Sympathomimetic Toxicity

Updated: Jul 17, 2018
  • Author: Paul Kolecki, MD, FACEP; Chief Editor: Asim Tarabar, MD  more...
  • Print
Overview

Practice Essentials

Poisoning from sympathomimetic agents occurs with both prescription and nonprescription drugs. Prescription sympathomimetic agents are in common use, especially for treating diseases such as asthma and narcolepsy. Examples of nonprescription sympathomimetic agents include the over-the-counter cold preparations (containing ephedrine), illegal street drugs (eg, cocaine, amphetamines, methamphetamine, mephedrone), 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. In 2016, approximately 66,132 cases of stimulant and street drug exposures were reported to the American Association of Poison Control Centers. [1]  Trauma in methamphetamine users has increased significantly, and these patients are posing a financial burden on trauma centers. [2]  Methamphetamine use has also been linked to a rise in HIV transmission. 

There has been an increase in synthetic alternatives to more traditional illegal drugs of abuse, so-called designer drugs, legal highs, or research chemicals, which are collectively known as new psychoactive substances (NPS). The global abuse of NPS is aided by easy access to information on the Internet. Between 2009 and 2016, the United Nations identifed 739 NPS in 106 countries with a core group of approximately 80 persistent NPS. [3]  

The first stimulant-like NPS to appear in the US, in late 2010, were the "bath salts". These are made up of three main synthetic compounds: 4-methyl-N-methylcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 3,4-methylenedioxypyrovalerone (MDPV) all of which are now illegal in the United States. Bath salts consist of powders or crystals that are administered intra-nasally or orally. In low doses they induce effects such as increased energy and mood elevation, but high doses or binge use causes severe symptoms that include hallucinations, psychosis, increased heart rate, high blood pressure ,and hyperthermia, often accompanied by combative or violent behaviors. These can result in breakdown of muscle tissue, and kidney failure, which could result in death. MDPV appears to be more likely to cause life-threatening complications than methylone or mephedrone. [4]

Among the most common NPS are the following [5]

  • Methylethcathinone (4-MEC)
  • 3-fluoromethcathinone (3-FMC)
  • 4-fluoromethcathinone (4-FMC)
  • Buphedrone (alpha-methylamino-butyrophenone)
  • Butylone (beta-keto-N-methyl-3,4-benzodioxyolybutanamine)
  • Methedrone (4-methoxymethcathinone)
  • Pentedrone (α-methylaminovalerophenone)
  • Naphyrone (naphthylpyrovalerone)

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

Because of that similarity in clinical presentation, the treatment for sympathomimetic toxicity follows the same overall approach regardless of the agent involved. It focuses on preventing the potentially significant end-organ damage that is possible after overdose. Overdose of most sympathomimetic agents produces central stimulation, and the most important treatment involves physical and, more importantly, pharmacological control of agitation.

For patient education information, see the Sleep Disorders Center, as well as Narcolepsy.

Next:

Pathophysiology

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

  • Direct stimulation of the alpha- and beta-adrenergic receptors. Albuterol is a very commonly used direct-acting beta2-agonist.
  • Indirect release of norepinephrine from the presynaptic cytoplasm through a process that bypasses exocytosis. Amphetamine and its derivatives work through this mechanism.
  • Direct stimulation of adrenergic receptors and an indirect release of presynaptic norepinephrine. Dopamine is the classic example of a mixed-acting agent.
  • Prevention of presynaptic uptake of norepinephrine. As a result, 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.
  • 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 the above list. 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 another sympathomimetic agent with a different mechanism of action.

Previous
Next:

Etiology

Poisoning from sympathomimetic agents occurs from prescription, nonprescription, and illegal drugs. Typically, prescription and over-the-counter sympathomimetic agents are inhaled or orally administered.

In general, all sympathomimetic agents are rapidly absorbed when ingested and the inhalational agents (eg, albuterol, crack cocaine) tend to 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 lasts 4-8 hours, but sustained-release preparations may have a different time course. The onset of toxicity following intravenous (IV) use of a sympathomimetic agent occurs within minutes. 

The popular designer amphetamines (eg, ecstasy) and ephedrine are taken mainly by the oral route. 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 inhaled (eg, crack cocaine, methamphetamine) or injected intravenously (eg, cocaine, methamphetamine, methcathinone) rather than ingested.

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).

Previous
Next:

Epidemiology

Sympathomimetic poisoning continues to be a very common toxicologic emergency. The 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System noted approximately 67,879 sympathomimetic and street drug exposures and approximately 260 fatalities. [1]

In the 2017 World Drug Report, the United Nations estimated the number of global users of methamphetamine at 22 million. The global use of amphetamines and other prescription stimulants was 37 million. [3]

Previous
Next:

Prognosis

Prolonged sympathomimetic drug use can induce hypertension, hyperthermia, myocardial infarction, cardiac arrhythmias, central nervous system (CNS) disasters, and thoracic and mesenteric vascular disasters. Individuals who present with cardiovascular collapse and hyperthermia tend to have a poor long-term prognosis. The prognosis also worsens for individuals who abuse multiple drugs in combination with alcohol.

Rhabdomyoysis was most prevalent in users of synthetic cathinones (63%) and was also seen in MDMA (40%) and cocaine users (33%). [6]  Other renal complications included pauci-immune crescentic glomerulonephritis, prerenal azotemia, malignant hypertensive nephropathy, hyponatremia, and necrotizing vasculitis. [7]

Previous