SYMPATHOMIMETICS, ORAL

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

1) Direct-acting agents are those that bind directly to alpha- or beta-adrenergic receptors. Most of these do not cross into the CNS in significant quantities.
2) Indirect-acting agents are those that cause the release of cytoplasmic NE from the nerve ending in the absence of vesicle exocytosis. Amphetamines are the prototype of this class. Overdose with amphetamines may be managed using the specific management.

Specific Substances

1) Clenbuterol
2) Epinephrine
3) Isoetharine
4) Isoproterenol
5) Metaproterenol
6) Norepinephrine
7) Reproterol Hydrochloride
8) Ritodrine
9) Terbutaline

1) Epinephrine
2) Methoxamine
3) Phenylephrine

1) Amphetamines
2) Cocaine
3) Fenfluramine
4) Pemoline
5) Phencyclidine
6) Phendimetrazine
7) Phenmetrazine
8) Propylhexedrine
9) Tyramine

1) Ephedrine
2) Ibopamine
3) Mephentermine
4) Phenylpropanolamine
5) Synephrine (Citrus aurantium or bitter orange)

1) 1,3-Dimethylethylamine (DMAA)

Available Forms Sources

1) Some of the more common sympathomimetics include ephedrine, phenylpropanolamine, phenylephrine, pseudoephedrine, metaproterenol (orciprenaline), albuterol (salbutamol), terbutaline, and isometheptene mucate.
2) Peripheral vasodilators with sympathomimetic effects include buphenine HCl, isoxsuprine, voxsuprine, isoetharine, pirbuterol, and bitolterol mesylate.
3) Ephedrine alkaloids, amphetamine-like compounds, have become popular as diet aids and stimulants, having strong stimulant effects on the central nervous system and heart. These agents are in dietary supplements and are derived from one of several species of herbs of the genus Ephedra, also known as Ma huang, Chinese Ephedra and epitonin. Sida cordifolia is another botanical source of ephedrine. The FDA is proposing legislation to limit the amount of ephedrine in dietary supplements (HHS News, 1997).

a) Gurley et al (2000) reported inconsistencies in the content versus label claims in ephedra-containing dietary supplements. Among 20 different ephedra-containing supplements, total alkaloid content ranged from 0.0 to 18.5 mg per dosage unit. For one product, lot-to-lot variation was reported which ranged from 180% to 1000% above the stated alkaloid contents.

4) Expensive, illegal psychostimulants, including cocaine or amphetamine, have been adulterated or substituted with the less expensive sympathomimetics, including ephedrine powder. The clinician should be aware in overdose cases of suspected cocaine or amphetamine, that ephedrine may have been substituted (Cockings & Brown, 1997).
5) CLENBUTEROL: A long acting beta-2 adrenoreceptor agonist, has been used illicitly in livestock feedings for its anabolic effects on muscle mass and body fat (Salleras et al, 1995; Hoffman et al, 2000; Mitchell & Dunnavan, 1998; Chan, 1999). Following ingestion of meat from these animals, there have been reports from Spain, Portugal, France, and Italy, of the occurrence of clinical effects in humans, including tremors, tachycardia, headaches, nausea and dizziness (Barbosa et al, 2005; Brambilla et al, 2000; Sporano et al, 1998; Brambilla et al, 1997; Maistro et al, 1995; Salleras et al, 1995a; Pulce et al, 1991). Bodybuilders have also used clenbuterol, illegally, for the purpose of increasing muscle mass and decreasing body fat (Hoffman et al, 2000).
6) The United States FDA is requesting all drug companies to discontinue marketing products containing phenylpropanolamine due to reports of increased risk of hemorrhagic stroke in patients using these products ((Anon, 2000)).
7) "LOOK-ALIKE" PRODUCTS: Caffeine was formerly available in combination with phenylpropanolamine and ephedrine in formulations designed to mimic controlled stimulants. In November, 1983 the FDA declared that caffeine alone may be marketed and labeled as a stimulant. Other oral sympathomimetics may not be labeled as stimulants.
8) SUSTAINED-RELEASE: Several sustained-release preparations containing phenylpropanolamine have been available.
9) DIETARY SUPPLEMENTS

a) On December 2003, the United States FDA announced plans to prohibit sales of dietary supplements containing ephedra (also known as Ma huang). The FDA has notified manufacturers that it plans to publish a final rule stating that dietary supplements containing ephedra present an unreasonable risk of illness or injury (Anon, 2003).

10) DMAA

a) SUMMARY

1) 1,3-DIMETHYLETHYLAMINE: It is also known as methylhexanamine, methylhexaneamine, 2-amino-4-methylhexane, 4-methyl-2-hexylamine, and 1,3-dimethylpentylamine and trade names Geranamine and Floradrene. It was originally created as a nasal decongestant called Forthane. It is a small molecule that shares structural similarity to amphetamines (Gee et al, 2012).
2) A single study alleges that DMAA can be isolated from the geranium plant and from geranium oil, although the methods used in this study are not described; however, this could not be confirmed in a number of other studies (Cohen, 2012).
3) Animal studies confirm DMAA's sympathomimetic properties; however, there is very little human pharmacologic data. In Ireland and New Zealand, it is sold as a legal recreational drug. The pills are often combined with caffeine (Gee et al, 2012).

a) Supplements that contain DMAA have been associated with several serious events including seizures, panic attacks and two fatalities. In several small trials, an increase in heart rate and blood pressure have also been observed with DMAA use (Cohen, 2012). There have also been several reports of cerebral hemorrhage following recreational use and reports of DMAA-induced cardiomyopathy (Gee et al, 2012; Cohen, 2012).

b) DMAA WITHDRAWN IN SEVERAL MARKETS

1) In Canada, DMAA has been banned from any dietary supplements as of 2011. In late 2011, the US military has also withdrawn the sale of any DMAA containing supplements (eg, Jack3d, OxyElite Pro, Nitric Blast, Code Red, Arson Fat Burner Capsule and HydroxyStim) (Cohen, 2012).

c) FDA WARNING

1) In April 2012, the US Food and Drug Administration has sent warning letters to some manufacturers and distributors of dietary supplements containing dimethylamylamine (DMAA) to provide evidence of product safety (Cohen, 2012).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Oral sympathomimetics are used as decongestants, weight loss agents, bronchodilators, anabolic bodybuilding agents, aphrodisiacs, mood stimulants, and to stay awake.
B) PHARMACOLOGY: Clinical effect is achieved by direct binding at beta and alpha-adrenergic receptors or by indirectly causing an increase of norepinephrine or dopamine (catecholamines) at the neural junction.
C) TOXICOLOGY: Direct receptor binding or catecholamine increase leads to a hyperadrenergic physiologic state.
D) EPIDEMIOLOGY: Toxicity is common due to the large number of agents with sympathomimetic activity. Severe poisoning is uncommon.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Adverse effects from oral sympathomimetics are common. The most common effects are hypertension, palpitations, nausea, and restlessness.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Most patients will experience tachycardia, hypertension, mydriasis, insomnia, headache, and agitation.
2) SEVERE TOXICITY: Large overdoses and severe toxicity may lead to seizures, hallucinations, agitated delirium, and tachydysrhythmias including supraventricular tachycardia and ventricular tachycardia. Vasospasm can lead to myocardial ischemia or focal cerebrovascular deficits. Severe hypertension may also result in intracranial hemorrhage or renal insufficiency. Reflex bradycardia due to significant hypertension is possible. Prolonged agitation can lead to rhabdomyolysis and hyperthermia. 1,3 DIMETHYLAMYLAMINE: Cerebral hemorrhage has been reported in several cases of recreational use of 1,3-dimethylethylamine (DMAA). CLENBUTEROL: The beta-2 agonists (clenbuterol) can cause significant electrolyte abnormalities including hypokalemia.

0.2.3)

A) Hypertension may occur, accompanied by tachycardia may occur.
B) Bradycardia has been reported following overdoses of phenylpropanolamine and as a late presentation following norepinephrine depletion.
C) Increased temperature may occur.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Cardiac dysrhythmias, tachycardia, precordial pain, and increased blood pressure may occur. Bradycardia may occur as a late presentation following profound depletion of norepinephrine.
2) Hypertensive crisis, cerebral hemorrhage, and myocardial ischemia and infarction may develop following acute ingestion of pseudoephedrine, PPA, phenylephrine, amphetamine, dexamphetamine, and methamphetamine.

0.2.6)

A) Sympathomimetics may cause hyperventilation. Bronchodilation may occur. Pulmonary edema may occur in massive overdoses.

0.2.7)

A) Anxiety, nervousness, insomnia, muscle tremor, headache, seizures, altered mental status and cerebral hemorrhage and ischemia may be noted.
B) Toxic psychosis may develop following acute overdoses or abuse of sympathomimetics.

0.2.8)

A) Anorexia, nausea and vomiting may occur following overdose.

0.2.10)

A) Acute renal failure, acute tubular necrosis and rhabdomyolysis may occur.
B) Chronic ephedra use may result in nephrolithiasis.

0.2.12)

A) Hypokalemia may occur. Volume depletion may occur.

0.2.13)

A) Leukocytosis has been reported following overdoses.

0.2.15)

A) Rhabdomyolysis has been reported following acute overdoses, and may result in acute tubular necrosis and acute renal failure.

0.2.16)

A) Hyperglycemia has been reported as an overdose effect.

0.2.19)

A) Allergic reactions, including anaphylaxis, have been reported following ingestions of sympathomimetics.

0.2.20)

A) Beta sympathomimetic drugs appear to cross the placenta. Albuterol, isoxsuprine, metaproterenol, and rivaroxaban are classified as FDA pregnancy category C. Terbutaline is classified as FDA pregnancy category B. Ephedrine, isoetharine, nylidrin, phenylephedrine, phenylpropanolamine, and pseudoephedrine are considered a risk category of C during pregnancy. According to a case series, cord serum insulin concentration was significantly higher in the treated group of 18 preterm infants whose mothers received beta sympathomimetic therapy (17 received salbutamol and one received terbutaline) for labor sedation compared with the 21 women who did receive sympathomimetic treatment.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Simple symptomatic care is all that is required in the vast majority of overdoses. Hydration and benzodiazepines may be used as needed for agitation and mild vital sign abnormalities.

