Sympathomimetic Toxicity 

Updated: Mar 02, 2021
Author: Paul Kolecki, MD, FACEP; Chief Editor: Asim Tarabar, MD 

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 2019, 66,822 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. According to the US Drug Enforcement Agency (DEA), reports of methamphetamine combined with fentanyl increased 173% from 2016 to 2017.[3]

There has been an increase in synthetic alternatives to more traditional illegal drugs of abuse; 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 identifed 541 different NPS on the market in 2018.[4]

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.

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.[5]

Among the most common NPS are the following[6]

  • 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. 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 involves physical and, more importantly, pharmacologic control of agitation.  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 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.

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).

Epidemiology

Sympathomimetic poisoning continues to be a very common toxicologic emergency. The 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 66,822 sympathomimetic and street drug exposures and 205 fatalities.[1]

In the 2020 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 27 million.[4]

According to the Centers for Disease Control and Prevention, in 2017 there were 10,333 psychostimulant drug-poisoning deaths in the United States, representing a 37% increase from 2016. The majority of these deaths were attributed to phenethylamines (including MDMA, amphetamine, and methamphetamine), and cathinones (eg, ethylone).[3]

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%).[7]  In addition to rhabdomyolysis, a systematic review of nephrotoxicity from drugs of abuse identified the following renal complications[8] :

  • Cocaine - Renal hypertension, renal infarction; with cocaine adulterated with levamisole, pauci-immune crescentic glomerulonephritis 
  • Methamphetamines -  Prerenal azotemia, malignant hypertensive nephropathy, hyponatremia, necrotizing vasculitis
  • Bath salts - Anuric acute kidney injury

 

 

Presentation

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 US Food and Drug Administration (FDA) because of the risk of intracranial hemorrhage associated with its use. The FDA has also banned the sale of ephedra and ephedra-containing products, but those can be purchased over the Internet..

Maintain a high index of suspicion of sympathomimetic poisoning when treating an unknown overdose, especially in patients who present with the sympathomimetic toxidrome.

Another aid in the history of sympathomimetic poisoning is that the onset of symptoms usually occurs within 2 hours after exposure. Life-threatening complications typically occur within 2-6 hours postexposure.

Inadvertent exposure to methamphetamine can occur in buildings that have been used for the clandestine manufacture of the drug and have become contaminated with it. In 2015, an Australian family was found to have elevated methamphetamine levels and related adverse health effects after moving into a house that had previously been used as a methamphetamine drug laboratory and had not been decontaminated. Testing performed a year after police seized the laboratory showed dangerously elevated methamphetamine levels on surfaces within the home.[9]

Physical Examination

In adults, 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 from the violent 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 torsade 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, from cocaine) also can occur.[10]

  • 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.

Nonlethal manifestations of sympathomimetic toxicity in adults include the following:

  • Mydriasis
  • Tachycardia
  • Diaphoresis
  • Acute psychosis
  • Paranoia
  • Delirium
  • Bruxism (amphetamines and bath salts)

Although pediatric sympathomimetic toxicity is not as well documented as adult toxicity, pediatric patients with sympathomimetic toxicity present with the same signs and symptoms observed in adults. Some pediatric patients with sympathomimetic toxicity initially presents 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), so these patients may receive expensive ancillary tests to rule out significant disease.

 

DDx

 

Workup

Approach Considerations

Drugs levels generally are not helpful. However, routine screening for other potentially treatable toxins is recommended (eg, acetaminophen, salicylate).

Measurement of electrolytes, blood urea nitrogen (BUN) and serum creatinine, fingerstick and laboratory blood sugar, and calculation of the anion gap is recommended. Special attention should be given to the sodium level, as there are reports of hyponatremia associated with the use of ecstasy. Significant free-water intake along with sodium loss from excessive dancing (eg, rave dancing) may contribute to the development of hyponatremia. Healthy young women have been reported to be at risk of potentially fatal hyponatremia associated with ecstasy use.[11]

Measure total creatine kinase (CK) levels to check for rhabdomyolysis. Risk factors for developing rhabdomyolysis include delirium, seizures, coma, hypotension, cardiac dysrhythmia, and cardiac arrest.

Obtain an electrocardiogram (ECG) to check for evidence of myocardial ischemia and dysrhythmias. Measurement of cardiac markers (eg, troponins, creatine phosphokinase–MB [CPK-MB]) is also appropriate to screen for cardiac injury.[10]

Performing a urine drug screen is recommended. Urine drug screening for cocaine is fairly sensitive and specific and typically can detect the presence of cocaine if used in the past 1-3 days. Drug screening for amphetamines, however, is not as specific. Standard drug screening typically does not detect the presence of bath salts.

Consider a computed tomography (CT) scan of the head to rule out intracerebral bleeds in unresponsive patients or those with focal neurologic deficits.

 

 

Treatment

Approach Considerations

Managing the airway and controlling agitation are the two main prehospital treatment concerns. Many patients with sympathomimetic poisoning present in an agitated state and may require physical and/or chemical restraint. A rapid bedside blood glucose test should be performed to rule out hypoglycemia. Hypoglycemia should be treated if detected.

