Amphetamine Toxicity

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Background

Amphetamines are a class of compounds increasingly abused in regions of the world such as the western United States, Australasia, and Europe. Synthetic amphetamine compounds commonly are produced in clandestine laboratories and vary in purity and potency. Other potentials for amphetamine abuse include prescription medications and various over-the-counter diet pills.

Clinical effects of amphetamine abuse are significant and commonly observed in EDs. The ED physician's ability to recognize and treat amphetamine intoxication is very important.[1]

The phenylethylamine structure of amphetamines (see the image below) is similar to catecholaminergic, dopaminergic, and serotonergic agonists (biogenic amines), which may explain their actions.


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Amphetamine and epinephrine.

The relative activities that amphetamines have to stimulate the receptors of these biogenic amines are dependent on the chemical substituents on the amphetamine molecule; thus, the clinical presentation is dependent on the type of amphetamine used. For example, methamphetamine lacks much of the peripheral stimulant properties of amphetamine while still offering euphoric and hallucinogenic properties. These actions are similar to those of cocaine; however, while effects of cocaine last for 10-20 minutes, duration of amphetamine action is much longer, lasting as long as 10-12 hours.

The routes of amphetamine administration may be oral (ingestion), inhalation (smoke), or injection (intravenous). Oral use is associated with an approximate 1-hour lag time before onset of symptoms, whereas inhaled and intravenous methods yield effects within a few minutes. Peak plasma concentrations occur in 5 minutes with intravenous use, 30 minutes with nasal or intramuscular use, and 2-3 hours postingestion.

Use appears to vary with gender and race. Recent work has found correlations between personality traits (risk taking and reward sensitivity) and responses to amphetamine use.[2]

Pathophysiology

Amphetamines are a group of structurally related compounds that produce central nervous system (CNS) and peripheral nervous system (PNS) stimulation.

Central nervous system

Amphetamine compounds cause a general efflux of biogenic amines from neuronal synaptic terminals (indirect sympathomimetics). They inhibit specific transporters responsible for reuptake of biogenic amines from the synaptic nerve ending and presynaptic vesicles. Amphetamines also inhibit monoamine oxidase, which degrades biogenic amine neurotransmitters intracellularly. The net effect is an increase of neurotransmitter release into the synapse. Physiological adaptation occurs through receptor or coupling down-regulation; this tolerance and an accompanying psychological tolerance[3] can lead to escalating use of the drug and increased toxicity.[4] Chronic use can lead to a depletion of biogenic amine stores and a paradoxical reverse effect of the drug—a wash out.

Elevated catecholamine levels usually lead to a state of increased arousal and decreased fatigue. Increased dopamine levels at synapses in the CNS may be responsible for movement disorders[5] , schizophrenia, and euphoria. Serotonergic signals may play a role in the hallucinogenic and anorexic[6] aspects of these drugs.

Other serotonergic and dopaminergic effects may include resetting the thermal regulatory circuits upward in the hypothalamus and causing hyperthermia. The hyperthermia produced by amphetamines is similar to that of the serotonin syndrome.

Laboratory studies reveal that amphetamines interfere with the normal control of the neurohumoral (hypothalamopituitary) axis, affecting secretion of such factors as adrenocorticotropic hormone (ACTH). Amphetamines may alter other neural functions such as complex behavioral and learning patternings; this may be important for understanding effects of amphetamine use during pregnancy.

Animal studies indicate that amphetamines interact with N -methyl-D-aspartate (NMDA) receptors on serotonergic neurons, leading to neuronal destruction. This interaction may contribute to seizure activity.

In vitro, amphetamines have been found to stimulate regulatory molecules, such as the oncogenes c-fos and ras and cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein. These proteins are responsible for signaling long-term changes at the transcriptional level.

Peripheral nervous system

Catecholaminergic (sympathomimetic) effects of amphetamines include inotropic and chronotropic effects on the heart, which can lead to tachycardia and other dysrhythmias. The vasoconstrictive properties of the drugs can lead to hypertension and/or coronary vasospasm.[7]

Serotonergic action of amphetamines on peripheral vasculature can lead to vasoconstriction, which is especially problematic in placental vessels. Animal studies have shown that serotonergic actions of amphetamines effect changes in plasma levels of oxytocin, somatostatin, gastrin, and cholecystokinin.[8]

Cardiovascular

Long-term use of the drugs can lead to myonecrosis and dilated cardiomyopathy.[9] Amphetamine use is also associated with increased risk of pulmonary hypertension.[10]

Epidemiology

Frequency

United States

Accurate estimation of illicit amphetamine use is difficult. An estimated 13 million Americans use these compounds without medical supervision. Random toxicologic screens performed in the ED indicate amphetamine presence in about 2% of patients. Self-reporting among college students indicates an approximate 4% prevalence. An aged-matched survey of fourth-year medical students revealed that about 1.2% use amphetamines.