B) MANAGEMENT OF SEVERE TOXICITY

1) VITAL SIGNS: Fluid resuscitation should be the first-line treatment for hypotension. Hyperthermia should be treated with benzodiazepines, cooled fluids, and external cooling measures if mild, however, for temperatures over 40 degrees Celsius, intubation and paralysis is recommended.
2) CARDIOVASCULAR: Antihypertensives can be used for severely elevated blood pressure associated with end organ effects such as myocardial ischemia or cerebrovascular ischemia. In the hypertensive tachycardic patient, one should avoid using beta-blockers in isolation due to the possibility of unopposed alpha effects worsening vasospastic ischemia. Nicardipine or labetalol are good antihypertensive choices because they have effects on both heart rate and blood pressure. Treat ventricular dysrhythmias with lidocaine or amiodarone, and cardioversion if hemodynamically unstable.
3) NEUROLOGIC: Large doses of benzodiazepines may be needed to control profound agitation and seizures. If benzodiazepines are ineffective, propofol or phenobarbital can be used to control the symptoms. Management of cerebrovascular hemorrhage should focus on blood pressure control and airway management as appropriate.
4) RENAL: Fluid resuscitation is the key to maintaining urine output. Acidosis can be treated with normal saline (and sedation to control agitation) until euvolemia is achieved, followed by bicarbonate for persistent severe acidosis.
5) MUSCULOSKELETAL: Sedation to control agitation; fluid resuscitation and maintenance of urine output will limit progression of rhabdomyolysis.

C) DECONTAMINATION

1) PREHOSPITAL: Generally not recommended due to the possibility for seizures in moderate to severe toxicity.
2) HOSPITAL: Administer activated charcoal to patients with recent significant overdose. Do not administer activated charcoal to patients that have a declining mental status, severe toxicity, or those that are at risk for seizures without first protecting the airway.

D) AIRWAY MANAGEMENT

1) Altered mental status, pulmonary edema, or profound agitation with resultant hyperthermia and acidosis are all indications for active airway management.

E) ANTIDOTE

1) None

F) ENHANCED ELIMINATION

1) There is little data to support hemodialysis for oral sympathomimetics, and symptomatic management is almost always sufficient.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Mild restlessness and insomnia can be managed at home if the exposure is inadvertent and medication is withdrawn.
2) OBSERVATION CRITERIA: Patients with mild tachycardia, hypertension, and agitation can be treated with benzodiazepines and observed until symptoms and vital signs normalize.
3) ADMISSION CRITERIA: Patients with moderate to severe toxicity should be admitted until symptoms have improved. Seizures, delirium, cardiac dysrhythmias, cardiac or cerebral ischemia, rhabdomyolysis or persistently abnormal vital signs are all indications for admission to an intensive care unit.
4) CONSULT CRITERIA: A toxicologist or poison center should be consulted for all patients with severe toxicity or patients that require hospital admission.

H) PITFALLS

1) Under-dosing of benzodiazepines in patients with significant agitation or seizures can lead to complications such as rhabdomyolysis, metabolic acidosis, or status epilepticus. Failure to maintain urine output with adequate hydration can lead to worsening acidosis and renal failure.

I) PHARMACOKINETICS

1) EPHEDRINE: Well absorbed; onset within 1 hour; duration 3 to 5 hours; minimal hepatic metabolism; primarily renally excreted (less renal excretion in alkaline urine); half-life 3 to 6 hours. CLENBUTEROL: Onset within 1 hour; duration 8 to 12 hours; well absorbed; 90% protein bound; slight hepatic metabolism; 30% renal excretion; half-life 25 to 39 hours. PHENYLEPHRINE: Onset within 15 minutes; moderate absorption; volume of distribution more than 40 L; moderate hepatic metabolism; renal elimination; half-life 2 to 3 hours.

J) DIFFERENTIAL DIAGNOSIS

1) Illicit drugs of abuse such as cocaine, amphetamines, or PCP should be considered. If symptoms occur following induction of general anesthesia, malignant hyperthermia must be considered. Neuroleptic malignant syndrome can lead to similar vital sign abnormalities, altered mental status, and muscular rigidity, though a history of temporal exposure to antipsychotics should be elicited. Medical disorders such as thyroid storm, hypertensive emergency, and pheochromocytoma can cause a similar clinical picture.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) ADVERSE EFFECTS: Adverse effects from oral sympathomimetics are common. The most common effects are hypertension, palpitations, nausea, and restlessness.

Vital Signs

3.3.1)

3.3.3)

A) FEVER: Acute overdoses may result in increased temperature due to increased psychomotor activity and alpha-adrenergic agonist effects that prevent vasodilation in response to heat stress. Rectal temperature of 100.9 degrees F was reported following an overdose of 140 mcg clenbuterol (Cortes-Belen et al, 1998).

Heent

3.4.3)

A) MYDRIASIS: Sympathetic stimulation from systemic or ocular exposures to sympathomimetic drugs will usually result in mydriasis.

1) CASE SERIES: Dilated pupils were reported in 4 of 5 salbutamol overdose patients. No mydriasis was reported in 3 terbutaline overdoses (Jarvie et al, 1987).

B) VISUAL LOSS has been reported following therapeutic use.

1) CASE REPORT: Transient blindness due to posterior reversible encephalopathy syndrome (PRES) was reported in a 29-year-old man one week after developing severe hypertension (systolic blood pressure 220 mm Hg) and multi-organ failure after taking a performance-enhancing ephedra-based supplement. Following supportive care and normalization of blood pressure (readmission blood pressure was markedly elevated), vision returned and cognitive depression resolved (Moawad et al, 2006). As in this case, the development of PRES may not occur for up to several weeks after the initial exposure.
2) CASE REPORT: Gilmer et al (1986) reported a case of a 48-year-old woman who took 1 capsule, containing 50 mg PPA and 200 mg caffeine, with a cup of coffee and 1500 mg of aspirin 6 to 8 hours prior to the onset of sudden visual loss. She had a history of controlled hypertension and mitral valve prolapse. A central retinal vein occlusion in the right eye was noted on ophthalmologic exam 13 days later. PPA is the only drug considered related (Gilmer et al, 1986).

C) BLEPHAROCONJUNCTIVITIS was seen after use of phenylephrine eye drops. The reaction was allergic in nature. Onset was 3 to 4 hours post administration and duration was 12 to 72 hours (Geyer et al, 1988).
D) ALLERGIC CONTACT DERMATITIS (erythema, edema, vesicles) occurred after use of phenylephrine eyedrops (Milpied et al, 1988).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) All of these agents have the potential to alter cardiac rhythm. Ephedrine and pseudoephedrine possess both alpha and beta receptor activity which may lead to tachycardia, precordial pain, and increased blood pressure (Mariani, 1986; Snook et al, 1992; Heyman et al, 1991).
b) CASE SERIES: Sinus dysrhythmias were reported in 6 healthy subjects after exercise following oral doses of 120 mg pseudoephedrine but not seen with a smaller 60 mg dose. Blood pressure was not noticeably different in the two groups (Bright et al, 1981).
c) Chronic exposure to meats contaminated with clenbuterol (100 to 200 g of contaminated meats may contain 5 times the therapeutic dosage of 0.8 mcg/kg) may put consumers at risk for adverse cardiac effects. Clenbuterol is heat stable, thus cooking does not affect concentrations in meat. Exact human cardiac effects of repeated clenbuterol exposure are not certain (Chan, 2001).

B) ATRIAL FIBRILLATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Rapid atrial fibrillation unresponsive to cardioversion, along with significant hypotension (78/42 mm Hg), was observed in a 55-year-old adult found unresponsive after heroin use adulterated with clenbuterol. ECG revealed ST elevation in the inferolateral leads with evidence of an acute myocardial infarction. Cardiac catheterization revealed normal coronary arteries and ejection fraction. A post catherization ECG showed a normal ST segment. CPK peaked at 1200 with a troponin-I of 29. Following supportive care, the patient was hemodynamically stable within 24 hours of admission (Bilkoo et al, 2007).
b) CASE REPORT: A 31-year-old male body builder took 1.5 mL of clenbuterol (72.5 mcg/mL) produced as a veterinary agent that was found over the Internet, and developed palpitations and shortness of breath within 30 minutes. An ECG showed an initial supraventricular tachycardia with a rate of 254 bpm; adenosine was found to be ineffective. Esmolol therapy was then started, and the heart rate improved over the next 16 hours (ventricular rate of 125 to 147 bpm). Potassium was 2.1 mmol/L on admission. A toxicology screen was negative for drugs of abuse. On hospital day 3, the patient was electively cardioverted for persistent atrial fibrillation and started on oral metoprolol. He was discharged in normal sinus rhythm and rate on day 4 (Daubert et al, 2007).

C) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Asymptomatic multifocal ventricular premature contractions were noted in a pilot taking 2 tablets, containing pseudoephedrine and triprolidine every 4 hours for several days. The authors attribute this effect to the pseudoephedrine without regard to the antihistamine it contains (Billings et al, 1974).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Peterson & Vasquez (1973) report a case of phenylpropanolamine overdose in a 15-year-old girl who presented to the ED with hypertensive crisis(Peterson & Vasquez, 1973). An ECG revealed frequent premature ventricular contractions and premature atrial contractions together with ventricular and atrial tachycardia.
b) CASE REPORT: Following the ingestion of 4 capsules of "herbal ecstasy" (ephedrine and caffeine), a 21-year-old man presented to the ED with hypertension (190/116 mmHg) and ventricular dysrhythmias (multiple ventricular ectopic beats and later bigeminy). Resolution of symptoms occurred in 9 hours after therapy with lidocaine and nitroprusside (Zahn et al, 1999).
c) CASE REPORT: Three hours after ingesting alcohol and an unknown number of "herbal ecstasy" tablets, an 18-year-old man was admitted to the ED with a ventricular bigeminy at 118/min as seen on ECG, with no ischemic changes. He recovered following symptomatic therapy (Yates et al, 2000).
d) CASE REPORT: A 20-year-old woman developed several episodes of polymorphic ventricular tachycardia that degenerated to ventricular fibrillation (requiring defibrillation) after ingesting approximately 200 diet tablets containing Citrus aurantium (the extract contains synephrine, a synthetic derivative of amphetamine; two capsules contain 325 mg of synephrine) and caffeine over several days. Measurements of serum electrolytes showed hypokalemia and hypomagnesemia. Following supportive treatment, she recovered without further sequelae (Srivatsa et al, 2003).

D) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Albuterol, terbutaline and metaproterenol have also been associated with tachycardia and precordial pain but may produce a decrease in diastolic blood pressure as a result of the selective beta activity which produces peripheral vasodilatation (Blake & Ryan, 1989).
b) CASE REPORT: A 34-year-old man presented to the ED with tachycardia (140 beats/min), hypertension (180/140 mmHg) and hyperventilation following the chronic use of nasal decongestant sprays and cough syrups containing sympathomimetics (Heyman et al, 1991).

