eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Sympathomimetic

Author: Paul Kolecki, MD, FACEP, Associate Professor, Department of Emergency Medicine, Thomas Jefferson University Hospital, Director of Undergraduate Emergency Medicine Student Education, Jefferson Medical College, Philadelphia, PA, Consultant, Philadelphia Poison Control Center, Philadelphia, PA
Contributor Information and Disclosures

Updated: Mar 24, 2009

Introduction

Background

Poisoning from sympathomimetic agents occurs secondary to the use of prescription and nonprescription agents. The public commonly uses prescription sympathomimetic agents, especially for treating diseases such as asthma and narcolepsy. Examples of nonprescription sympathomimetic agents include the over-the-counter cold agents (containing ephedrine), illegal street drugs (eg, cocaine, amphetamines, methamphetamine), dietary supplements (eg, ephedra alkaloids), and the very popular illicit designer drugs (eg, 3,4-methylenedioxy methamphetamine [MDMA, "ecstasy"]).

Cocaine is one of the most commonly abused drugs in the United States, especially in urban areas. Methamphetamine is frequently made and abused throughout the United States. Recent reports state that methamphetamine use has been linked to a rise in HIV transmission. In 2007, approximately 46,000 cases of sympathomimetic and street drug exposures were reported to the American Association of Poison Control Centers.¹ Even more alarming are the number of out-of-hospital cardiac arrests secondary to sympathomimetic toxicity reported in the Seattle area and the number of deaths nationally secondary to sympathomimetics. Cocaine, methamphetamine, and ecstasy are 3 of the most common drug-related causes of emergency department visits in the United States. Methamphetamine use in trauma patients has increased significantly and has been associated with a financial burden on trauma centers.²

The many different sympathomimetic agents produce their physiologic and toxicologic properties through several different mechanisms. Toxicity secondary to these agents typically presents with classic sympathomimetic signs and symptoms that include tachycardia, hypertension, diaphoresis, hyperthermia, agitation, and combativeness.

The general treatment for preventing the potentially significant end-organ damage that is possible after overdose is similar for the sympathomimetic agents because their clinical presentation of toxicity is similar. Most sympathomimetic agents produce central stimulation following overdose. When central stimulation occurs in patients, the most important treatment involves physical and, more importantly, pharmacological control of their agitation.

Pathophysiology

Sympathomimetic agents produce their physiologic and toxic effects by 5 different mechanisms, as follows:

• The first mechanism involves direct stimulation of the alpha- and beta-adrenergic receptors. Albuterol is a very commonly used direct-acting beta2-agonist.
• The second mechanism involves the indirect release of norepinephrine from the presynaptic cytoplasm through a process that bypasses exocytosis. Amphetamine and its derivatives work through this mechanism.
• The third mechanism involves direct stimulation of adrenergic receptors and an indirect release of presynaptic norepinephrine. Dopamine is the classic example of a mixed-acting agent.
• The fourth mechanism involves the prevention of presynaptic uptake of norepinephrine. By preventing uptake, norepinephrine concentration rises in the synapse, leading to excessive stimulation of adrenergic receptors. Cocaine and the tricyclic antidepressants produce their sympathomimetic effects mainly by inhibiting presynaptic norepinephrine uptake.
• The final mechanism involves the prevention of norepinephrine metabolism. As norepinephrine is mainly metabolized by the enzyme monoamine oxidase, the monoamine oxidase inhibitors (MAOIs) are the class of drugs that produce their sympathomimetic effects through this final mechanism.

The pathophysiology of sympathomimetic toxicity is much more involved than what was just listed. To explore these mechanisms in more detail, references for further reading are provided in the reference section. An important clinical point is that the signs and symptoms produced by these 5 different mechanisms are very similar. In most cases, clinical poisoning by one sympathomimetic agent is indistinguishable from that of a second sympathomimetic agent with a different mechanism of action.

Frequency

United States

Sympathomimetic poisoning continues to be a very common toxicologic emergency. The 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported approximately 46,000 sympathomimetic and street drug exposures and approximately 180 fatalities.¹ This category includes exposures to amphetamines, cocaine, and methamphetamine.

Mortality/Morbidity

In 2007, the AAPCC reported approximately 180 deaths from stimulants and street drugs.¹
 
The exact number of stimulant deaths in 2006 is unknown but is expected to be greater than the number reported by the AAPCC.

Race

No scientific data have demonstrated that outcomes of sympathomimetic exposure are dependent on race.

Sex

No scientific data have demonstrated that outcomes of sympathomimetic exposure are dependent on sex.

Clinical

History

• Knowing that a sympathomimetic agent was ingested is helpful for treating a poisoned patient. Query patients about the use of cocaine, methamphetamine, and ecstasy. In addition, patients should be asked about their use of over-the-counter cold medications (containing ephedrine) and herbal preparations (eg, ephedra, Ma-Huang). Phenylpropanolamine used to be a very popular amphetamine sold over-the-counter; however, it was taken off the market by the Food and Drug Administration (FDA) because of the risk of intracranial hemorrhage associated with its use. The FDA banned the sale of ephedra and ephedra-containing products.
• Maintain a high index of suspicion of sympathomimetic poisoning when treating an unknown overdose, especially in patients that present with the sympathomimetic toxidrome.
• Another aid in the history of sympathomimetic poisoning is that the onset of symptoms usually occurs within 2 hours postexposure.
• Life-threatening complications typically occur within 2-6 hours postexposure.

