Epidemiology

A sympathomimetic agent is defined as any agent that may emulate the clinical effects of the endogenous sympathetic catecholamines epinephrine and norepinephrine. An exhaustive list of drugs falls into the class of sympathomimetics, ranging from over-the-counter and prescription agents to drugs of misuse and abuse (Box 149.1).

Clinically, sympathomimetics have been used as arousal agents in patients with barbiturate overdose, as weight loss preparations, and in the treatment of depression. Over-the-counter products are predominantly available as decongestants, and they also include weight loss and energy products. The U.S. Food and Drug Administration banned ephedrine and sibutramine, once popular dietary supplements for weight loss and arousal, but they can still be obtained illicitly.

Prescription and parenteral sympathomimetic agents are available for myriad medical illnesses, including hypersensitivity reactions, reactive airway disease, attention-deficit hyperactivity disorder, and cardiovascular compromise. Misused and abused licit and illicit agents comprise the remainder of sympathomimetics: cocaine, amphetamine derivatives (i.e., 3,4-methylenedioxymethamphetamine), and clenbuterol.

In 2010, data released by the University of Michigan in their Monitoring the Future Survey demonstrated that cocaine use among high school students had declined since 2007.¹ A difference in prevalence, which had decelerated, was noted. However, the year 2010 also saw a dramatic increase in the use of ecstasy, or 3,4-methylenedioxymethamphetamine (MDMA). Researchers believe that this shift may be the result of the adolescent population’s perception of a lower risk associated with MDMA.

Prescription agents continue to be a source of misuse. The rate of misuse of combination sympathomimetic products rose from 2009 to 2010. Overall, sympathomimetics remain a public health concern. According to the Drug Abuse Warning Network, these drugs accounted for almost 30% of all emergency department (ED) substance-related visits in 2009.²

Pathophysiology

The biogenic amines (histamine, tyrosine, and serotonin) and the catecholamines (epinephrine, norepinephrine, and dopamine) are found within the central nervous system (CNS) and their synthesis, release, and metabolism are very similar. Tyrosine is converted into dopamine, and subsequently norepinephrine, whereas serotonin is derived from tryptophan and resides in separate vesicles. Despite differences in synthesis and packaging, calcium is the common stimulus for exocytosis. Once an amine is released into the synapse, reuptake can occur through transport proteins. Intracellularly, these products are either metabolized by the enzyme monoamine oxidase or repackaged and recycled. In the periphery, these amines may undergo extracellular metabolism by catechol-O-methyltransferase.

Sympathetic stimulation triggers the release of epinephrine and norepinephrine from the adrenal medulla. However, norepinephrine can also be released into the circulation, with effects consistent with α-adrenergic stimulation (i.e., vasoconstriction). Dopamine, found within nerve terminals in the CNS, is also present in the periphery. Excessive dopamine concentrations in the CNS can manifest as psychosis, which is clinically indistinguishable from primary psychosis. Similarly, serotonin found both centrally and peripherally can have a broad spectrum of effects modulating mood, appetite, sleep, and thermoregulation. In the CNS, an abundance of serotonin can induce euphoria, or an elevated mood.

Pharmacotherapeutics can mimic catecholamine release by stimulating release, inhibiting metabolism, and impairing reuptake. The specific clinical effects produced by a sympathomimetic agent are related to its pharmacology, whereas the relative effect on the two distinct adrenergic receptors, α and β, can be used to predict the clinical response. Generally, α-adrenergic receptor agonism results in vasoconstriction, whereas the inverse effect is appreciated with β-adrenergic receptor stimulation. The resultant vasodilatation produces hypotension and tachycardia. β-Adrenergic agonism can also lead to hypokalemia, hyperglycemia, tremor, and acidemia.

Sympathomimetics may act directly, indirectly, or in combination to produce sympathomimesis. Direct-acting sympathomimetics are the catecholamines epinephrine and norepinephrine, directly administered to the patient. Indirect-acting sympathomimetics are agents that either increase the release of endogenous catecholamines or impair their reuptake. In addition, indirect-acting sympathomimetics can trigger the release of other biogenic amines such as serotonin and dopamine. Finally, mixed-acting sympathomimetics exert their effect through direct and indirect-acting properties. Despite these underlying differences, the clinical presentation can be virtually indistinguishable. Clinical manifestations may also vary according to the location where the neurotransmitter predominance occurs.

Presenting Signs and Symptoms

Tachycardia, hypertension, diaphoresis, mydriasis, hyperthermia, and psychomotor agitation characterize the sympathetic toxidrome, which can be further divided according to α- and β-adrenergic receptor effects. α-Adrenergic subtype 1, or α₁, receptor agonism results in vasoconstriction, whereas postsynaptic α₂ agonism results in hypotension and sedation. These effects are classically observed in the therapeutic use of clonidine. Like α receptors, β-adrenergic receptors have clinically distinct subtypes, 1 and 2. β₁ agonism increases cardiac output by improving chronotropy. β₂ agonism is specifically responsible for vasodilation, as well as secondary effects such as hypokalemia, hyperglycemia, acidemia, and tremor.

Methylxanthine exposure is virtually indistinguishable from β stimulation because of a shared final pathway, which increases intracellular cyclic adenosine monophosphate. Methylxanthines also result in increased circulating catecholamines and inhibit adenosine receptors. Potential clinical effects associated with sympathomimetics are listed in Box 149.2.

Box 149.2 Clinical Manifestations of Sympathomimetics

Cardiovascular

Hypertensive emergencies

Acute coronary syndrome

Cerebrovascular accident

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