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 widely abused throughout the United States, and its market has expanded in areas where in the past it did not have a major presence, particularly the Northeast. [1] In 2022, 46,753 single cases of stimulant and street drug exposures were reported to the American Association of Poison Control Centers. [2] Trauma in methamphetamine users has increased significantly, and these patients are posing a financial burden on trauma centers. [3] Methamphetamine use has also been linked to a rise in HIV transmission.
According to the US Drug Enforcement Agency (DEA), reports of methamphetamine combined with fentanyl increased 173% from 2016 to 2017 and continues to climb. Cases increased from 656 in 2017 to 1618 in 2019. [1]
Synthetic alternatives to more traditional illegal drugs of abuse have been increasing; these are the 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.
The United Nations Office on Drugs and Crime identified 618 different NPS on the market in 2021, 87 of which were newly identified. [4] The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has been monitoring around 880 NPS, 52 of which were first reported in Europe in 2021. EMCDDA reported that of the NPS seized in 2021, the majority (65%) consisted of three cathinone powders: 3-methylmethcathinone (3-MMC), 3-chloromethcathinone (3-CMC), and N-ethylexedrone. [5]
The first stimulant-like NPS to appear in the US, in late 2010, were the synthetic cathinones—"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. [6]
Bath salts consist of powders or crystals that are taken 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 and signs 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 does methylone or mephedrone. [7]
Among the most common NPS are the following [8]
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Methylethcathinone (4-MEC)
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3-fluoromethcathinone (3-FMC)
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4-fluoromethcathinone (4-FMC)
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Buphedrone (alpha-methylamino-butyrophenone)
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Butylone (beta-keto-N-methyl-3,4-benzodioxyolybutanamine)
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Methedrone (4-methoxymethcathinone)
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Pentedrone (α-methylaminovalerophenone)
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Naphyrone (naphthylpyrovalerone)
The many different sympathomimetic agents produce their physiologic and toxicologic properties through several different mechanisms. Nevertheless, 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. The treatment 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 intervention is control of agitation, principally with pharmacologic measures. If physical restraints are necessary, rapid administration of a pharmacologic agent to control agitation is recommended.
For patient education information, see Drug Overdose, as well as Synthetic Cathinones ("Bath Salts").
Pathophysiology
Sympathomimetic agents produce their physiologic and toxic effects by five different mechanisms, as follows:
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Direct stimulation of the alpha- and beta-adrenergic receptors. Albuterol is a very commonly used direct-acting beta2-agonist.
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Indirect release of norepinephrine from the presynaptic cytoplasm through a process that bypasses exocytosis. Amphetamine and its derivatives work through this mechanism.
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Direct stimulation of adrenergic receptors and an indirect release of presynaptic norepinephrine. Dopamine is the classic example of a mixed-acting agent.
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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.
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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.
Etiology
Poisoning from sympathomimetic agents occurs from prescription, nonprescription, and illegal drugs. Typically, prescription and over-the-counter sympathomimetic agents are inhaled or ingested.
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).
Epidemiology
Sympathomimetic poisoning continues to be a very common toxicologic emergency. The 2022 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 46,753 sympathomimetic and street drug exposures and 186 fatalities. [2]
In the 2023 World Drug Report, the United Nations Office on Drugs and Crime estimated the combined number of global users of amphetamines, methamphetamine, and other pharmaceutical stimulants at 42 million. [4]
According to the Centers for Disease Control and Prevention, in 2021 there were more than 33,000 psychostimulant drug-poisoning deaths in the United States, representing a 37% increase from 2020. The majority of these deaths were attributed to phenethylamines (including MDMA, amphetamine, and methamphetamine), and cathinones (eg, ethylone). [9]
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.
In a study of 102 patients with sympathomimetic toxicity, rhabdomyolysis occurred in 42% of subjects. Rhabdomyoysis was most prevalent in users of synthetic cathinones (63%) but was also seen in MDMA (40%) and cocaine users (33%). [10] In addition to rhabdomyolysis, a systematic review of nephrotoxicity from drugs of abuse identified the following renal complications [11] :
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Cocaine - Renal hypertension, renal infarction; with cocaine adulterated with levamisole, pauci-immune crescentic glomerulonephritis
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Methamphetamines - Prerenal azotemia, malignant hypertensive nephropathy, hyponatremia, necrotizing vasculitis
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Bath salts - Anuric acute kidney injury