Physical

Adult sympathomimetic toxicity produces typical adrenergic signs and symptoms, some of which can be deadly.

• Bronchospasm and wheezing can occur in patients who smoke crack cocaine. In addition, crack cocaine use can cause asthma exacerbations, pneumothorax, and lung injury.
• Hyperthermia associated with sympathomimetic toxicity may result secondary to the destructive behavior and extreme agitation experienced by these patients. The abuse of sympathomimetic agents in hot, humid environments (eg, dance clubs, summer evenings) can further exacerbate hyperthermia. Seizures resulting from overdose can also produce hyperthermia. Sympathomimetic-induced hyperthermia can produce significant morbidity (from end-organ damage) and death.
• Extreme hypertension can result in headache, hypertensive encephalopathy, and intracranial hemorrhage.
• Sympathomimetic toxicity also can result in asymptomatic hypertension, which may require an urgent reduction in blood pressure.
• The following cardiac arrhythmias may result from sympathomimetic toxicity:
  • Sinus and supraventricular tachycardia (including atrial fibrillation and atrial flutter)
  • Premature ventricular beats
  • Accelerated idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
  • Second-degree and third-degree heart block (as a reflex response to hypertension)
• Sympathomimetic-induced chest pain, myocardial ischemia, myocardial infarction, and cardiomyopathy (eg, cocaine) also can occur.
• Seizures, strokes, and intracerebral bleeds are well-documented complications of sympathomimetic toxicity.
• Dissecting thoracic aneurysms and mesenteric ischemia are rare but deadly consequences of sympathomimetic poisoning.
• Sympathomimetic toxic adult patients may also experience some nonlethal signs and symptoms, as follows:
  • Mydriasis
  • Tachycardia
  • Diaphoresis
  • Acute psychosis
  • Paranoia
  • Delirium Bruxism (amphetamines)
• Although adult poisoning is well documented, pediatric sympathomimetic toxicity is not. Pediatric patients with sympathomimetic toxicity present with the same signs and symptoms observed in adults.
  • One study noted that some pediatric patients with sympathomimetic toxicity initially presented with inconsolable crying, vomiting, and abdominal pain.
  • These signs and symptoms are also the presenting features of many serious pediatric diseases (eg, sepsis, intussusception, intracranial lesion), and several of these pediatric patients received expensive ancillary tests to rule out significant disease.

Causes

• Poisoning from sympathomimetic agents occurs secondary to the use of prescription agents, nonprescription agents, and illegal agents.
• Typically, prescription and over-the-counter sympathomimetic agents are inhaled or orally administered.
• In general, the inhalational agents (eg, albuterol, crack cocaine) have a quicker onset of action than the oral agents and a shorter duration of action.
• Sympathomimetic toxicity following ingestion typically peaks 1-4 hours postingestion and last 4-8 hours, but sustained-release preparations may alter this time course.
• The onset of toxicity following intravenous use of a sympathomimetic agent occurs within minutes.
• Presently, many illegal sympathomimetic agents are commonly abused.
  • On the streets, some of these illegal agents have interesting names that, for the most part, are based on the psychological effects produced by the specific drug.
  • In general, all sympathomimetic agents are rapidly absorbed when ingested.
  • The popular designer amphetamines (eg, ecstasy) and ephedrine are abused mainly by the oral route.
  • Abuse of sympathomimetic agents often occurs at contemporary disco or rave party scenes, where adolescents use them before and during hours of rigorous dancing in crowded rooms with a hot and humid atmosphere.
  • Many reports of adolescent morbidity (eg, dehydration, hyperthermia, cardiac dysrhythmias) and mortality are associated with the use of illegal sympathomimetic agents at discos and rave parties. Other recreational drugs used at rave parties include marijuana, ketamine, gamma-hydroxybutyrate (GHB), and gamma-butyrolactone (GBL).
  • Some of the illegal sympathomimetic agents are more commonly abused by the inhalational route (eg, crack cocaine, methamphetamine) or the IV route (eg, cocaine, methamphetamine, methcathinone) than by the oral route.
• The duration of action of illegal sympathomimetic agents differ based on their chemical structure. Methamphetamine has the chemical structure of amphetamine with an additional methyl group. The half-life of methamphetamine, however, is much longer (2-24 h) than that of amphetamine, thus partially accounting for methamphetamine's present popularity.
• The route of abuse also contributes to the duration of action of some of these illegal sympathomimetic agents. The duration of action of cocaine is more than 3 hours if ingested. However, the duration of action is much shorter after nasal snorting (1-2 h), inhalation (15-30 min), or IV injection (15-30 min).

• Search for CME/CE on This Topic »

• Toxicity, Lidocaine (Emergency Medicine)
• Toxicity, Mercury (Emergency Medicine)
• Toxicity, Fluoride (Emergency Medicine)
• Toxicity, Lead (Emergency Medicine)

• Sleep Disorders Center
• Narcolepsy Overview
• Narcolepsy Causes
• Narcolepsy Symptoms
• Narcolepsy Treatment

• Serotonin Toxicity, ECG Abnormalities Seen With Escitalopram Overdose
• Genetically Diverse Mouse Panel Predicts Individual Variability in Drug Toxicity
• "Substantial" Toxicity With Peginterferon Use: FDA Staff

• Bottoms Up: Methamphetamine Toxicity From an Unusual Route
• The Clinical Pharmacology of Intranasal l-Methamphetamine
• Impact of Tobacco Smoking and Smoking Cessation on Cardiovascular Risk and Disease