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Sympathomimetics
Indications
Sympathomimetic agents are used to augment the endogenous catecholamines of the sympathetic nervous system for therapeutic benefit. The body has a wide distribution of different adrenergic receptors across many organ systems. Without a thorough understanding of the adrenoreceptor subtypes involved in various tissues, the clinical effects observed can seem confusing due to overlapping receptor activities and different effects seen at different doses. Although beyond the scope of this review, the following is a summary with examples of currently FDA approved sympathomimetic indications:
- Cardiac: includes the treatment of hypotension, including those caused by hypovolemic, distributive, and neurogenic shock.[1][2]
- Pulmonary: include the treatment of asthma and COPD.[3][4][5]
- Sympathomimetic agents are used as nasal decongestants for the treatment of allergic rhinitis and conjunctivitis.[6]
- Ophthalmic indications: include open-angle glaucoma.[7]
- Neurologic: can even include local anesthetic effects.[8]
- Psychiatric: include the treatment of ADHD and narcolepsy.[9]
- Endocrine: include the treatment for obesity.[10]
- Genitourinary: include urinary incontinence.[11]
These indications are currently FDA approved; however, future applications for this versatile drug class are currently under investigation.
Mechanism of Action
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Mechanism of Action
Sympathomimetic agents may categorize as direct or indirect. Direct sympathomimetics function as agonists upon one or more adrenergic receptors. The pharmacological profile of direct sympathomimetics has its primary basis on the subtype of adrenergic receptors. Adrenergic receptor activity largely depends on the receptor's molecular structure, signaling pathway, anatomic distribution, and dosing concentration. Adrenergic receptors include the alpha and beta families. Direct sympathomimetics may act as selective or mixed agonists at the alpha and beta-adrenergic receptors. Alpha-adrenergic receptors subdivide into alpha-1 and alpha-2.[12]
Beta-adrenergic receptors subdivide into beta-1, beta-2, and beta-3. Adrenergic receptors are G-protein-coupled metabotropic receptors that use guanosine triphosphate as a cofactor.[13][14] The exact nature of the coupled G-protein determines its identity and the corresponding effect of the downstream secondary signaling cascade, which is beyond the scope of this review. Indirect sympathomimetic agents achieve a similar effect via increasing the concentration of endogenous catecholamines within the synaptic cleft. This increase may occur via the displacement of stored norepinephrine or epinephrine from within presynaptic vesicles, reuptake inhibition, or inhibition of their metabolism by monoamine oxidase or catechol-o-methyltransferase.[15]
Administration
Sympathomimetics administration may be via virtually any route available, including oral, rectal, topical, IO, IV, IM, intrauterine, endotracheal, and inhalation. The term sympathomimetic forms a broad classification of medications, which is why a complete review of the wide variety of administration routes is beyond the scope of this article. Single sympathomimetic agent routes of administration may differ according to different desired pharmaceutical effects. Epinephrine administration – IV, IM, IO, endotracheal – is indicated emergently. Airway swelling requires inhaled epinephrine. Epinephrine and isoproterenol administration may be via the intramuscular route.[16][17] Dobutamine, norepinephrine, terbutaline, and ritodrine may be administered intravenously.[18][19][20] Midodrine, ritodrine, and clonidine may be administered orally.[21][22][23]
Oral administration may be further subdivided based on temporal characteristics. Pseudoephedrine extended-release capsules are designed to release their medication gradually. After the capsule dissolves, the medication granules dissolve at different rates. Interference with the capsule may alter the rate of the capsule's dissolution, thus modifying the pharmacological onset, duration, and effect. For this reason, extended-release capsules should not be crushed or broken.[24] Albuterol and salmeterol administration is via inhalation.[25] Terbutaline may be administered subcutaneously, leading to local vasoconstriction.[26] Brimonidine and pseudoephedrine may be administered topically.[27][28] Phenylephrine may also be administered rectally.[29] There are cases reported with the epidural administration of phenylephrine or ephedrine for regional anesthesia.[30]
Adverse Effects
A thorough understanding of the pharmacological effect and the adrenergic receptor activity of sympathomimetic agents renders their adverse effects as the logical extension of excessive or unwanted adrenergic receptor activity, which can be fatal. Following a comprehensive literature review, the following is a brief survey of sympathomimetic agent adverse effects. Alpha-1 adrenergic receptor activity-predominant sympathomimetics such as phenylephrine or norepinephrine are associated with hypertension (with the possibility of hypertensive emergency), reflex bradycardia, piloerection, and urinary retention. Vasoconstriction may lead to ischemia and necrosis of the digits of the distal appendages.[31][32] Alpha-2 adrenergic receptor activity-predominant sympathomimetics such as clonidine are associated with sedation, respiratory depression, bradycardia and hypotension, miosis, rebound hypertension, and dry mouth.[33]
Beta-1 adrenergic receptor activity-predominant sympathomimetics such as dobutamine are associated with tachycardia and arrhythmias. In patients with coronary artery disease, these adverse effects of beta-2 adrenergic receptor activity-predominant sympathomimetics may lead to acute coronary syndrome.[34] Beta-2 adrenergic receptor activity-predominant sympathomimetics such as albuterol or salmeterol are most commonly associated with tremor.[35] Additional adverse effects include agitation, insomnia, and diaphoresis. Beta-2-mediated coronary artery and skeletal muscle vasodilation may lead to hypotension and reflex tachycardia. Hyperinsulinemia, hyperglycemia, and hypokalemia are endocrine-associated adverse effects.[36][37]
