Ephedrine

Statler AK, Maani CV, Kohli A.

Publication Details

Continuing Education Activity

Ephedrine is a medication used in the management and treatment of clinically
significant hypotension. It is in the sympathomimetic class of medications. This
activity illustrates the indications, action, and contraindications for ephedrine as
a valuable agent in the treatment of clinically significant hypotension. This
activity will highlight the mechanism of actions, adverse event profile, and
other key factors pertinent to interprofessional healthcare team members
involved in the care of patients with clinically significant hypotension and
related conditions.
Objectives:
 Identify the indications for treatment with ephedrine.
 Describe the common complications of managing clinically significant
hypotension intraoperatively with the ephedrine.
 Explain the mechanism of action and alternative options to the treatment
of significant intraoperative hypotension.
 Review the importance of communication among the interprofessional
team to improve outcomes for the patient requiring ephedrine.
Earn continuing education credits (CME/CE) on this topic.

Indications
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]

Mechanism of Action
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]

Administration
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.

Adverse Effects
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]

Contraindications
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]

Monitoring
Although there are no specific drug monitoring requirements, variations in gene
codons for receptor type can yield various sensitivity to ephedrine. Specifically,
variations at codons 16 and 27 for the beta-2 adrenoreceptor have significant
differences for ephedrine requirement to combat hypotension post-spinal
anesthesia.[22] Due to variation in responses and the fact that vasoactive
medications can have a rapid effect on vitals, blood pressure, heart rate, and
pulse oximetry require close monitoring.

Toxicity
The most concerning effect of ephedrine overdose is the manifestation of
excessive hypertension. If blood pressure rises to unacceptable levels, a
parenteral administration of antihypertensive medication is necessary. There is
no specific agent recommended, and the choice depends on clinical judgment.
Treatments for excessive hypertension include nitrates, labetalol, esmolol,
nicardipine, and nitroglycerine. A less common effect experienced mostly by
illicit users of ephedrine and its derivatives is the development of radiolucent
urological ephedrine containing stones and paranoid schizophrenia.[23][24] 

Enhancing Healthcare Team Outcomes

Though anesthetists are some of the only providers to administer ephedrine
routinely, they do not do so within a vacuum, and all team members providing
care for that patient should know its effects and different routes of
administration. When given intravenously, drug effects are often of short
duration (minutes), and tachyphylaxis is common. However, if given
intramuscularly, the vasopressor effects typically remain for 60 to 90 minutes.
[12] These effects are of particular importance on the labor and delivery ward
where patients often receive intramuscular injections of ephedrine following
spinal block to attenuate the sympathectomy and nausea that frequently
accompany spinal blockade. The effects of an IM injection may last much
longer than the procedure itself, and nurses and techs should not rely on
hypotension as the primary indicator of postpartum hemorrhage as IM
ephedrine may mask this sign.
When planning to use ephedrine, the pharmacist should verify the dose and that
there are no significant drug-drug interactions, and report these findings to the
clinical team. Nursing must be cognizant of the adverse effects of the drug, and
be prepared to inform the clinician regarding their observations. Nursing will
also commonly be involved in administration, so they must collaborate with the
pharmacist on dosing and administration. These examples show how all
members of the interprofessional team working together can optimize ephedrine
therapy when it is necessary while mitigating its adverse effects. [Level 5]

Continuing Education / Review Questions

 Access free multiple choice questions on this topic.
 Earn continuing education credits (CME/CE) on this topic.
 Comment on this article.

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Publication Details

Author Information

Authors
Alec K. Statler; Christopher V. Maani1; Arpan Kohli2.

Affiliations
1
 US Army
2
 West Virginia University

Publication History
Last Update: July 10, 2020.

Copyright
Copyright © 2021, StatPearls Publishing LLC.
This book is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and
reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Publisher
StatPearls Publishing, Treasure Island (FL)

NLM Citation
Statler AK, Maani CV, Kohli A. Ephedrine. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island
(FL): StatPearls Publishing; 2021 Jan-.