2) WITH POISONING/EXPOSURE

a) Clenbuterol, a potent beta-2 agonist, has been reported to cause tachycardia in poisonings (Bilkoo et al, 2007; Cortes-Belen et al, 1998; Maistro et al, 1995; Salleras et al, 1995) and a sustained tachycardia with hypokalemia and hypophosphatemia in one case (Hoffman et al, 2001; Hoffman et al, 2000).
b) Palpitations and tachycardia have rarely been associated with the use of ephedra alkaloids in dietary supplements (Schier et al, 2003; Shekelle et al, 2003; Haller & Benowitz, 2000).
c) 1,3 DIMETHYLAMYLAMINE (DMAA): There have been several small trials that have reported an increase in heart rate and blood pressure following the use of DMAA found in some dietary supplements (Cohen, 2012).
d) CASE SERIES: Six of 12 study participants developed significant increases in heart rate following the ingestion of 4 capsules of powdered ma-huang at hours 8 and 17. Effects on blood pressure were variable. A four capsule dose was reported to contain ephedrine 19.4 mg, pseudoephedrine 4.9 mg and methylephedrine 1.2 mg (White et al, 1997).

E) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Massive overdoses of sympathomimetics may result in initial tachycardias followed by bradycardia, heart block, and eventually asystole. Bradycardia is a result of profound depletion of norepinephrine from peripheral sympathetic nerves and may be a late presentation (Hessler, 1998).
b) Hessler (1998) reports bradycardia as a phenylpropanolamine overdose effect . Phenylpropanolamine has been reported to cause bradycardia with second degree atrioventricular block (Wenckebach type) in two patients (Woo et al, 1985).

F) HYPERTENSIVE EPISODE

1) SUMMARY

a) DIRECT AND INDIRECT SYMPATHOMIMETICS: Direct (phenylephrine) and indirect sympathomimetic drugs, may cause hypertension in overdoses. Phenylephrine and especially phenylpropanolamine have a propensity to produce significant hypertension due to increased peripheral vascular resistance (Cantu et al, 2003; Bravo, 1988; Howrie & Wolfson, 1983; Horowitz et al, 1979), and resultant reflex bradycardia (Fredriksen, 1982), extensive myocardial ischemia, cerebral hemorrhage ((Anon, 2000)) or renal toxicity.
b) PHENYLPROPANOLAMINE: The hypertension seen with phenylpropanolamine is more severe when the patient is supine (Horowitz et al, 1980).
c) NASAL DECONGESTANTS: Hypertensive crises have been seen with chronic use of nasal decongestants (phenylephrine, ephedrine, oxymetazoline) (Heyman et al, 1991). Hypertensive crisis has been reported following the use of "herbal ecstasy" (Yates et al, 2000).
d) 1,3 DIMETHYLAMYLAMINE (DMAA): There have been several small trials that have reported an increase in heart rate and blood pressure following the use of DMAA found in some dietary supplements (Cohen, 2012).

2) CASE REPORTS

a) CASE REPORT: Mariani (1986) reports the case of a 23-year-old man presenting with hypertensive crisis (200/160 mmHg) following the ingestion of 840 mg pseudoephedrine. His blood pressure improved following 2 doses of IV labetalol (Mariani, 1986).
b) Ephedrine alkaloids may cause cardiovascular stimulation and hypertension. Cases of hypertension have been reported following use of ephedrine in diet aids, through the FDA Medwatch program (Shekelle et al, 2003; HHS, 1997). Hypertension was the single most frequent cardiovascular effect reported following the use of ephedra alkaloids (Haller & Benowitz, 2000), however, some of these patients had conditions predisposing to hypertension (Hutchins, 2001).

G) HYPOTENSIVE EPISODE

1) Phenylpropanolamine, which is both a direct and indirect acting sympathomimetic, may cause a transient hypertension followed by hypotension. Other indirect acting sympathomimetics may also cause hypotension preceded by hypertension.
2) CLENBUTEROL: Rapid atrial fibrillation unresponsive to cardioversion, along with significant hypotension (78/42 mm Hg), was observed in a 55-year-old adult found unresponsive after heroin use adulterated with clenbuterol. Following supportive care, the patient was hemodynamically stable within 24 hours of admission (Bilkoo et al, 2007).
3) TERBUTALINE: A 33-year-old, 38-week pregnant woman felt dizzy following administration of 0.25 mg terbutaline subcutaneously. Her heart rate increased from 84/minute to 132/minute and blood pressure fell from 130/98 mmHg to a palpable 50 mmHg.

a) She responded to fluid replacement without compromise to the fetus. Altered hemodynamic status of the pregnancy combined with a possible lowering of systemic vascular resistance may have contributed to this effect (Margulies & Kallus, 1986).

4) TERBUTALINE: Lee (1995) reports the case of a 21-year-old woman, who was 26 weeks pregnant, and ingested 10 5-mg terbutaline tablets (Lee, 1995). No other medications were taken. She presented to the ED with a blood pressure of 70/40 mmHg and a pulse of 140. ECG revealed a sinus tachycardia.

a) Decontamination with activated charcoal was administered, and hydration with IV normal saline was given. Hypotension was initially treated with vigorous fluid replacement (4 liters in 2 hours) and IV esmolol was given at a rate of 150 mg/hour and then titrated to pulse and blood pressure which improved. Four hours later her pulse and blood pressure returned to normal.

H) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Myocardial infarction has been reported with these agents.

b) CASE REPORTS/CASE SERIES

1) EPHEDRINE: Seven of 8 fatalities due to ephedrine use were attributed to myocardial infarction or cerebrovascular accident (Shekelle et al, 2003; CDC, 1996).
2) Myocardial infarction has been seen in a patient who received an overdose via instillation of eye drops (Lai, 1989).
3) CLENBUTEROL: Rapid atrial fibrillation unresponsive to cardioversion, along with significant hypotension (78/42 mm Hg), was observed in a 55-year-old adult found unresponsive after heroin use adulterated with clenbuterol. ECG revealed ST elevation in the inferolateral leads with evidence of an acute myocardial infarction. Cardiac catheterization revealed normal coronary arteries and ejection fraction. A post-catherization ECG showed a normal ST segment. CPK peaked at 1200 with a troponin-I of 29. Following supportive care, the patient was hemodynamically stable within 24 hours of admission (Bilkoo et al, 2007).
4) EPHEDRINE: A 25-year-old man presented to the ED 2 hours after injecting himself with a white powder initially believed to be amphetamine, but later discovered to be ephedrine. Cardiogenic shock developed. ECG revealed widespread ST-segment depression with T-wave inversion, diagnosed as subendocardial infarction and ischemia. A technetium Tc 99m perfusion scan verified diffuse myocardial damage and acute posterolateral infarction (Cockings & Brown, 1997).
5) EPHEDRINE: Myocardial infarction has been reported in several patients with minimal or no evidence of artherosclerosis of coronary arteries following the use of dietary supplements (eg; Metabolife 356) containing ephedrine (Enders et al, 2003; Traub et al, 2001; CDC, 1996).
6) EPHEDRINE: A previously healthy 35-year-old woman experienced a myocardial infarction following approximately 30 days use of a daily dietary supplement containing ephedrine for weight loss. She had no history of cardiovascular risk factors and had normal coronary arteries on catheterization. No additional cardiac symptoms were reported after discontinuing the ephedrine product (CDC, 1996).
7) EPHEDRA: A previously healthy 19-year-old man developed myocardial infarction (evidenced on ECG, CK-MB, and echocardiography) following the labeled recommended dose (2 tablets) of a dietary supplement containing ephedra alkaloids and caffeine (24 mg and 100 mg per tablet, respectively). Cardiac catheterization showed minimal initial disease of the LAD artery. The patient recovered following therapy with oxygen, aspirin, heparin, nitroglycerin, phentolamine and labetalol (Traub et al, 2001).
8) MA HUANG: A 30-year-old man developed Ma Huang-induced myocardial infarction with normal coronary arteries following the acute ingestion of 4 tablets (considered a normal dose per product label). The patient had no underlying heart disease. Following symptomatic therapy, the patient recovered and was discharge on day 3 (Sharma et al, 2000).
9) PHENYLPROPANOLAMINE: Myocardial injury, including transient increases in creatine kinase and MB isoenzyme fractions and ST depressions were reported in 3 patients following overdoses of phenylpropanolamine (Pentel et al, 1982).

I) ACUTE ISCHEMIC HEART DISEASE

1) Sympathomimetics, most notably ephedra, cocaine, and phenylpropanolamine, may cause hypersensitivity or eosinophilic myocarditis following chronic use or abuse of these agents (Leikin & Klein, 2000; Zaacks et al, 1999). Improvement of symptoms generally occurs on withdrawal of the drug and symptomatic therapy.

a) The FDA has reported clinical summaries of 24 cases of documented myocardial ischemia, including 13 fatalities, following abuse of ephedrine (Theoharides, 1999).

2) CASE REPORT: Theoharides (1997) reported sudden death in a 23-year-old man following chronic use (6 months) of a food supplement containing Ma Huang extract equivalent to 25 mg ephedrine and 15 mg caffeine per teaspoonful (Theoharides, 1997). Necropsy revealed large vascular obstructions resulting in myocardial damage. It was suggested that ongoing insults may have resulted in vasoconstriction of small arterial vessels and myocyte toxicity. Karch (1999) suggests a contributory role of caffeine or phenylpropanolamine to the cardiomyopathy seen in this case (Karch, 1999).

J) CORONARY ARTERY THROMBOSIS

1) CASE REPORT: Acute coronary artery thrombosis was reported as the cause of death in a 44-year-old man, with no known cardiovascular risk factors, following 3 weeks of daily ephedrine use (CDC, 1996).

K) CYANOSIS

1) CASE REPORT: A 3-week-old neonate under halothane anesthesia experienced cardiovascular depression, including cyanosis, hypotension, ST depression, and bradycardia after administration of phenylephrine eyedrops. The patient recovered after stopping anesthesia and administration of 100% oxygen. The role of both halothane and phenylephrine must be considered in this adverse event (Van der Spek, 1987).

L) CHEST PAIN

1) CASE SERIES: In a prospective study using a convenience sample of adolescents presenting to the ED with chief complaint of chest pain, 5 out of 28 cases had urine tests with confirmed presence of ephedrine. None of the cases had reported ephedrine use on a patient questionnaire. Only one case had an ECG performed, which revealed right ventricular conduction delay (James et al, 1997).

M) ISCHEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 22-year-old woman developed nausea and vomiting, tremulousness, abdominal pain and tachycardia (pulse 133 bpm) after ingesting two Xenadrine(R) tablets (ephedrine 10 mg and caffeine 100 mg in each tablet) in the morning and three in the afternoon (instead of 2 tablets twice a day). Approximately 8 hours after the last dose of ephedrine, serum ephedrine level was 150 ng/mL which is approximately twice the level expected with therapeutic use (Costello et al, 1975). The ECG showed a sinus rhythm at 92 bpm with 1 mm of ST segment depression in leads V3 and V4 and T waves inversions in leads V1-V4. Serial serum troponins were negative. An echocardiogram revealed only trace tricuspid regurgitation. Following supportive care, she recovered completely (Schier et al, 2003).

N) CARDIOMYOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 47-year-old man developed congestive heart failure and a dilated cardiomyopathy following the ingestion of dietary supplement, containing ephedrine and caffeine for 12 months (80 mg of ephedrine daily). On presentation to the hospital, he experienced fatigue and paroxysmal nocturnal dyspnea; bibasilar rales and an S3 gallop were noted during examination. Chest x-ray revealed cardiomegaly and interstitial pulmonary edema and ECG showed left atrial enlargement and poor R-wave progression. An ejection fraction of 20% to 25% was observed on an echocardiogram. After 3 days of drug therapy, a cardiac catheterization revealed an ejection fraction of 15%. Following supportive care, his symptoms resolved. His ejection fraction was 45 to 50% seven months after the supplement was discontinued (Tarabar et al, 2003). It is unclear if ephedrine was the direct cause of the cardiomyopathy.

Respiratory

3.6.1)

A) Sympathomimetics may cause hyperventilation. Bronchodilation may occur. Pulmonary edema may occur in massive overdoses.

3.6.2)

A) HYPERVENTILATION

1) Sympathomimetics may cause an increase in respiratory drive, an increase in oxygen consumption, and thus hyperventilation (Hessler, 1998).

B) ACUTE LUNG INJURY

1) Sympathomimetic stimulants may cause a neurogenic pulmonary edema due to massive catecholamine discharge in overdoses.
2) CASE REPORT: A 25-year-old man presented to the ED with cardiogenic shock and pulmonary edema, shown as bilateral "bat's wing" opacification on chest x-ray, after injecting himself intravenously with a white powder later identified as ephedrine. The patient recovered and was discharged 9 days later following symptomatic treatment (Cockings & Brown, 1997).

Neurologic

3.7.1)

3.7.2)

A) SEIZURE

1) TERBUTALINE

a) CASE REPORT: A 7-year-old girl with asthma developed left-sided focal seizures, right-sided seizures and generalized seizures on four separate occasions 1 to 2 hours following the ingestion of 5 to 7.5 mg terbutaline sulfate (Friedman et al, 1982).

2) PHENYLPROPANOLAMINE

a) CASE REPORT: PPA-induced hypertensive seizures have been reported. A 13-year-old girl ingested a time-released diet capsule (75 mg PPA and 200 mg caffeine) daily for 2 weeks. She developed hypertension (BP 210/100 mmHg) and seizures on the morning following the ingestion of 2 time-released diet capsules (Howrie & Wolfson, 1983).
b) Seizures, cerebral hemorrhage (and resultant altered mental status) and hallucinations have been reported following phenylpropanolamine ingestion. Right-sided hemiparesis after phenylpropanolamine ingestion was reported by Johnson et al (1983).

3) EPHEDRINE

a) Because a significant number of seizures have been reported through the FDA Medwatch system in relation to use of ephedrine containing dietary aids, new regulations may be issued to restrict the amount of ephedrine in diet aids (HHS, 1997). Haller & Benowitz (2000) reported 7 FDA Medwatch reports of seizures out of 140 ephedra-related adverse event reports from June 1997 through March 1999. Other studies have documented an increased incidence of seizures associated with ephedrine use (Shekelle et al, 2003; Haller & Benowitz, 2000).
b) CASE REPORT: A 38-year-old woman experienced new onset of tonic-clonic seizures with complex partial seizures following the ingestion of 4 tablets of an ephedrine-containing dietary aid within a 5 hour period. Other possible causes for the seizures were ruled out. No further seizure activity was reported after discontinuation of the ephedrine product (CDC, 1996).

4) PSEUDOEPHEDRINE

a) CASE REPORT: A 19-month-old woman was witnessed to suffer a 60-second generalized tonic-clonic seizure (which resolved spontaneously) approximately 2 hours after she ingested an unknown amount of 30 mg tablets (greater than 20 missing) of pseudoephedrine (Clark & Curry, 1990).

5) SYNEPHRINE

a) CASE REPORT: One patient developed seizures and intractable ventricular fibrillation after the overdose of diet pills containing Citrus aurantium (the extract contains synephrine, a synthetic derivative of amphetamine; two capsules contain 325 mg of synephrine) and caffeine (Srivatsa et al, 2003).

B) CEREBRAL HEMORRHAGE

1) SUMMARY: Cerebral hemorrhage has been reported (Cantu et al, 2003). Anecdotal reports of associated SIDE EFFECTS can be found associated with both the use and abuse of amphetamines, phenylpropanolamine, and other sympathomimetics.
2) PHENYLPROPANOLAMINE

a) SUMMARY: Due to reports of increased risk of hemorrhagic stroke with phenylpropanolamine use, the United States FDA is requesting drug companies to discontinue marketing of products containing phenylpropanolamine ((Anon, 2000)).
b) CASE REPORT: Jackson et al (1985) reported a case of fatal intracranial hemorrhage associated with PPA, pentazocine and tripelennamine overdose. Over the 6 hours prior to admission, the patient and his wife had shared five sets of "T's and Blues", a combination of 50 mg pentazocine and 50 mg tripelennamine crushed and injected intravenously. Within 30 minutes of the last set, the patient vomited and complained of right-hand pain and numbness. He became unresponsive shortly thereafter. Neuroimaging identified a large intracranial hemorrhage and the patient did not recover. This patient had a long history of regular oral and intravenous drug abuse. The neurologic symptoms leading up to his death appeared over 20 hours after the last oral ingestion of a single extended-release capsule of PPA 75 mg and caffeine 200 mg. The causal association of this finding with PPA use is overwhelmed by the intravenous abuse of other drugs.
c) CASE REPORT: Maher (1987) reported a 3-week postpartum gravida 1 para 1, 30-year-old woman who collapsed 30 minutes after ingesting a single Extra-Strength Dexatrim(R) "tablet". Left hemiplegia, left hemihypesthesia and left homonymous hemianopia were noted. A CT scan showed a large intra-axial hematoma with subarachnoid extension. No other risk factors were demonstrated. Blood pressure on admission was 110/80 and pulse was 80 and regular. The vascular sensitivity following childbirth was not considered a risk factor (Maher, 1987).
d) CASE REPORT: A similar case was reported, involving a 3-week postpartum para 5, 35-year-old woman who developed prominent symptoms of headache, nausea, vomiting, photophobia and extreme fatigue 1 1/2 hours after taking a single Extra-Strength Dexatrim(R) pill. Four days later a diagnosis was made of a frontal intracerebral hematoma and subarachnoid blood. She had a 10-year history of oral contraceptive use, a family history remarkable for stroke and myocardial infarction, and a recent pregnancy which were largely discounted as causal or predisposing (Glick et al, 1987).
e) Intracerebral hemorrhage and angiographic evidence of carotid and vertebral artery vasculitis or vasospasm ("beading") has been reported in 7 patients taking only one 25 to 75 mg dose of phenylpropanolamine (Kase et al, 1987; McDowell & LeBlanc, 1985; Fallis & Fisher, 1985; Traynelis & Brick, 1986; Glick et al, 1987; Maher, 1987).
f) CASE REPORT: Similar findings were reported in a 17-year-old obese girl who ingested 375 mg of PPA (Forman et al, 1989) and in a 27-year-old man who ingested 585 mg of PPA (Maertens et al, 1987).
g) CASE REPORT: 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 (LeCoz et al, 1988).

3) EPHEDRINE

a) CASE REPORT: SUBARACHNOID HEMORRHAGE and cerebral angitis has been reported in a 20-year-old man following the ingestion of ephedrine (Wooten et al, 1983).
b) CASE REPORT: Matthews et al (1997) report a 19-year-old woman who presented to the ED after ingestion of 15 to 18 tablets containing ephedrine 25mg and guaifenesin 100mg along with alcohol. Signs/symptoms included severe headache, right sided paralysis, and marked facial drooping. CT scan showed a large, left parieto-frontal parenchymal hemorrhage extending into the left lateral ventricle. No anatomic reason for the hemorrhage (aneurysm, arteriovenous malformation, etc) was found on angiography or surgical exploration (Matthews et al, 1997).
c) PONTINE HEMORRHAGE was reported following the maximum recommended dose (4 capsules 3 times daily) of Hydroxycut (containing ephedrine) in a 41-year-old man. The patient was taking this as a thermogenic sports nutrition supplement. No other concomitant OTC or prescription drugs were taken. He had taken the supplement for 18 months prior to symptoms of lightheadedness, double vision, and numbness and tingling of the left hand and foot. A small hemorrhage in the central pons was confirmed by an MRI exam. Recovery occurred over several weeks, with sequelae of disconjugate gaze and diplopia (Roberts et al, 2002).

4) PSEUDOEPHEDRINE

a) CASE REPORT: A case report attributing intracranial hemorrhage and segmental narrowing of the major and small branches of the intracranial carotid arteries to an overdose of 1200 mg of PSEUDOEPHEDRINE has been published. Sensory loss and right hemiparesis developed over the 24 hours following admission. She had an admission blood pressure of 120/70 and pulse of 84/min in sinus rhythm. The patient recovered with conservative therapy (Loizou et al, 1982).
b) Carotid angiography showing a "beaded" appearance and areas of segmental narrowing and dilatation has been described in numerous situations including drug abuse alone (Loizou et al, 1982). It is not pathognomonic of any specific drug or drug class nor does it suggest the pharmacologic reasons for the finding.

5) DMAA

a) 1,3-DIMETHYLETHYLAMINE/CASE REPORTS: Cerebral hemorrhage was associated with DMAA, recreational drug use in 3 adults who developed symptoms rapidly, but recovered with no permanent neurologic deficits (Gee et al, 2012).

1) A 23-year-old woman ingested 2 tablets of "Pure X-S" (the main ingredient described as Pelargonium extract 75 mg) and within 30 min developed a severe frontal headache, dizziness and several episodes of vomiting. Upon arrival to the ED, she was agitated, hypertensive (185/100 mmHg) with no focal motor deficits or lateralizing cerebellar signs. A CT showed a subarachnoid hemorrhage extending 23 mm over the right frontal lobe and extending into the underlying sulcus. She improved several days later with no permanent sequelae. A second adult ingested 50 mg of DMAA powder with alcohol and within 60 min developed a severe headache, right hand weakness and feeling unstable on his feet. He did not immediately seek medical care and the following day he awoke with left facial droop and left-sided weakness. A CT showed a right-sided 64 x 27x23 mm intraparenchymal hemorrhage. His symptoms resolved over 2 weeks with nonsurgical care. The last patient, a 41-year-old man collapsed with a severe headache 30 min after ingesting a white powder. At presentation, he was agitated and confused with a blood pressure of 240/120 mmHg; labetalol was given for blood pressure control. A CT showed an 11 x 6 x 3 mm hemorrhage in the left basal ganglia. Neurologic improvement was observed within 24 hours and the patient was discharged within 2 days with no clinical symptoms or neurologic deficits. All 3 patients had laboratory confirmation of DMAA use; no other drugs of abuse were found except for ethanol in one patient and a trace of cannabis in the urine of one patient (Gee et al, 2012).

