Amphetamine Toxicity

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Background

Amphetamines are a class of compounds that are abused in many regions of the world, including the 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 often used for attention deficit disorder and various over-the-counter diet pills.

Clinical effects of amphetamine abuse are significant and commonly observed in emergency departments (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.



View Image

Amphetamine and epinephrine.

The relative activities that amphetamines have to stimulate the receptors of these biogenic amines depend on the chemical substituents on the amphetamine molecule; thus, the clinical presentation depends 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. Research 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] Long-term 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.

Cardiovascular

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]

Long-term use of the drugs can lead to myonecrosis and dilated cardiomyopathy.[9, 10] Amphetamine use is also associated with myocardial infarction[11]

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.

According to National Institute on Drug Abuse estimates for 2015, 4.1% of 8th graders, 6.8% of 10th graders, and 7.7% of 12th graders had used amphetamines during the past year.[12] 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.

International

According to the United Nation's World Drug Report, amphetamine use worldwide declined overall from 2009 to 2013, mainly due to  trends in the Americas and Europe. However, a survey of students at institutes for higher education in Belgium found no change in the pattern of amphetamine use from 2005 to 2013.[13] Estimated worldwide prevalence of illicit use of amphetamine type stimulants in 2013 was 0.3-1.1%.[14]

Mortality/Morbidity

Acute overdose of amphetamines can result in the following:

Habitual amphetamine use produces toxic psychosis resembling paranoid schizophrenia. Hallucinations, delusions, and bizarre violent behavior are common.In a few patients, amphetamine use produces long-term paranoid schizophrenia; whether this results from unmasking underlying disease is unclear. Severe psychological depression and prolonged sleep follow chronic use and binges.

Race- and sex-related demographics

Amphetamine use characteristically occurs among single white men aged 20-35 years who are typically unemployed.[17] Data from rural populations reveal that whites use amphetamines significantly more than African Americans.[18] However, amphetamine use is becoming more common among women and other ethnic groups.

One 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.[19]

History

Patients with amphetamine intoxication often are identified by a change of mental status alone or associated with another injury and/or illness.Trauma often accompanies amphetamine intoxication and should be sought in the evaluation of the patient.

Central nervous system manifestations are as follows:

Cardiovascular manifestations are as follows:

Gastrointestinal manifestations are as follows:

Skin/cutaneous manifestations are as follows:

Genitourinary (GU) manifestations include difficult micturition. Ocular manifestations include mydriasis.

Physical

Physical examination findings may demonstrate the strong central nervous system and peripheral nervous system stimulation produced by amphetamine compounds. Hyperthermia accompanies and complicates significant amphetamine intoxication.[20] 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.

General findings are as follows:

Cardiovascular findings are as follows:

Central nervous system findings are as follows:

Cutaneous findings are as follows:

Other organ system findings are as follows:

Causes

See the list below:

Laboratory Studies

Patients with amphetamine intoxication who present with no life-threatening signs or symptoms may be treated with sedation and observation and may require no laboratory workup.

Patients who are experiencing seizures or prolonged mental status changes require rapid serum glucose determination (eg, fingerstick) and electrolyte testing.

Patients with suicidal ideations should have serum acetaminophen level checked.

Evaluate renal and hepatic function of patients who are demonstrating significant or prolonged hyperthermia and search for infectious causes.

When appropriate, evaluation may include urinalysis, urine culture, blood culture, spinal fluid analysis and staining, and culture of material from cutaneous sources.

Because hyperthermia may induce disseminated intravascular coagulation (DIC), monitor for DIC and treat appropriately if it occurs.

Obtain urine and serum creatinine kinase levels to monitor for rhabdomyolysis. If the dipstick result is positive for blood but shows few or no red blood cells on microscopic examination, rhabdomyolysis may be present.

Urine specimens for drug and toxicologic screens may be collected after Foley catheter placement if the physician believes that these tests will help guide therapy.

Usually, the presence of pure sympathomimetic toxidrome precludes the need for drug screening. However, with methamphetamine and other designer amphetamines, peripheral effects may not be observed.

Imaging Studies

Patients who are demonstrating only mild symptoms from amphetamine intoxication often respond to sedation and recover rapidly under observation. Such patients require no imaging studies unless trauma is suspected.

Obtain a chest radiograph for patients complaining of chest pain or respiratory distress. Obtain a CT scan of the head for patients with recurrent seizures or prolonged mental status changes if no metabolic cause can be quickly found and corrected.

Look for infectious causes in patients who are demonstrating significant or prolonged hyperthermia; this may include chest radiography, echocardiography, CT of the head and abdomen, and extremity ultrasonography of suspected abscesses.