Indirect sympathomimetics such as amphetamines, cocaine, or ephedrine are associated with anorexia, weight loss, insomnia, nausea, vomiting, abdominal cramps, mesenteric ischemia, motor tics, and seizures. Cardiovascular complications of indirect sympathomimetics similar to the direct agents may also include hypertension with reflex bradycardia, aortic dissection, tachycardia, myocardial infarction, and strokes.[9][38] Classically, beta-blockers must not be administered to patients misusing cocaine due to the risk of severe hypertension and end-organ damage resulting from the unopposed-alpha activity.[39] Indirect sympathomimetic-associated rhabdomyolysis may lead to acute renal injury and, ultimately, multiple organ failure.[38]
Contraindications
No universal set of contraindications exists for all sympathomimetics, but a patient’s current condition may offer relative contraindications and the need for careful titration or selection of a more appropriate sympathomimetic. Although extremely rare, true hypersensitivity reactions would be considered a contraindication to specific agents. Following a comprehensive literature review, the following is a brief survey of contraindications for major sympathomimetic agents. High doses of phenylephrine may also be associated with extreme reflex bradycardia or asystole. For this reason, phenylephrine is a relative contraindication in patients with a history of extreme bradycardia.[40] Hypertrophic obstructive cardiomyopathy, also known as idiopathic hypertrophic subaortic stenosis, is a relative contraindication for dobutamine. Dobutamine administration in these patients may precipitate an episode of hypotension secondary to functional left ventricular outflow tract obstruction.[41]
Heart failure or cardiac injury is a relative contraindication for isoproterenol. The administration of isoproterenol may exacerbate an episode of decompensated heart failure due to the inotropic effects that increase myocardial oxygen demand while simultaneously decreasing myocardial oxygen supply.[42] Asthma or hypersensitivity reactions are relative contraindications for cocaine, a local anesthetic, due to its tendency to precipitate allergic episodes.[43][44] Hypertension or cardiovascular disease such as arteriosclerosis is another contraindication for cocaine as well as amphetamine.[45][46][47]
Monitoring
Sympathomimetic is a broad pharmacological classification. A wide variation in the therapeutic index exists among pharmacological agents in this class. Due to the high rates of complications, the supervision of a physician with extensive experience with sympathomimetics is the recommendation when administering catecholamines. More sensitive monitoring with intra-arterial blood pressures is necessary for the administration of high-dose catecholamines.[48]
Toxicity
No universal antidote or treatment exists for all sympathomimetic agents and is beyond the scope of this review. Although specific adrenergic antagonists may prove beneficial in certain adrenergic toxicities, frequently, withdrawal of the offending agent and supportive care is sufficient. When available, the correct balance of adrenergic antagonists may prove beneficial, but choosing the incorrect agents and/or dosing them incorrectly makes it possible to exacerbate toxic effects. The classic example of this is the use of beta-blockers in acute cocaine intoxication, potentially causing hypertensive crisis through unopposed alpha-1 vasoconstriction.[49][50]
Phentolamine, for another example, is an effective treatment for pheochromocytoma or norepinephrine overdose by antagonizing alpha-1 receptors.[51] Metoprolol or esmolol intravenously are effective antidotes for dobutamine by blocking beta-1 receptors.[52] Nonselective beta receptor antagonists effectively treat refractory hypotension, dysrhythmias, or tachycardia in beta-2 adrenergic receptor predominant sympathomimetic agents such as albuterol.[53] However, although direct antagonists exist, frequently supportive care is all that is required, and treatment involves a variety of medication classes: benzodiazepines for seizures or sedation, calcium channel blockers for blood pressure control, and/or heart rate control, nitroglycerin or nitroprusside for vasodilation are among available options.[36]
Enhancing Healthcare Team Outcomes
Sympathomimetic agents are useful in a wide variety of indications across numerous clinical settings. For this reason, many types of healthcare team members such as physicians, nurses, or pharmacists must be knowledgeable of the adverse effects, contraindications, and toxicity management. Patients must receive education from the team and be encouraged to immediately seek help if there is an overdose. [Level 5]
Due to the high rates of complications, the supervision of a physician with extensive experience with sympathomimetics is the recommended approach for administering catecholamines. The physician should also consult with a pharmacist to preclude any potential drug-drug interactions or additive effects with these medications; the pharmacist can recommend alternative agents or other modifications to the regimen to achieve therapeutic goals and minimize adverse effects. All healthcare team members should consult with a pharmacist regarding any concerns.[48]
More sensitive monitoring with intra-arterial blood pressures is necessary for the administration of high-dose catecholamines. [Level 4] Nursing staff need to be well-versed in recognizing adverse events associated with sympathomimetic drugs. Since they will have more contact with the patient on an ongoing basis than other providers, the ability to monitor the patient effectively will fall under their duties. Nursing should be able to alert the doctor or contact the pharmacist with any questions or concerns.
Best practice involves an interprofessional approach, with physicians, pharmacists, and nursing collaborating in a team effort to optimize patient care. [Level 5]
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