C) DISORDER OF BRAIN

1) WITH THERAPEUTIC USE

a) POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME

D) CEREBRAL ARTERY OCCLUSION

1) WITH THERAPEUTIC USE

a) CHRONIC PPA USE: Nonhemorrhagic cerebral infarction has been reported following prolonged use of phenylpropanolamine (Cantu et al, 2003; Johnson et al, 1983).
b) ACUTE ON CHRONIC PPA USE: Cerebral infarct was also reported in a woman taking a 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).
c) ISOMETHEPTENE MUCATE/CASE REPORT: Raroque et al (1993) report a case of postpartum cerebral angiopathy in a patient following the ingestion of 8 tablets containing 65 mg isometheptene mucate per tablet for headache within a 24 hour period (Raroque et al, 1993). She experienced photophobia and generalized tonic-clonic seizures. Cerebral angiography 4 days later revealed widespread segmental vasoconstriction. Seizures were treated with phenytoin. Ten days later, a repeat MRI was normal.
d) EPHEDRINE/CASE REPORTS: HHS (1997) has reported cases of strokes through the Medwatch reporting system related to use of ephedrine containing diet aids. Haller & Benowitz (2000) reported 10 FDA Medwatch reports of strokes out of 140 ephedra-related adverse event reports from June 1997 through March 1999; however, some of these patients had conditions predisposing to stroke (Haller & Benowitz, 2000; Hutchins, 2001).
e) EPHEDRINE/CASE REPORT: A 20-year-old woman developed a transient ischemic attack after ingesting 4 tablets of Metabolife 356 (ma huang [containing 12 mg ephedrine], guarana extract [40 mg caffeine], chromium picolinate, and other herbal and vitamins) approximately 30 minutes before the episode. In addition, she ingested 6 to 15 tablets daily for 3 days. On presentation to the hospital, she complained of numbness to her left face, arm, and leg, mild headache, and nausea. Following supportive care, her symptoms resolved within 4 hours and she was discharged home the next day (Lo Vecchio et al, 2005).

E) ANXIETY

1) Nervousness, insomnia, and muscle tremor (most notably of the hands) may occur following ingestion of any of these compounds.

F) TREMOR

1) Tremor has been reported following terbutaline and salbutamol overdose (Heath & Hulten, 1987; Jarvie et al, 1987), pseudoephedrine overdose (Clark & Curry, 1990) and clenbuterol overdose (Bilkoo et al, 2007; Cortes-Belen et al, 1998; Hoffman et al, 2000; Maistro et al, 1995; Salleras et al, 1995).
2) In a meta analysis, the use of ephedrine or ephedra was associated with increased risk of psychiatric, autonomic hyperactivity (eg; tremor, twitching, jitteriness), gastrointestinal symptoms, and heart palpitations (Shekelle et al, 2003).

G) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache has been reported following the use of ephedra or ephedrine (Shekelle et al, 2003).

Gastrointestinal

3.8.1)

A) Anorexia, nausea and vomiting may occur following overdose.

3.8.2)

A) GASTROINTESTINAL COMPLICATION

1) Symptoms may include anorexia, nausea, and vomiting (Snook et al, 1992; Wooten et al, 1983; Glick et al, 1987). Abdominal cramping has been reported following a clenbuterol overdose (Cortes-Belen et al, 1998).
2) In a meta analysis, the use of ephedrine or ephedra was associated with increased risk of psychiatric, autonomic hyperactivity, or gastrointestinal symptoms (eg; nausea, vomiting, abdominal pain), and heart palpitations (Shekelle et al, 2003).

Genitourinary

3.10.1)

A) Acute renal failure, acute tubular necrosis and rhabdomyolysis may occur.
B) Chronic ephedra use may result in nephrolithiasis.

3.10.2)

A) RENAL FAILURE SYNDROME

1) SUMMARY: Acute interstitial nephritis (Lee et al, 1979), acute tubular necrosis (Duffy et al, 1981), and acute renal failure accompanied by rhabdomyolysis have been reported in patients ingesting phenylpropanolamine (Swenson et al, 1982; Rumpf et al, 1983) or terbutaline (Blake & Ryan, 1989).
2) ONSET/DOSE: 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 the other case presented (Swenson et al, 1982).
3) CASE REPORT: Renal failure and rhabdomyolysis were reported in a 22-year-old woman after ingestion of 225 milligrams terbutaline as sustained release tablets (Blake & Ryan, 1989).

B) KIDNEY STONE

1) CASE REPORT: Nephrolithiasis was reported in a 27-year-old man following a 10-month history of Ma-Huang consumption for enhancement of body building. Kidney stone analysis revealed composition to be 95% ephedrine metabolite and 5% protein matrix. The Louis C. Herring and Company kidney stone database has shown this to be a complication of ephedrine with hundreds of previous episodes recorded (Powell et al, 1998).
2) CASE REPORT: Renal calculi were reported in a patient with a history of ingesting large quantities of an over-the-counter stimulant. Kidney stone analysis revealed increased amounts of ephedrine. The patient was treated successfully with alkalinization (Hoffman et al, 2003).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CLENBUTEROL: An anion gap metabolic acidosis was reported in an adult following the use of heroin adulterated with clenbuterol, a long acting beta2-agonist used in veterinary medicine (Bilkoo et al, 2007).
b) TERBUTALINE: High anion gap lactic acidosis was reported in a 22-year-old asthmatic woman after an overdose of terbutaline (Blake & Ryan, 1989).

Hematologic

3.13.1)

A) Leukocytosis has been reported following overdoses.

3.13.2)

A) LEUKOCYTOSIS

1) CASE REPORT: Leukocytosis has been reported after terbutaline overdose, possibly secondary to rhabdomyolysis (Blake & Ryan, 1989).
2) CASE REPORT: Illicit intravenous injection of a compound identified on a toxicology screen as PPA, caffeine and an unidentified amine (not methamphetamine) produced an impressive leukocytosis of 52,000 WBC which gradually resolved over 5 days (Paulman et al, 1986).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) Skin and mucous membranes may be moist following overdose with a sympathomimetic agent.

Musculoskeletal

3.15.1)

A) Rhabdomyolysis has been reported following acute overdoses, and may result in acute tubular necrosis and acute renal failure.

3.15.2)

A) RHABDOMYOLYSIS

1) Rhabdomyolysis, associated with acute renal failure, has been reported after overdose with phenylpropanolamine (Swenson et al, 1982; Rumpf et al, 1983), terbutaline (Blake & Ryan, 1989), and pseudoephedrine (Salmon & Nicholson, 1988). Rhabdomyolysis has been reported following the labeled use of nutritional supplements containing Ma Huang (ephedra) (Scroggie et al, 2000).

a) CASE REPORT: Blake & Ryan (1989) report a case of a 22-year-old woman who presented to the ED after ingestion of thirty 7.5 mg sustained-release terbutaline tablets (Blake & Ryan, 1989). Generalized myalgia developed. CPK rose to greater than 30,000 Units/L and LDH was 6720 Units/L. Urine was positive for myoglobinuria. Renal biopsy, after 14 days of oliguria, revealed an acute tubular necrosis. A diagnosis of rhabdomyolysis induced acute renal failure was made. The patient recovered following hemodialysis treatments.
b) CASE REPORT: Following one week use of a supplement (3 tablets 3 times daily) containing Ma Huang (equivalent of 20 mg ephedra per tablet) to assist in strength training, a previous healthy 23-year-old man presented with mild, diffuse muscle tenderness and abdominal pain. Laboratory examination revealed creatine kinase of over 56,000 Units/L, which peaked at 616,000 Units/L on hospital day 1, and aldolase of 241 Units/L as well as elevated serum transaminases. Renal function was normal and there was no evidence of cardiac muscle damage. Following one week of symptomatic care and aggressive hydration therapy, the patient recovered (Scroggie et al, 2000).

B) INCREASED MUSCLE TONE

1) CASE REPORT: Castelani (1985) reports a case of a 45-year-old man on chronic fluphenazine decanoate therapy who overdosed with an oral anorectic agent containing PPA and caffeine. Mild leukocytosis (12,300) and elevated CPK (511 International Units/L) were evident on laboratory analysis. The patient displayed rigid, bizarre limb postures and appeared to be in a catatonic state. Cogwheel rigidity developed on day 4. Benztropine 2 mg IM was administered with a resultant significant reduction in muscle rigidity. The patient recovered over a 3 week period following the administration of benztropine 1 mg PO twice daily. It is possible that a drug interaction between fluphenazine and PPA may have occurred resulting in muscle rigidity.

Endocrine

3.16.1)

A) Hyperglycemia has been reported as an overdose effect.

3.16.2)

A) HYPERGLYCEMIA

1) Hyperglycemia has been reported after overdose with terbutaline, presumably related to beta-sympathomimetic stimulation of glycogenolysis (Heath & Hulten, 1987; Blake & Ryan, 1989).

Immunologic

3.19.1)

A) Allergic reactions, including anaphylaxis, have been reported following ingestions of sympathomimetics.

3.19.2)

A) ACUTE ALLERGIC REACTION

1) Speer et al (1978) reported 2 cases of an allergic response to phenylpropanolamine (Speer, 1978).
2) CASE REPORT: The first case was a 17-year-old girl who had hay fever and asthma. 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.
3) CASE REPORT: The second case involved a 41-year-old woman, 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). When evaluated 2 months later she reported that her skin was clear.

B) CONTACT DERMATITIS

1) Allergic contact dermatitis (erythema, edema, vesicles) occurred after use of phenylephrine eyedrops (Milpied et al, 1988).

Reproductive

3.20.1)

3.20.2)

A) ANIMAL STUDIES

1) METAPROTERENOL

a) RATS: Conflicting results have been published from studies with rabbits ranging from multiple teratogenic effects (Iida et al, 1988) to unattributable malformations (Matsuo et al, 1982). Metaproterenol exhibited teratogenic and embryocidal effects in rabbit studies with oral and inhaled administration at 620 and 62 (100 mg/kg) times the human therapeutic dose, respectively (Prod Info metaproterenol sulfate oral tablets, 2010; Matsuo et al, 1982; Iida et al, 1988). Observed congenital malformations included skeletal anomalies, cleft palate, and hydrocephalus. The incidence of cleft palate was attributed to increased maternal corticosterone and was not considered drug-related (Matsuo et al, 1982). In other studies in rabbits dosed at 50 mg/kg and rats dosed at 40 mg/kg, embryotoxic or fetotoxic effects were not reported (Prod Info metaproterenol sulfate oral tablets, 2010).

3.20.3)

A) PLACENTAL BARRIER

1) Beta sympathomimetic drugs appear to cross the placenta.
2) CASE SERIES: Cord serum insulin concentration was measured in 18 preterm infants whose mothers received beta sympathomimetic therapy (17 received salbutamol and one received terbutaline) for labor sedation. The cord serum insulin concentration was significantly higher in the treated group compared with a controlled group of 21 women who delivered preterm infants and had not taken any sympathomimetic drugs. The mean length of treatment with sympathomimetics was 2.9 plus or minus 1.8 days. Hypoglycemia was not observed on admission or at one hour of age (Procianoy & Pinheiro, 1982).