General supportive care is the main treatment measure for sympathomimetic toxicity because no antidote exists. Immediate assessment of the airway, breathing, and circulation is recommended, followed by continuing close monitoring of vital signs. Benzodiazepines remain the initial agent of choice to treat sympathomimetic-induced tachycardia, agitation, seizures, hypertension, and hyperthermia.

If inpatient care is required, it should be under the direction of a medical toxicologist or a physician with expertise in critical care.

Emergency Department Care

Sympathomimetic toxicity is frequently associated with significant agitation, thus necessitating the use of physical restraints and chemical sedation. However, physically restrained patients with sympathomimetic-associated agitation or hyperthermia have an associated significant risk of sudden death. If physical restraints are necessary, the rapid and liberal use of chemical sedation to control agitation is strongly recommended. Benzodiazepines (eg, diazepam) are the safest first approach in calming sympathomimetic-poisoned patients. They should be administered frequently in titrated doses.

Consider gastric decontamination for oral ingestions of sympathomimetic agents. Gastric decontamination is associated with subsequent vomiting and aspiration, so airway control is strongly recommended prior to any gastric decontamination. In addition, the patient's airway, breathing, circulation, and agitation should be stabilized beforehand.

Measurement of the core temperature of sympathomimetic poisoned patients is imperative. If hyperthermia is present, standard cooling measures should be initiated. Controlling agitation significantly helps in cooling a hyperthermic patient.

Hypertension unresponsive to sedation should be treated with a rapidly acting and easily titrated agent (eg, nicardipine).

Seizures should be promptly controlled with benzodiazepines and/or barbiturates. Obtaining a CT scan of the brain for all sympathomimetic toxic patients who seize, develop a focal neurologic deficit, or experience a severe headache with or without accompanying hypertension is recommended.

Consider psychiatric evaluation before discharging patients from the hospital. Most patients with sympathomimetic toxicity who remain asymptomatic after 6 hours postingestion may be medically discharged; however, patients who have ingested long-acting preparations typically should be monitored for 24 hours. Most of these patients are admitted to a telemetry floor or an intensive care unit. 

 

Synthetic cathinones

The toxicologic effects of synthetic cathinones mimic those of the amphetamines and MDMA, and treatment is primarily supportive, focusing on management of the agitation, fever, hyponatremia, and end-organ complications that can occur with these agents. The main adverse effects are cardiovascular (hypertension, tachycardia, angina, myocarditis) and neuropsychiatric (agitation, aggression, dystonia, and hyperreflexia). Hyponatremia may result in cerebral edema and death, and should be managed like MDMA-related hyponatremia, with fluid restriction for mild cases and hyperosmotic agents for cerebral edema.[12]  

For a patient with MDMA-induced severe hyponatremia, a rapid increase in serum sodium by 4 - 6 mEq/L (4-6 mmol/L) is recommended. This is customarily accomplished by prompt administration of a 100 ml IV bolus of 3% sodium chloride (hypertonic saline) over 10 minutes.

Consultations

Consultation from the regional poison control center or a local medical toxicologist (certified by the American Board of Medical Toxicology and/or the American Board of Emergency Medicine) for additional information and patient care recommendations is recommended.

Prolonged critical care management often is required for the numerous complications that may occur with severe overdose (eg, hyperthermia, seizures, acute respiratory distress syndrome [ARDS], acute kidney injury, rhabdomyolysis, central nervous system dysfunction).

 

Medication

Medication Summary

Treatment of sympathomimetic toxicity is focused on controlling agitation, managing seizure activity, and treating hypertension unresponsive to sedation. The most accepted pharmacologic option for controlling agitation is the use of benzodiazepines. Butyrophenones (eg, droperidol, haloperidol) lower the seizure threshold, increase the risk of hyperthermia, and may prolong the QT interval; the use of butyrophenones is NOT recommended. Sympathomimetic-induced seizures should be treated with benzodiazepines or barbiturates (eg, phenobarbital). Hypertension that is not controlled with benzodiazepine-induced sedation should be managed with a short-acting, easily titrated agent (eg, nicardipine).

Benzodiazepines and other sedatives

Class Summary

Used for controlling sympathomimetic-induced agitation.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Individualize dosage and increase cautiously to avoid adverse effects. Easily titrated with a long half-life.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life.

By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Excellent when patient requires sedation for more than 24 h.

Midazolam (Versed)

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 fully evaluate sedative effects 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.

Phenobarbital (Barbita, Luminal)

Interferes with transmission of impulses from thalamus to cortex of brain. Used for sympathomimetic-induced seizure unresponsive to diazepam.

Cardiovascular agents

Class Summary

Control sympathomimetic-induced hypertension.

Nitroglycerin IV (Deponit, Nitrostat)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production, resulting in a decrease in blood pressure.

May administer bolus of 12.5-25 mcg 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 have occasionally been required.

Calcium Channel Blockers

Nicardipine (Cardene, Cardene IV, Cardene SR)

Rapidly acting, easily titratable calcium channel blocker.