Other Tests

Perform electrocardiographic testing and monitor patients complaining of chest pain. Obtain appropriate cardiac enzyme testing if pain is prolonged or cardiac injury is suspected.

Procedures

A lumbar puncture (LP) should be performed in hyperthermic patients with altered mental status, where CNS infection cannot be excluded.

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

Patients with amphetamine intoxication who present with no life-threatening signs or symptoms may be treated with sedation and observation.

Complications may require the physician to perform procedures to establish airway management or fluid resuscitation or to initiate vigorous cooling measures.

In patients with acute oral ingestion, GI decontamination is performed by the administration of activated charcoal. Orogastric lavage often is not necessary but may be performed when the patient presents with immediately life-threatening intoxication shortly after ingestion. Whole-bowel irrigation may be indicated in suspected cases of body stuffing or body packing (large quantities of drugs in wrapping for international transport or drug hiding, respectively).

Foley catheter placement may be useful to monitor urine output, particularly in situations in which diuretics are administered to manage pulmonary edema. Patients often have decreased urination due to the effects on bladder sphincter muscles to prevent passing urine. Other individuals may be dehydrated after recreational use in raves and club events. Quick assessment of bladder fullness can be performed with bedside ultrasonography or bladder palpation.

Agitation or persisting seizures in patients with amphetamine toxicity requires generous titration of benzodiazepines and a calm soothing environment. Avoid physical restraints, if possible.

Significant cardiac dysrhythmias may require cardioversion, defibrillation, and antidysrhythmics. Prolonged hypertension may present a cardiovascular risk. Use benzodiazepine sedation (nonspecific sympatholysis) to initially manage hypertension, if present. Refractory cases or cases associated with significant end-organ toxicity (eg, cardiovascular accident [CVA], myocardial ischemia) can be managed with intravenous phentolamine, nitroprusside, or nitroglycerin.

Avoid use of beta-blockers in order to prevent unopposed alpha effect (vasoconstriction). Note that combination alpha-adrenergic and beta-adrenergic antagonists may play a valuable role in managing tachycardias; this recommendation is based on class IIb evidence in the revision of unstable angina/non-ST segment elevation myocardial infarction guidelines by the American Heart Association (based on similarities of amphetamine and cocaine toxicities).[24]

Cardiogenic pulmonary edema can be managed with nitroglycerin and diuretics.

Aggressively cool hyperthermic patients with evaporative cooling, ice packs to the groin and axilla, and use of "ice-bath" (total body immersion in ice). Patients with severe hyperthermia (temperature >104°F) associated with psychomotor agitation may require immediate neuromuscular paralysis to rapidly decrease temperature. Temperature control should be achieved within 15-20 minutes upon presentation in order to prevent multiorgan failure and death.

Haloperidol is controversial[25] in the treatment of agitation in any patient with the potential to seize or develop hyperthermia because of associations with lowering the seizure threshold and altering thermoregulation.

Of all neuroleptic drugs, however, haloperidol rarely is associated with seizures (minimal effects on seizure threshold). In addition, animal studies suggest that haloperidol can antagonize amphetamine-induced hyperthermia. Haloperidol can be considered as an adjunct to benzodiazepines for afebrile patients with normal vital signs and psychomotor agitation that requires chemical restraint.

Look for and treat traumatic injuries in patients with amphetamine intoxication.

Consultations

A medical toxicologist may be consulted for assistance in the management of amphetamine toxicity cases. Patients who demonstrate focal neural deficits or have CT scans of the head that indicate bleeding may need neurologic or neurosurgical consultations. Patients who show significant cardiac injury may require cardiologic consultation.

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. 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.

Labetalol

Clinical Context:  Blocks beta1-, alpha-, and beta2-adrenergic receptor sites decreasing blood pressure.

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- and beta-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 can cause vasoconstriction. Combination alpha- and beta-adrenergic antagonists, such as labetalol, may have therapeutic value. 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 Outpatient Care

Patients may need referral for outpatient detoxification centers or for management of addictive behaviors.

Further Inpatient Care

Admission is appropriate for monitoring and treatment of the following severe sequelae of amphetamine use:

Transfer

A patient with stable vital signs who exhibits paranoid psychosis and has no evidence of cardiac, cerebral, renal, hepatic, or pulmonary complications of amphetamine use may need to be transferred to a psychiatric hospital for observation and treatment.

Complications

See the list below:

Prognosis

See the list below:

Patient Education

See the list below:

Author

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

Disclosure: Nothing to disclose.

Specialty Editors

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.

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.

Additional Contributors

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.

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Amphetamine and epinephrine.

Amphetamine and epinephrine.