B) PREGNANCY CATEGORY

1) Albuterol is classified as FDA pregnancy category C (Prod Info Vospire ER (R) extended release oral tablets, 2006).
2) Isoxsuprine is classified as FDA pregnancy category C (Prod Info isoxsuprine hcl oral tablets, 2005).
3) Metaproterenol is classified as FDA pregnancy category C (Prod Info metaproterenol sulfate oral tablets, 2010).
4) Rivaroxaban is classified as FDA pregnancy category C (Prod Info XARELTO(R) oral tablets, 2011).
5) Terbutaline is classified as FDA pregnancy category B (Prod Info terbutaline sulfate oral tablet, USP, 2001).

C) ANIMAL STUDIES

1) RIVAROXABAN

a) In animal studies, there was no increase in structural malformations with rivaroxaban administration; however, there was increased postimplantation loss in rabbits and pronounced maternal hemorrhagic complication in rats. Increased fetal toxicity (increased resorptions, decreased number of live fetuses, decreased fetal body weight) occurred in rabbits given oral rivaroxaban doses of 10 mg/kg or greater (approximately 11 times the maximum recommended human dose of 10 mg/day) during organogenesis. Decreased fetal body weight was reported with rivaroxaban doses of 120 mg/day (about 40 times the human exposure of unbound drug) administered to pregnant rats. Rivaroxaban crossed the placenta in animal studies (Prod Info XARELTO(R) oral tablets, 2011).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to ISOETHARINE, ISOXSUPRINE, METAPROTERENOL, PHENYLEPHEDRINE, or during lactation in humans (Prod Info metaproterenol sulfate oral tablets, 2010).

B) LACK OF EFFECT

1) Pseudoephedrine is excreted into breast milk; breastfeeding is not recommended by the manufacturer due to the higher risk of exposure to sympathomimetic amines to the infant (Prod Info pseudoephedrine hcl, guaifenesin extended-release oral tablets, 2006).
2) Terbutaline: It is unknown if the drug is excreted into breast milk; therefore, its potential risk to the nursing infant should be considered (Prod Info terbutaline sulfate oral tablet, USP, 2001).

C) ANIMAL STUDIES

1) RIVAROXABAN

a) In animal studies, rivaroxaban has been shown to be excreted in the milk of lactating rats (Prod Info XARELTO(R) oral tablets, 2011).

3.20.5)

A) ANIMAL STUDIES

1) METAPROTERENOL

a) RATS: No impairment of fertility was reported in reproduction studies in rats (Prod Info metaproterenol sulfate oral tablets, 2010).

2) RIVAROXABAN

a) No impairment of fertility was observed when oral rivaroxaban was administered to male and female rats at doses up to 200 mg/kg/day (at least 33 times the human exposure of 10 mg/day) (Prod Info XARELTO(R) oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Obtain a 12 lead ECG and institute continuous cardiac monitoring in the severely poisoned patient. Cardiac biomarkers should be measured in patients with chest pain.
B) Monitor serum electrolytes, blood sugar, and blood pressure.
C) Creatinine phosphokinase should be measured if severe agitation is present and persistent.
D) Obtain a head CT for focal neurologic deficits or depressed mental status.
E) Monitor arterial or venous blood gases to monitor acidosis in the severely poisoned patient.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Serum drug levels are not normally useful in acute toxicities of oral sympathomimetics (Cetaruk & Aaron, 1994).
2) Monitor serum electrolytes, blood sugar, and blood pressure.
3) Obtain a 12 lead ECG and institute continuous cardiac monitoring in the severely poisoned patient. Cardiac biomarkers should be measured in patients with chest pain.
4) Creatinine phosphokinase should be measured if severe agitation is present and persistent.
5) Assess renal dysfunction in symptomatic patients. Measure serum creatinine, creatinine clearance and BUN.

4.1.3)

A) URINALYSIS

1) Monitor urine myoglobin if rhabdomyolysis is suspected.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor chest x-ray and arterial blood gases in patients with pulmonary edema.

Radiographic Studies

1) Obtain a chest x-ray in patients with severe respiratory or CNS depression.

Methods

1) Identification in biological fluids not readily available.
2) Urine screen by thin layer chromatography is available in some labs for qualitative identification.
3) Phenylpropanolamine may be detected by enzyme-multiplied-immunoassay technique (EMIT) assays as amphetamine. However, many newer assays will not detect phenylpropanolamine or pseudoephedrine. It is important to evaluate the specific cross reactions for the assay.
4) Thin layer chromatography followed by gas chromatography can differentiate between amphetamine and phenylpropanolamine (Mueller, 1983).
5) Salbutamol and terbutaline plasma concentration has been determined by ion-pair high-performance liquid chromatography with amperometric detection (Jarvie et al, 1987).
6) Phenylpropanolamine (d,l-norephedrine) and its diastereomer d-norpseudoephedrine are indistinguishable on the Toxilab TLC system. The drugs differ pharmacologically and therapeutically (Gal & Lichtenstein, 1987).
7) Clenbuterol serum concentrations have been determined by a liquid chromatography/mass spectrometry (LC/MS) method (Hoffman et al, 2001).
8) de Jong et al (1990) compared the use of a GC/MS ion trapping technique with GC-FTIR for the identification of stimulants, including sympathomimetics, in urine drug testing. They found the chemical ionization option on the ion trap mass detector (ITD) offered the fastest and most sensitive means for confirmation of positive samples, with detection limits of 1 to 10 nanograms (de Jong et al, 1990).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with moderate to severe toxicity should be admitted until symptoms have improved. Seizures, delirium, cardiac dysrhythmias, cardiac or cerebral ischemia, rhabdomyolysis or persistently abnormal vital signs are all indications for admission to an intensive care unit.

6.3.1.2) HOME CRITERIA/ORAL

A) Mild restlessness and insomnia can be managed at home if the exposure is inadvertent and medication is withdrawn.

6.3.1.3) CONSULT CRITERIA/ORAL

A) A toxicologist or poison center should be consulted for all patients with severe toxicity or patients that require hospital admission.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with mild tachycardia, hypertension, and agitation can be treated with benzodiazepines and observed until symptoms and vital signs normalize.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital decontamination is generally not recommended due to the possibility for seizures in moderate to severe toxicity.
B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) Administer activated charcoal to patients with recent significant overdose. Do not administer activated charcoal to patients that have a declining mental status, severe toxicity, or those that are at risk for seizures without first protecting the airway.
B) 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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) MONITORING OF PATIENT

1) Obtain a 12 lead ECG and institute continuous cardiac monitoring in the severely poisoned patient. Cardiac biomarkers should be measured in patients with chest pain.
2) Monitor serum electrolytes, blood sugar, and blood pressure.
3) Creatinine phosphokinase should be measured if severe agitation is present and persistent.
4) Obtain a head CT for focal neurologic deficits or depressed mental status.
5) Monitor arterial or venous blood gases to monitor acidosis in the severely poisoned patient.

B) FLUID/ELECTROLYTE BALANCE REGULATION

1) MONITOR URINARY OUTPUT and serum electrolytes in symptomatic patients. Fluid replacement may be necessary.

C) 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).

D) OXYGEN

1) Patients with cyanosis should be evaluated for airway patency and oxygenation, and corrective measures including endotracheal intubation or administration of supplemental oxygen done as indicated.

E) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.

F) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

G) PSYCHOMOTOR AGITATION

1) INDICATION

a) If patient is severely agitated, sedate with IV benzodiazepines.

2) DIAZEPAM DOSE

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) 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 (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

3) LORAZEPAM DOSE

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
5) Phenothiazines should be avoided due to possible hypotension.

H) DRUG-INDUCED DYSTONIA

1) DYSTONIC REACTION: ADULT: BENZTROPINE: 1 to 4 mg once or twice daily IV or IM (max, 6 mg/day); 1 to 2 mg of the injection will usually provide quick relief in emergency situations, OR DIPHENHYDRAMINE: ADULT: 10 to 50 mg IV at a rate not exceeding 25 mg/minute or deep IM (max, 100 mg/dose; 400 mg/day). CHILDREN: Diphenhydramine: 5 mg/kg/day or 150 mg/m(2)/day IV divided into 4 doses at a rate not to exceed 25 mg/min, or deep IM (max,, 300 mg/day). Not recommended in premature infants and neonates.

I) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia should be managed with external cooling. Avoid phenothiazines. Severe hyperthermia should be managed by intubation, paralysis and ventilation of the patient.

J) 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).

K) 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/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).

b) 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).

c) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) PROCAINAMIDE

a) PROCAINAMIDE/ADULT LOADING DOSE

1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).

b) PROCAINAMIDE/CONTROLLED INFUSION

1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)

c) PROCAINAMIDE/ADULT MAINTENANCE DOSE

1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).

d) PROCAINAMIDE/PEDIATRIC LOADING DOSE

1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).

e) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE

1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

f) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE

1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

g) MONITORING PARAMETERS

1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).

h) AVOID

1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

L) BRADYCARDIA

1) Extreme caution should be used when treating bradycardia secondary to hypertension or AV block. Atropine could aggravate hypertension.
2) Bradycardia has been observed following phenylpropanolamine ingestion, but could occur following intoxication with other sympathomimetics.
3) ATROPINE

a) ATROPINE/DOSE

1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

a) There is no minimum dose (de Caen et al, 2015).
b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

M) 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).

16) LABETALOL

a) INTRAVENOUS INDICATIONS

1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.

b) ADULT DOSE

1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).

c) PEDIATRIC DOSE

1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).

d) ADVERSE REACTIONS

1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).

e) PRECAUTIONS

1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).

f) MONITORING PARAMETER

1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

17) Propranolol, 1 mg IV, was used successfully to treat hypertension in a pseudoephedrine overdose and an ephedrine overdose (Burkhart, 1992).

N) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) If dopamine is involved in the sympathomimetic overdose, do NOT treat hypotension with dopamine. However, it is unlikely that dopamine overdoses would result in hypotension.

a) DOPAMINE

1) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
2) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) If norepinephrine is involved in the sympathomimetic overdose, do NOT treat hypotension with norepinephrine. However, it is unlikely that norepinephrine overdoses would result in hypotension.

a) NOREPINEPHRINE

1) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
2) DOSE

a) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
b) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
c) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

4) PRECAUTIONS

a) Profound hypotension requiring vasopressor support may develop.
b) Since the agents used to treat the hypotension may be the same as those causing the overdose, care should be used in determining whether a vasopressor is required and in the selection of that agent.

O) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

1) There is little data to support hemodialysis for oral sympathomimetics, and symptomatic management is almost always sufficient.