Locations of amphetamine drug factories may establish the regional nature of amphetamine use.[11] Use of these drugs in the United States mostly occurs in the large cities of the southwest. Of all amphetamine drug factory busts, 75% have occurred in California, Texas, and Oregon. At UC Davis's ED in the late 1980s, the prevalence of amphetamine toxicity was found to be 0.69%.

Despite the large focus of use in the western United States during the 1980s, many episodes of methamphetamine complications occurred in Minneapolis and Philadelphia. Importation of amphetamines from the Far East fuels Hawaiian drug use. As of August 1999, amphetamine-producing laboratories have sprung up in Mexico; border city narcotics officers blame the more lucrative street valuation of methamphetamine in the United States compared with cocaine. Amphetamines then are imported through cities along the US-Mexico border for sale at prices up to $26,000 per kilogram (cocaine is approximately $14,000 per kilogram).

International

Amphetamine use has been found to be increasing in Europe. In 1993, in the Frankfurt area, 9% of reckless driving arrests were associated with amphetamine use.[12] A study among adolescents in Taiwan found a prevalence of 2.7% and an estimated lifetime amphetamine use of about 4%.[13] In the United Kingdom, the number of amphetamine confiscations by law enforcement is only exceeded by that of cannabis.

Ring methoxylated amphetamine compounds have been found in a number of autopsies performed in Europe. Whether these are contaminants or byproducts in the production of methylenedioxymethamphetamine (MDMA) preparations, also known as Ecstasy, is unclear. Neither amphetamine nor methamphetamine was found in the blood of these individuals, suggesting that amphetamines were not deliberately added in the compounding of these Ecstasy tablets.

Mortality/Morbidity

Acute overdose of amphetamines produces seizures, hypertension, tachycardia, hyperthermia, psychosis, hallucinosis, stroke, and fatality.

Race

In the United States, amphetamine use characteristically occurs among single white men. Data from rural populations reveal that Caucasians use amphetamines significantly more than African Americans.[16]

Sex

Amphetamine use characteristically occurs among single white men aged 20-35 years who are typically unemployed.[17] However, amphetamine use is becoming more common among women and other ethnic groups.

A recent study suggests that the action of estrogen within the CNS might explain why fewer women than men use amphetamines. Women in their late follicular phase (when estrogen levels are high and progesterone levels are low) were more likely to report "unpleasant stimulation" when exposed to amphetamine. This effect was not observed in the early follicular phase, when both hormone levels are low.[18]

History

Physical

Physical examination findings may demonstrate the strong central nervous system and peripheral nervous system stimulation produced by amphetamine compounds. Modification of the basic amphetamine molecule produces compounds with variable effects on target organs. Methamphetamine produces prominent central nervous system effects with minimal cardiovascular stimulation.

Individuals who chronically use amphetamines intravenously are at risk of infection and vascular injury.

Causes

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Prehospital Care

Prehospital care of patients with amphetamine intoxication often requires physical and chemical restraint of the patient and treatment of complications of intoxication, including seizures, loss of competent airway, cardiac dysrhythmias, and trauma.

Emergency Department Care

Consultations

Medication Summary

Medications available for amphetamine toxicity include gastric decontaminants (charcoal with or without sorbitol), sedatives to control CNS stimulation caused by amphetamines (benzodiazepines, antipsychotics), muscle relaxants (benzodiazepines, dantrolene), and several drugs to control possible hemodynamic cardiovascular disturbances (alpha-adrenergic blockers, nitrates, diuretics).

Activated charcoal

Clinical Context:  Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingestion of poison. May administer as aqueous suspension or combine with cathartic (usually sorbitol 70%) in the presence of active bowel sounds.

Repeat dose, if necessary (without cathartic), to adsorb large pill masses or drug packages.

With superactivated forms, use of doses of 0.5 g/kg PO may be possible.

