DESCRIPTION

• Excess autonomic stimulation by adrenergic agents produces the clinical syndrome typically described as “sympathomimetic.”
• The sequelae of sympathomimetic overdose are generally neurologic, cardiovascular, and psychiatric.
• Severe problems may include agitation-induced hyperthermia, cardiac dysrhythmia, hypertension, myocardial ischemia, infarction, cerebrovascular accident (CVA), seizure, and cardiovascular collapse.

EPIDEMIOLOGY

• Cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA; commonly called “Molly” or “ecstasy”) are the three most common illicit stimulant drugs causing emergency visits in the United States.
• Prescription stimulants such as methylphenidate and albuterol are often frequent causes of intentional as well as unintentional poisoning.
• Bath salts (mephedrone and methylenedioxypyrovalerone [MDPV] among others) appear to be associated with a much higher incidence of psychotic events than other sympathomimetics.
• A number of potent amphetamine analogs, such as paramethoxymethamphetamine (PMA), which have a high incidence of morbidity and mortality, are increasingly common components of tablets sold as MDMA.

PATHOPHYSIOLOGY

• Relevant pathophysiology is based on the adrenergic receptor type stimulated by the drug in question. The adrenergic receptors of relevance include α₁, β₁, and β₂ receptors.
• Common adverse effects of stimulant toxicity include the following:
  • Tachycardia, palpitations, chest pain, and tremor
  • Hypertension
  • Nausea, vomiting
  • Anxiety, fear, and headache also may occur.
  • More severe symptoms may be associated, if associated with end-organ injury such as stroke or intracranial hemorrhage, myocardial infarction, or other cardiovascular injury.
• Sympathomimetic toxicity is highly variable depending on the half-life. For most amphetamines and cocaine, this typically peaks in 1 to 2 hours and lasts 4 to 8 hours. Sustained-release medications may alter this time course and cause much longer toxicity.
• Ephedrine and pseudoephedrine stimulate both α and β receptors:
  • Excessive cardiovascular stimulation results in symptoms qualitatively similar to those that occur with catecholamines.
  • Ephedrine and pseudoephedrine have weaker penetration of the CNS relative to drugs of abuse.
  • As a result, users may suffer from systemic complications of the relatively larger doses necessary to achieve the CNS “high” of other stimulants.
• Isoproterenol, rarely used, is the prototypical nonselective β-agonist causing the following:
  • Tachycardia, hypotension, tachydysrhythmia, myocardial ischemia, and flushing due to its cardiostimulatory and vasodilatory properties
  • Commonly, CNS effects of anxiety, fear, and headache occur.
• Selective β₂-adrenergic agonists are commonly used, and these include albuterol, levalbuterol, salmeterol, terbutaline, and others. Besides stimulant toxicity, other effects of β₂ agonists include:
  • Hypotension, often with widened pulse pressure
  • Hyperglycemia and hypokalemia
  • Elevation of creatine phosphokinase (CPK) as well as troponin, although myocardial infarction is never expected to occur in otherwise healthy children with selective β₂ agonist exposure
• Selective α₁ agonists include phenylephrine and phenylpropanolamine, although the latter is no longer commercially produced in any meaningful quantity in the United States.
  • Hypertension due to direct vasoconstrictive effects is the most common effect.
  • Reflex bradycardia may occur, particularly with phenylpropanolamine.
  • Headache due to elevated BP and even CVA may occur.

ETIOLOGY

Causative agents:

• Agents with combined α- and β-adrenergic activity: all amphetamines, cocaine, ephedrine, norepinephrine, pseudoephedrine, and dopamine
• α₁-Adrenergic agonists: phenylephrine, phenylpropanolamine
• β-adrenergic agonists: nonselective β-agonist isoproterenol
• Selective β₁ agonists: dobutamine
• Selective β₂ agonists: albuterol, salmeterol, terbutaline
• Overdose from sympathomimetic agents occurs secondary to the use of prescription drugs, nonprescription drugs such as over-the-counter (OTC) cold medicine (e.g., pseudoephedrine), dietary supplements (e.g., ephedra, synephrine), and illicit drugs such as cocaine, amphetamine, and methamphetamine.
• Illicit drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), MDPV (bath salts)
• Recently, many newer amphetamine congeners have come into use. These are available for purchase over the internet, and until specific legislation can be passed against a certain new drug, it can be legal.
  • Examples of new but illegal stimulants are mephedrone and MDPV (“bath salts”).
  • 1,3-dimethylamylamine (DMAA) is an example of a stimulant widely sold over the internet. DMAA was briefly banned in the United States but is currently legal again.
• Theophylline and caffeine may cause a clinical syndrome of sympathomimetic poisoning.

ASSOCIATED-CONDITIONS

• Many sympathomimetic agents are capable of producing psychiatric symptoms, particularly psychosis.
• This psychosis is similar to or indistinguishable from schizophrenia.
• Two rare results of MDMA use include serotonin syndrome and syndrome of inappropriate antidiuretic hormone (SIADH) with symptomatic hyponatremia.