Sympathomimetic Toxicity
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.
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 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]
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]
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 has also banned the sale of ephedra and ephedra-containing products, but these 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 postexposure. 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. [8]
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. [9]
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:
MydriasisTachycardiaDiaphoresisAcute psychosisParanoiaDeliriumBruxism (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.
Differential Diagnoses
Hypertensive Emergencies
Scorpion Envenomations
Toxicity, Thyroid Hormone
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.
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. [9]
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.
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. The liberal use of chemical sedation in such instances 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, sodium nitroprusside).
Seizures should be rapidly 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. [10]
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 the severe overdose (eg, hyperthermia, seizures, acute respiratory distress syndrome [ARDS], renal failure, rhabdomyolysis, central nervous system dysfunction).
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 should be managed with a short-acting, easily titrated agent (eg, nitroprusside) if it is not controlled with benzodiazepine-induced sedation.
Benzodiazepines and other sedatives
Used for controlling sympathomimetic-induced agitation.
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.
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.
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.
Interferes with transmission of impulses from thalamus to cortex of brain. Used for sympathomimetic-induced seizure unresponsive to diazepam.
Cardiovascular agents
Control sympathomimetic-induced hypertension.
Rapidly acting, easily titrated antihypertensive. Produces vasodilation and increases inotropic activity of the heart. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate.
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.
References
1 Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 2017 Dec. 55 (10):1072-1252. [Medline]. [Full Text].
2 Swanson SM, Sise CB, Sise MJ, Sack DI, Holbrook TL, Paci GM. The scourge of methamphetamine: impact on a level I trauma center. J Trauma. 2007 Sep. 63(3):531-7. [Medline].
3 United Nations Office on Drugs and Crime. Market Analysis of Synthetic Drugs: Amphetamine-type stimulants, new psychoactive substances. World Drug Report 2017: Booklet 4. United Nations; 2017. 1-57. [Full Text].
4 Baumann MH, Bukhari MO, Lehner KR, Anizan S, Rice KC, Concheiro M, et al. Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs. Curr Top Behav Neurosci. 2017. 32:93-117. [Medline]. [Full Text].
5 Karila L, Megarbane B, Cottencin O, Lejoyeux M. Synthetic cathinones: a new public health problem. Curr Neuropharmacol. 2015 Jan. 13 (1):12-20. [Medline]. [Full Text].
6 O'Connor AD, Padilla-Jones A, Gerkin RD, Levine M. Prevalence of Rhabdomyolysis in Sympathomimetic Toxicity: a Comparison of Stimulants. J Med Toxicol. 2015 Jun. 11 (2):195-200. [Medline]. [Full Text].
7 Mansoor K, Kheetan M, Shahnawaz S, Shapiro AP, Patton-Tackett E, Dial L, et al. Systematic review of nephrotoxicity of drugs of abuse, 2005-2016. BMC Nephrol. 2017 Dec 29. 18 (1):379. [Medline]. [Full Text].
8 Wright J, Kenneally ME, Edwards JW, Walker GS. Adverse Health Effects Associated with Living in a Former Methamphetamine Drug Laboratory - Victoria, Australia, 2015. MMWR Morb Mortal Wkly Rep. 2017 Jan 6. 65 (52):1470-1473. [Medline]. [Full Text].
9 Schwartz BG, Rezkalla S, Kloner RA. Cardiovascular effects of cocaine. Circulation. 2010 Dec 14. 122(24):2558-69. [Medline].
10 Caffrey CR, Lank PM. When good times go bad: managing 'legal high' complications in the emergency department. Open Access Emerg Med. 2018. 10:9-23. [Medline]. [Full Text].
11 Wood DM, Davies S, Greene SL, Button J, Holt DW, Ramsey J, et al. Case series of individuals with analytically confirmed acute mephedrone toxicity. Clin Toxicol (Phila). 2010 Nov. 48(9):924-7. [Medline].
12 Centers for Disease Control and Prevention. Emergency department visits after use of a drug sold as "bath salts" --- michigan, november 13, 2010--march 31, 2011. MMWR Morb Mortal Wkly Rep. 2011 May 20. 60(19):624-7. [Medline].
13 Budisavljevic MN, Stewart L, Sahn SA. Hyponatremia associated with 3,4-methylenedioxymethylamphetamine ("Ecstasy") abuse. Am J Med Sci. 2003 Aug. 326(2):89-93. [Medline].
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