Abstracts

Case Reports

1) PHENYLEPHRINE: A 57-year-old with no cardiovascular disease history was given eye drops containing phenylephrine 10% and homatropine 2% (1 drop in each eye every 30 minutes for 2 hours). Acute hypertension, cardiac arrhythmia, and myocardial infarction developed (Lai, 1989).
2) PHENYLPROPANOLAMINE: Kase et al (1987) reported 2 cases of intracerebral hemorrhage in a 39-year-old woman who ingested 75 mg phenylpropanolamine and a 32-year-old man who ingested 150 mg phenylpropanolamine. "Beading" of the vertebral and carotid arteries were seen on arteriogram (Kase et al, 1987).

1) ALBUTEROL

a) CASE REPORT: Following ingestion of one hundred 2 mg tablets in a 44-year-old woman, the patient presented with peripheral vasodilation and sweating, heart rate of 170 beats/minute, and blood pressure of 130/90 mmHg. She also exhibited extreme agitation, marked increase in deep tendon reflexes, and sustained ankle clonus, but no cardiac arrhythmias. The patient was treated initially with practolol 20 mg IV and diazepam 5 mg IV followed by propranolol 10 mg every 6 hours orally. Symptoms gradually subsided (Morrison & Farebrother, 1973).
b) CASE REPORT: A 76-year-old woman was admitted 2 hours after taking a total of forty 4 mg albuterol and Distalgesic(R) tablets. On admission she was conscious, agitated, sweating and tremulous. There was a regular tachycardia of 140 beats/min, blood pressure was 90/50 mmHg, respiratory rate 40/min and temperature 37.5 degrees C. Laboratory studies resulted in a plasma sodium of 140 mEq/L, potassium 2.3 mEq/L, chloride 100 mEq/L, bicarbonate 27 mEq/L, urea 34 mg/100 ml and glucose 139 mg/100 ml. Serum acetaminophen concentration on admission was 55 mg/L. An ECG showed sinus tachycardia without the characteristic changes of hypokalemia. She was treated with 80 mEq potassium chloride and an IV infusion of 2 L normal saline given over 24 hours. One day after admission the plasma potassium concentration had risen to 4.4 mEq/L, but subsequently remained normal without further supplementation (O'Brien et al, 1981).

2) METAPROTERENOL

a) CASE REPORT: Sailer et al (1968) reported cardiac abnormalities following overdose of 220 mg of oral metaproterenol in a 19-year-old man. Symptoms included tachycardia, flushing, pulse frequency of 135/min and a systolic blood pressure of 140 mmHg. Electrocardiogram revealed a P-Q time of 0.16 seconds and QT interval of 0.32 seconds. Propranolol 5 mg IV was administered and pulse frequency decreased to 90/min and blood pressure normalized at 130/90 mmHg.

3) PSEUDOEPHEDRINE

a) CASE REPORT: Severe hypertension (peak blood pressure of 200/160 mmHg) was recorded in a 23-year-old 70 kg , man within 3 hours of ingestion of seven Trinalin tablets (120 mg pseudoephedrine and 1 mg azatadine per tablet). This ingestion of 12 mg/kg of pseudoephedrine and 0.1 mg/kg of azatadine was unaccompanied by other drugs or alcohol. There were no significant findings on physical examination. An ECG showed a sinus tachycardia with nonspecific S-T changes. All electrolytes were within normal values. Specific patient complaints included a severe diffuse headache, dizziness and epigastric pain. Full recovery was noted following a 25 mg, 40 mg and final 25 mg dose of labetalol. Within four hours the blood pressure was 106/82 mmHg (Mariani, 1986).

4) TERBUTALINE

a) A 22-year-old asthmatic woman ingested 225 mg of sustained-release terbutaline, and presented with agitation, tachycardia, and tremor. Bronchospasm, hypotension, leukocytosis, hypokalemia, and hyperglycemia developed, along with a metabolic acidosis (pH 7.09, PO2 51, PCO2 22, bicarbonate 6.5 mmol/L). She required ventilation for 12 hours, and then developed acute renal failure and rhabdomyolysis. Oliguria was present for 20 days, with full recovery within 3 months (Blake & Ryan, 1989).

1) PHENYLPROPANOLAMINE

a) Weesner et al (1982) reported a case of a 14-year-old girl who 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. These signs were unresponsive to lidocaine, but converted to a normal sinus rhythm following the administration of 1 mg IV propranolol (Weesner et al, 1982).

2) PSEUDOEPHEDRINE

a) Severe hypokalemia (1.8 mEq/L) despite normal body potassium content developed in a 17-year-old boy who overdosed on an unknown amount of pseudoephedrine and choline theophyllinate. Serum glucose on admission was 17.6 mmol/L. Aside from muscle pain and weakness during recovery, the patient had no symptoms of hypokalemia. It was postulated that the drugs produced hyperglycemia and hyperinsulinemia, resulting in a shift of potassium from extracellular to intracellular space (McCleave et al, 1978).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) ALBUTEROL EXTENDED RELEASE (oral): 4 to 8 mg every 12 hours (Prod Info Proventil Repetabs(R), albuterol, 1999).
2) ISOMETHEPTENE MUCATE: The usual adult dose is 130 mg initially, followed by 65 mg every hour until the migraine is relieved. The maximum recommended dose is 325 mg in 12 hours (Prod Info DURADRIN(R) oral capsules, 2001).
3) METAPROTERENOL: 20 mg 3 to 4 times a day orally (Prod Info metaproterenol sulfate oral tablets, 2010).
4) PHENYLEPHRINE: 10 to 20 mg every 4 hours for nasal decongestion (Prod Info NASOP(TM) orally-dissolving tablets, 2004).
5) PSEUDOEPHEDRINE: 60 mg every 4 to 6 hours as needed for nasal decongestion (Prod Info Sudafed(R) nasal decongestant tablets, 2005).
6) TERBUTALINE: 5 mg every 6 hours while awake (maximum dose 15 mg/day) (Prod Info terbutaline sulfate oral tablet, USP, 2001).

7.2.2)

A) SPECIFIC SUBSTANCE

1) ALBUTEROL

a) INHALATION

1) ACUTE ASTHMA EXACERBATION

a) Inhalation: Metered-dose inhaler: Less than 12 years of age: Inhale 4 to 8 puffs (90 mcg/puff) every 20 minutes for 3 doses, then every 1 to 4 hours as needed (National Institute of Health National Asthma Education and Prevention Program, 2007).
b) Inhalation: Metered-dose inhaler: 12 years of age and older: Inhale 4 to 8 puffs (90 mcg/puff) every 20 minutes up to 4 hours, then every 1 to 4 hours as needed (National Institute of Health National Asthma Education and Prevention Program, 2007).
c) Solution for inhalation: Less than 12 years of age: 0.15 mg/kg (minimum dose 2.5 mg) by nebulizer every 20 minutes for 3 doses, then 0.15 to 0.3 mg/kg (maximum 10 mg) every 1 to 4 hours as needed (National Institute of Health National Asthma Education and Prevention Program, 2007; Khine et al, 1996).
d) Solution for inhalation: 12 years of age and older: 2.5 to 5 mg by nebulizer every 20 minutes for 3 doses, then 2.5 to 10 mg every 1 to 4 hours as needed (National Institute of Health National Asthma Education and Prevention Program, 2007).
e) Continuous nebulization: Less than 12 years of age: 0.5 mg/kg/hour by continuous nebulization (National Institute of Health National Asthma Education and Prevention Program, 2007; Khine et al, 1996).
f) Continuous nebulization: 12 years of age and older: 10 to 15 mg/hour by continuous nebulization (National Institute of Health National Asthma Education and Prevention Program, 2007).
g) Note: The addition of ipratropium bromide to albuterol nebulizations is recommended for treatment of moderate-to-severe acute asthma exacerbations treated in the emergency room or acute (urgent) care setting (National Institute of Health National Asthma Education and Prevention Program, 2007; Rodrigo & Castro-Rodriguez, 2005; Plotnick & Ducharme, 2000; Qureshi et al, 1998; Zorc et al, 1999).

2) ASTHMA RELIEF OF ACUTE BRONCHOSPASM

a) Inhalation: Metered-dose inhaler: Inhale 2 puffs every 4 to 6 hours as needed for acute bronchospasm (Prod Info VENTOLIN(R) HFA oral inhalation aerosol, 2009). Chronic daily use of short-acting beta2-agonists is not recommended (National Institute of Health National Asthma Education and Prevention Program, 2007).
b) Solution for inhalation: 4 years of age and younger: 0.63 to 2.5 mg/dose by nebulizer every 4 to 6 hours as needed. For children less than 15 kg, weight-based dosing is also used: 0.1 to 0.15 mg/kg/dose by nebulizer 3 to 4 times daily as needed (National Institute of Health National Asthma Education and Prevention Program, 2007; Prod Info albuterol sulfate inhalation solution, 2006; Prod Info AccuNeb(R) inhalation solution, 2011).
c) 5 years of age and older: 1.25 to 5 mg/dose by nebulizer every 4 to 8 hours as needed. Chronic daily use of short-acting beta-agonists is not recommended (National Institute of Health National Asthma Education and Prevention Program, 2007).

3) EXERCISE-INDUCED ASTHMA PROPHYLAXIS

a) 4 years of age and older: Inhale 2 puffs 15 to 30 minutes prior to exercise (Prod Info VENTOLIN(R) HFA oral inhalation aerosol, 2009); some experts recommend administration 5 minutes before exercise (National Institute of Health National Asthma Education and Prevention Program, 2007).

b) ORAL

1) ASTHMA RELIEF OF BRONCHOSPASM

a) Syrup and Tablets: Note: According to asthma guidelines, oral systemic beta2-agonists are not recommended for relief of acute asthma symptoms (National Institute of Health National Asthma Education and Prevention Program, 2007).
b) 2 to 5 years of age (syrup): Initial, 0.1 mg/kg/dose (maximum 2 mg/dose) orally 3 times daily; if inadequate response, dose may be increased incrementally to 0.2 mg/kg/dose 3 times daily (maximum 4 mg/dose) (Prod Info albuterol sulfate oral syrup, 2006).
c) 6 to 12 years of age (syrup and tablets): Initial, 2 mg given orally 3 or 4 times daily; if fail to respond, dose may be increased incrementally to a maximum of 6 mg 4 times daily (Prod Info albuterol sulfate oral tablet, 2009; Prod Info albuterol sulfate oral syrup, 2006).
d) Greater than 12 years of age (syrup and tablets): Initial, 2 or 4 mg orally 3 or 4 times daily; if fail to respond, dose may be increased incrementally to a maximum of 8 mg 4 times daily (Prod Info albuterol sulfate oral tablet, 2009; Prod Info albuterol sulfate oral syrup, 2006).

