am Vet Med Assoc 1985; 187:605-610.
    113) Rumpf KW, Kaiser HF, & Horstkotte H: Rhabdomyolysis after ingestion of an appetite suppressant. JAMA 1983; 250:2112.
    114) 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.
    115) Singh D, Akingbola O, Yosypiv I, et al: Emergency management of hypertension in children. Int J Nephrol 2012; 2012:420247.
    116) Sloan MA, Kittner SJ, & Rigamonti D: Occurrence of stroke associated with use/abuse of drugs. Neurology 1991; 41:1358-1364.
    117) Smookler S & Bermudez AJ: Hypertensive crisis resulting from an MAO inhibitor and an over-the-counter appetite suppressant. Ann Emerg Med 1982; 11(a):482-484.
    118) Speer F: Allergy to phenylpropanolamine. Ann Allergy 1978; 40:32.
    119) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    120) 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.
    121) Swenson RD, Golper TA, & Bennett WM: Acute renal failure and rhabdomyolysis after ingestion of phenylpropanolamine-containing diet pills. JAMA 1982; 248:1216.
    122) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    123) Theil A & Dressler D: Dyskinesias possibly induced by norpseudoephedrine. J Neurol 1994; 241:167-169.
    124) Traynelis VC & Brick JF: Phenylpropanolamine and vasospasm. Neurology 1986; 36:593.
    125) U.S. Department of Health and Human Services; National Institutes of Health; and National Heart, Lung, and Blood Institute: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. U.S. Department of Health and Human Services. Washington, DC. 2004. Available from URL: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. As accessed 2012-06-20.
    126) USPDI: Drug Information for the Health Care Professional, 19th ed, US Pharmacopeial Convention, Inc, Rockville, MD, 1999.
    127) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    128) Walker JS: Phenylpropanolamine potentiates caffeine neurotoxicity in rats. J Pharm Sci 1989; 78:986-989.
    129) Weesner KM, Denison M, & Roberts RJ: Cardiac arrhythmias in an adolescent following ingestion of an over-the-counter stimulant. Clin Pediatr 1982; 21:700-701.
    130) Werler MM, Mitchell AA, & Shapiro S: First trimester maternal medication use in relation to gastroschisis. Teratology 1992; 45:361-367.
    131) Wolowich WR, Casavant MJ, & Ekins BR: Phenylpropanolamine and hemorrhagic stroke (letter). N Eng J Med 2001; 344:1094-1095.
    132) Woo OF, Benowitz NL, & Bialy FW: Atrioventricular conduction block caused by phenylpropanolamine. JAMA 1985; 253:2646-2647.
    133) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.