Class Summary

These agents are used to adsorb amphetamine after acute ingestion and to limit absorption into systemic circulation. Limited utility beyond 4 h of ingestion, unless the patient ingested sustained-release formulation or is suspected of being a body packer (ie, ingestion of a large amount of drug in a plastic bag or condom to smuggle or avoid arrest). Charcoal is not beneficial for other routes of exposure (eg, IV, inhalation or injection). Clinician should be aware of potential risk of charcoal aspiration and death due to aspiration pneumonia, especially in patients with altered mental status and/or having seizures. Prudent airway control is recommended in such population.

Lorazepam (Ativan)

Clinical Context:  Beneficial for sedative and anticonvulsant effects. In addition, the calming effects may prove beneficial for the adverse cardiovascular effects (eg, hypertension, tachycardia) of amphetamines.

Diazepam (Valium)

Clinical Context:  Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Third-line agent for agitation or seizures because of shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.

Midazolam (Versed)

Clinical Context:  Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to evaluate sedative effects fully before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Class Summary

These agents are important for sedation counteracting the CNS and PNS excitation of amphetamines. A benzodiazepine is generally considered as the first agent of choice for hypertension and agitation, in addition to their utility for treating seizures.

Haloperidol (Haldol)

Clinical Context:  DOC for patients with acute psychosis when no contraindications exist. Noted for high potency and low potential for causing orthostasis. Downside is the high potential for EPS (dystonia) and lowering the seizure threshold.

Use in acute amphetamine toxicity is controversial.[20] If haloperidol is being considered, administer a benzodiazepine first. May then be used as adjunctive therapy to control agitation in afebrile patients with normal vital signs.

Parenteral dosage form may be admixed in syringe with 2 mg lorazepam for better anxiolytic effects.

Class Summary

Antipsychotics are used to manage psychosis, agitation, and hyperthermia that may result from amphetamine use.

Dantrolene (Dantrium)

Clinical Context:  Has been used successfully in isolated case reports to control hyperthermia; however, efficacy has not been established for amphetamine-associated hyperthermia. Reverse of hyperthermic effects may take several hours. Because morbidity and mortality from hyperthermia is closely correlated with severity and duration of hyperthermia, aggressive cooling (eg, ice bath) and agents that work more readily to reverse hyperthermia are preferred over dantrolene.

Class Summary

These agents are used to control or reverse hyperthermic effects. Most hyperthermia is mediated by neuromuscular agitation.

Phentolamine (Regitine)

Clinical Context:  Alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on the alpha-adrenergic receptors.

Nitroprusside (Nitropress)

Clinical Context:  Produces vasodilation and increases inotropic activity of the heart. May exacerbate myocardial ischemia at higher doses by increasing heart rate.

Nitroglycerin IV (Deponit, Nitro-bid, Nitrostat)

Clinical Context:  Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure. Valuable for controlling cardiac pain and pulmonary edema.

May administer bolus of 12.5-25 mcg or give a 400-mcg tab SL as a bolus before continuous infusion.

Initial infusion rate of 10-20 mcg/min may be increased 5-10 mcg/min q5-10min until desired clinical or hemodynamic response is achieved. Infusion rates of 500 mcg/min occasionally have been required.

Class Summary

Alpha-adrenergic antagonists control peripheral vasoconstriction that results from sympathetic stimulation due to amphetamines. Treating with a beta-blocker to control the heart rate will leave unopposed alpha activity that causes vasoconstriction. Alpha-adrenergic antagonists specifically may be used to treat severe headache, SAH, cardiac ischemia, and hypertension associated with amphetamines. Use nitrates to control vasoconstriction and hypertensive emergency.

Furosemide (Lasix)

Clinical Context:  Increases excretion of water by interfering with chloride-binding cotransport system that, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.

Class Summary

These agents are used to control and treat pulmonary edema and could be beneficial in a hypertensive crisis.

Further Inpatient Care

Further Outpatient Care

Transfer

Complications

Prognosis

Author

Neal Handly, MD, MS, MSc, Associate Research Director, Department of Emergency Medicine, Hahnemann Hospital; Assistant Professor of Emergency Medicine, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Miguel C Fernandez, MD, FAAEM, FACEP, FACMT, FACCT, Associate Clinical Professor, Department of Surgery/Emergency Medicine and Toxicology, University of Texas School of Medicine at San Antonio; Medical and Managing Director, South Texas Poison Center

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

References

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Amphetamine and epinephrine.

Amphetamine and epinephrine.