2) EXTENDED-RELEASE TABLETS

a) Note: According to guidelines, inhaled long-acting beta2-agonists are preferred over oral extended-release albuterol for long-term control of asthma symptoms (National Institute of Health National Asthma Education and Prevention Program, 2007).
b) 6 to 12 years of age: Initial, 4 mg orally every 12 hours; may increase cautiously to a maximum of 12 mg twice a day according to response (Prod Info albuterol sulfate oral extended-release tablets, 2008).
c) Greater than 12 years of age: Initial, 4 mg or 8 mg orally every 12 hours; may increase cautiously to a maximum of 16 mg twice a day according to response (Prod Info albuterol sulfate oral extended-release tablets, 2008).
d) Switching from immediate-release albuterol tablets: One 4-mg albuterol extended-release tablet every 12 hours is comparable to one 2-mg albuterol immediate-release tablet every 6 hours; multiples of this regimen up to the maximum recommended daily dose also apply (Prod Info albuterol sulfate oral extended-release tablets, 2008).

2) METAPROTERENOL

a) Less than 6 years: Not recommended (Prod Info metaproterenol sulfate oral tablets, 2010).
b) 6 to 9 years: 10 mg orally 3 to 4 times daily (Prod Info metaproterenol sulfate oral tablets, 2010).
c) More than 9 years: 20 mg orally 3 to 4 times daily (Prod Info metaproterenol sulfate oral tablets, 2010).

3) PHENYLEPHRINE

a) 6 to 12 years: 10 mg every 4 hours (Prod Info NASOP(TM) orally-dissolving tablets, 2004).
b) 2 to 6 years: 5 mg every 4 hours (Prod Info NASOP(TM) orally-dissolving tablets, 2004).

4) PSEUDOEPHEDRINE

a) 12 years and older: 60 mg every 4 to 6 hours as needed (Prod Info SUDAFED(R) oral tablet, 2005).
b) 6 to 12 years: 30 mg every 4 to 6 hours as needed (Prod Info SUDAFED(R) oral tablet, 2005).

5) TERBUTALINE

a) 12 to 15 years: 2.5 mg 3 times a day (maximum dose 7.5 mg/day) (Prod Info terbutaline sulfate oral tablet, USP, 2001).

Maximum Tolerated Exposure

1) EPHEDRINE

a) Two to three times the single therapeutic dose of ephedrine can produce clinically important hypertension (Brater et al, 1980).
b) Toxicity of ephedrine-theophylline combinations have been more common and is potentially serious (See ephedrine theophylline combination management).
c) CASE REPORT: A 22-year-old woman developed nausea and vomiting, tremulousness, abdominal pain and tachycardia (pulse 133 bpm) after ingesting 2 Xenadrine(R) tablets (ephedrine 10 mg and caffeine 100 mg in each tablet) in the morning and 3 in the afternoon (instead of 2 tablets twice a day). Approximately 8 hours after the last dose of ephedrine, serum ephedrine level was 150 ng/mL (Schier et al, 2003).
d) CASE REPORT: A 20-year-old woman developed a transient ischemic attack after ingesting 4 tablets of Metabolife 356 (ma huang [containing 12 mg ephedrine], guarana extract [40 mg caffeine], chromium picolinate, and other herbal and vitamins) approximately 30 minutes before the episode. In addition, she ingested 6 to 15 tablets daily for 3 days. On presentation to the hospital, she complained of numbness to her left face, arm, and leg, mild headache, and nausea. Following supportive care, her symptoms resolved within 4 hours and she was discharged home the next day (Lo Vecchio et al, 2005).

2) METAPROTERENOL

a) ALUPENT: Oral ingestion of 220 mg resulted in tachycardia and systolic hypertension which resolved following propranolol therapy in a 19-year-old man (Sailer, 1968).

3) OTHER AGENTS

a) ISOPROTERENOL: Maximum tolerated exposure is unknown.
b) PHENYLEPHRINE: Maximum tolerated exposure is unknown.

4) PHENYLPROPANOLAMINE

a) Maximum tolerated exposure is 2 to 3 times the therapeutic dose (Ekins & Spoerke, 1983).
b) MINIMUM TOXIC DOSE: A 5 month study of 70 patients reports that a minimum toxic dose of PPA in children is 8 to 10 mg/kg when combined in fixed concentration with caffeine.

1) Symptoms will generally develop in patients following the ingestion of 17.5 mg/kg PPA alone within 2 hours and persist for 6 to 13 hours.
2) The combination of caffeine and PPA results in additive pharmacologic effects of both drugs (Ekins & Spoerke, 1983).

c) USUAL THERAPEUTIC DOSE: Ingestion of 75 mg sustained-release capsule or 25 mg immediate-release capsule 3 times a day in 881 normotensive volunteers resulted in an increase in blood pressure of 2 to 4 mmHg (Blackburn et al, 1989).
d) TWO-FOLD DOSE INCREASE: Clinically significant, transient hypertension was reported following 150 mg of sustained release phenylpropanolamine and following 75 mg of sustained release phenylpropanolamine plus 400 mg caffeine in a trial in 6 patients (Lake et al, 1988).
e) THREE-FOLD DOSE INCREASE: 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).
f) Moderate or severe hypertension occurred in children who ingested 10.3 to 50 mg/kg of phenylpropanolamine (Larson & Rogers, 1986).
g) Ekins and Spoerke (1983) conducted a study, involving 70 cases, to determine the toxicity of phenylpropanolamine, alone or in combination with caffeine. A minimum toxic dose in children, of phenylpropanolamine and caffeine combined, was reported to be approximately 10 mg/kg. A minimum toxic dose in children, of phenylpropanolamine and caffeine combined, was reported to be approximately 10 mg/kg.
h) According to Pentel (1984), phenylpropanolamine has an extremely low therapeutic index and may produce severe or even life-threatening hypertension at less than 3 times the maximal OTC dose of 37.5 mg.

5) SYNEPHRINE

a) CASE REPORT: A 20-year-old woman developed several episodes of polymorphic ventricular tachycardia that degenerated to ventricular fibrillation (requiring defibrillation) after ingesting approximately 200 diet tablets containing Citrus aurantium (the extract contained synephrine, a synthetic derivative of amphetamine; two capsules contain 325 mg of synephrine) and caffeine over several days. Measurement of serum electrolytes showed hypokalemia and hypomagnesemia. Following supportive treatment, she recovered without further sequelae (Srivatsa et al, 2003).

6) TERBUTALINE

a) Experience with newer beta-2 agonists (terbutaline, albuterol, metaproterenol) is limited, but severe toxicity at present appears to be limited.
b) A 7-year-old girl developed seizures 1 to 2 hours following the ingestion of 5 to 7.5 mg of terbutaline sulfate (Friedman et al, 1982).
c) A 22-year-old developed nausea, tachycardia, tremor, hyperglycemia, and hypokalemia following an ingestion of 500 mg terbutaline (Heath & Hulten, 1987).
d) A 22-year-old woman developed hypotension, lactic acidosis, hyperglycemia, hypokalemia, rhabdomyolysis, and acute renal failure after ingestion of 225 mg of sustained-release terbutaline (Blake & Ryan, 1989).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) PHENYLPROPANOLAMINE: Serum concentrations are reported to be approximately 60 to 200 nanograms/milliliter after a therapeutic dose (Pentel, 1984).
b) TERBUTALINE: Normal therapeutic concentration is 2 to 6 micrograms/liter (Heath & Hulten, 1987).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) ALBUTEROL

1) THERAPEUTIC DOSE: Single therapeutic doses of salbutamol produced maximum plasma concentrations ranging from 2.5 to 4.5 micrograms/liter (Oosterhuis & van Boxtel, 1982; Tan & Soldin, 1984).
2) OVERDOSE: In 8 overdose patients maximum serum concentrations were 50 to 76 mcg/L (Jarvie et al, 1987).

b) CLENBUTEROL

1) OVERDOSE: Following the ingestion of an unknown quantity of clenbuterol powder, a 28-year-old woman developed sustained tachycardia, hypokalemia, and hypophosphatemia. Serum clenbuterol concentration was reported to be 2.93 mcg/L (Hoffman et al, 2000).

c) DMAA

1) 1,3-DIMETHYLETHYLAMINE: Following the ingestion of DMAA for recreational use, an adult developed severe hypertension and cerebral hemorrhage; blood drawn 2 hours postingestion showed a DMAA concentration of 2.31 mg/L. No other drugs of abuse were detected; the patient had a trace of cannabis in the urine. In another patient with the same exposure and similar clinical events, blood drawn 100 min postingestion showed a plasma DMAA concentration of 1.09 mg/L. Both patients recovered completely (Gee et al, 2012).

d) EPHEDRINE

1) THERAPEUTIC SERUM LEVEL: 0.04 to 0.08 mcg/mL (Snook et al, 1992)
2) OVERDOSE: A woman who ingested 7.5 grams ephedrine in diet pills had a serum concentration of 22.8 mcg/mL 90 minutes postingestion (Snook et al, 1992).

e) TERBUTALINE

1) THERAPEUTIC DOSE: Normal therapeutic concentrations are 2 to 6 mcg/L (Heath & Hulten, 1987).
2) OVERDOSE: Plasma terbutaline concentration of 200 mcg/L was reported 6 hours after ingestion of 500 mg terbutaline in a 22-year-old woman (Heath & Hulten, 1987).

a) A 3-year-old child had a plasma terbutaline concentration of 33.9 mcg/L 3 hours after an accidental ingestion (Host & Foged, 1983).
b) Maximum serum concentrations of terbutaline were 41 to 88 mcg/L in 3 overdose patients (Jarvie et al, 1987).

Pharmacology Toxicology

Pharmacologic Mechanism

1) Phenylpropanolamine is a mixed-acting sympathomimetic, acting both directly and indirectly. It indirectly causes NE release, and directly it acts as an alpha agonist. PPA crosses the blood-brain barrier to produce central effects (reviewed in Goldfrank, 1994).

Toxicologic Mechanism

1) 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, 1988). Ten of these cases had intracranial hemorrhage and significant neurologic deficits.
2) Cantu et al (2003) described several mechanisms by which over-the counter sympathomimetics cause cerebrovascular complications: the development of hypertensive crisis as a consequence of a direct vasoconstrictive action of the drugs, or the development of angiitis. Although most cases were due to phenylpropanolamine use, stroke may also occur with the use of other agents (eg; pseudoephedrine) (Cantu et al, 2003).

Physicochemical

Animal Toxicology

Range Of Toxicity

11.3.1)

A) DOG

1) Phenylpropanolamine 1.5 milligrams/kilogram orally three times daily has been used for treating primary sphincter incompetence (Richter & Ling, 1985).

11.3.2)

A) LACK OF INFORMATION

1) No specific information on a minimal toxic dose was available at the time of this review.

References

General Bibliography

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SYMPATHOMIMETICS, ORAL

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

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Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Pharmacologic Mechanism

Toxicologic Mechanism

Range Of Toxicity

General Bibliography