The FDA approved primary indication for ephedrine is the treatment of clinically significant hypotension perioperatively. Induction of general anesthesia and ongoing anesthesia during operative cases results in vasodilatation and hypotension requiring treatment with vasopressors.[1] It is also frequently the agent of choice for hypotension induced by spinal or epidural anesthesia. In obstetrics, sympathectomy during spinal anesthetics results in hypotension in 80% of patients [2]. Although phenylephrine selection is due to fewer effects on umbilical arterial acidity, ephedrine is a frequent choice due to less alpha-adrenergic action on the uterine vasculature which preserves uterine blood flow.[3] Also, it is sometimes given intramuscularly to achieve a longer-lasting effect.[4]

Since ephedrine results in both alpha and beta-adrenoreceptor stimulation, it is most beneficial in the setting of hypotension along with bradycardia or a low-normal heart rate, and caution is necessary for patients with hypotension and coexisting tachycardia. As with most vasopressors used during anesthesia, its use should be viewed as a temporizing measure while determining and addressing the source of hypotension. Another notable indication of ephedrine is for allergy relief. Due to constriction of smooth muscle via alpha receptor binding and bronchi dilation due to beta-2 receptor agonism, most sympathomimetics including ephedrine, work effectively to decrease allergic symptoms.[5]

Oral formulations of ephedrine have been used historically to treat asthma via pulmonary vasoconstriction and reduction in airway edema along with beta-induced bronchodilation, but it is rarely used for this purpose in modern medicine due to unwanted cardiac effects and availability of more selective beta-agonists such as albuterol.[6]

Other less typical indications include bronchoconstriction, myasthenia gravis, and previously weight loss. In the early 2000s, the drug became very popular among over the counter supplements because it was found to work synergistically with caffeine to promote weight loss by stimulating metabolism.[7] However, ephedrine lost favor as a supplement after research established links to ventricular arrhythmias, nausea, and psychiatric issues with use.[8] Patients with myasthenia gravis may also show benefit from treatment with ephedrine; however, evidence for its specific mechanism of action and benefit in this disease has not come from randomized controlled trials and only observational, and non-randomized trials are currently available.[9] Lastly, case reports demonstrate the use of ephedrine to alleviate bronchoconstriction during induction for patients on beta-blocker maintenance therapy.[10]

Ephedrine, a stereoisomer to better-known pseudoephedrine, is a sympathomimetic amine that has unique effects due to its indirect mechanism compared to other sympathomimetic agents like pseudoephedrine and phenylephrine.[11] Ephedrine acts as both a direct and indirect sympathomimetic. It binds directly to both alpha and beta receptors; however, its primary mode of action is achieved indirectly, by inhibiting neuronal norepinephrine reuptake and by displacing more norepinephrine from storage vesicles.[12] This action allows norepinephrine to be present in the synapse longer to bind postsynaptic alpha and beta receptors.[13] Ephedrine’s indirect mechanism results in a sustained or even increased heart rate due to norepinephrine’s ability to bind both alpha and beta receptors, whereas more direct sympathomimetics like phenylephrine result in reflex bradycardia. While the indirect effect is most profound on the arterial blood pressure, the direct vasoconstricting action functions more on the venous system. It is, therefore, effective in elevating central venous pressure when the patient is fluid challenged.[12]

Stimulation of alpha-1-adrenergic receptors of smooth muscle within vasculature results in a rise in systemic vascular resistance and, consequently, both systolic and diastolic blood pressure. Direct stimulation of beta-1-receptors by ephedrine and norepinephrine increase cardiac chronotropy and inotropy. Finally, beta-2-adrenergic receptor stimulation in the lungs results in bronchodilation with ephedrine administration, though this effect is not as pronounced as its cardiovascular effects.[14]

In treating hypotension, cardiovascular effects via the indirect mechanism are dependent on adequate native stores of norepinephrine and tachyphylaxis will develop with prolonged and repeated use as this depletes endogenous norepinephrine stores. For this reason, it is administered in intravenous boluses when used intravenously and rarely as a continuous infusion. For adults, bolus dose recommendations are currently at 5 to 10 mg, and intramuscular doses for a prolonged desired effect are at 25 to 50mg.[12] The FDA has not formally established safety and effectiveness in pediatric populations.[2] Additionally, ephedrine is distributed by the manufacturer in 50mg/mL vials and requires dilution before intravenous use.

In the conscious patient, ephedrine may produce palpitations, headache, dizziness, nausea, vomiting, restlessness, and anxiety. Ephedrine is also arrhythmogenic, and caution should be used during administration to patients who are predisposed to arrhythmias or taking other arrhythmogenic medications, particularly digitalis. When used long term, the catecholamine excess can result in contraction band necrosis of the myocardium which predisposes the heart to ventricular arrhythmias.[15]

Another common effect of ephedrine is alteration in the time until onset and duration of action of other drugs. This effect is most notable during induction when giving ephedrine for a hypotensive patient before rocuronium.[16][17] Additionally, ephedrine may be hepatotoxic, but there seems to be unclear evidence for such. This idea stems from case reports where ephedra species containing several compounds resulted in liver damage as opposed to a direct correlation.[18]

Ephedrine is contraindicated in a patient with acute hypertension or tachycardia. Ephedrine increases both chronotropy and inotropy and therefore increases myocardial oxygen demand, and its use requires caution in patients with ischemic heart disease or heart failure. Additionally, it should be avoided in situations where tachycardia would be undesirable, such as aortic stenosis. Alpha-adrenergic stimulation caused by ephedrine results in contraction of the smooth muscle at the base of the bladder, resulting in resistance to urine outflow, and caution is necessary for patients with urinary retention and prostatic hyperplasia.[14] The use of ephedrine should be avoided or used with caution within 14 days of MAOI therapy due to excessive norepinephrine availability at the synapse, which could cause a hypertensive crisis through the indirect sympathomimetic effect of ephedrine.[12][19]

Though ephedrine is frequently used in obstetric patients just before and during delivery, there is insufficient data to support using the drug in earlier stages of pregnancy, and no animal reproductive studies have been performed, making it is a category C drug in pregnancy. Norepinephrine and phenylephrine are other appropriate choices to maintain blood pressure post-spinal anesthesia. Norepinephrine was shown to have fewer episodes of hypotension in comparison to ephedrine, and l phenylephrine showed less extensive effects on umbilical artery acidity.[20][21]