Ephedrine

Article Author:
Alec Statler
Article Author (Archived):
Christopher Maani
Article Editor:
Arpan Kohli
Updated:
10/3/2019 9:46:15 AM
PubMed Link:
Ephedrine

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]


References

[1] Südfeld S,Brechnitz S,Wagner JY,Reese PC,Pinnschmidt HO,Reuter DA,Saugel B, Post-induction hypotension and early intraoperative hypotension associated with general anaesthesia. British journal of anaesthesia. 2017 Jul 1;     [PubMed PMID: 28974066]
[2] Clark RB,Thompson DS,Thompson CH, Prevention of spinal hypotension associated with Cesarean section. Anesthesiology. 1976 Dec     [PubMed PMID: 984486]
[3] Guo R,Xue Q,Qian Y,Hu Y,Tan J, The Effects of Ephedrine and Phenylephrine on Placental Vascular Resistance During Cesarean Section Under Epidual Anesthesia. Cell biochemistry and biophysics. 2015 Dec     [PubMed PMID: 27259311]
[4] Mon W,Stewart A,Fernando R,Ashpole K,El-Wahab N,MacDonald S,Tamilselvan P,Columb M,Liu YM, Cardiac output changes with phenylephrine and ephedrine infusions during spinal anesthesia for cesarean section: A randomized, double-blind trial. Journal of clinical anesthesia. 2017 Feb;     [PubMed PMID: 28235526]
[5] Laccourreye O,Werner A,Giroud JP,Couloigner V,Bonfils P,Bondon-Guitton E, Benefits, limits and danger of ephedrine and pseudoephedrine as nasal decongestants. European annals of otorhinolaryngology, head and neck diseases. 2015 Feb;     [PubMed PMID: 25532441]
[6] Anderson SD, Repurposing drugs as inhaled therapies in asthma. Advanced drug delivery reviews. 2018 Aug     [PubMed PMID: 29906501]
[7] Astrup A,Toubro S,Christensen NJ,Quaade F, Pharmacology of thermogenic drugs. The American journal of clinical nutrition. 1992 Jan;     [PubMed PMID: 1345887]
[8] Rakovec P,Kozak M,Sebestjen M, Ventricular tachycardia induced by abuse of ephedrine in a young healthy woman. Wiener klinische Wochenschrift. 2006 Sep;     [PubMed PMID: 17009070]
[9] Vrinten C,van der Zwaag AM,Weinreich SS,Scholten RJ,Verschuuren JJ, Ephedrine for myasthenia gravis, neonatal myasthenia and the congenital myasthenic syndromes. The Cochrane database of systematic reviews. 2014 Dec 17     [PubMed PMID: 25515947]
[10] Oshika H,Koyama Y,Usuda Y,Andoh T, Intravenous ephedrine abolished suspected bronchoconstriction during general anesthesia in a patient undergoing beta-adrenergic blocker therapy for hypertension. Saudi journal of anaesthesia. 2019 Jan-Mar;     [PubMed PMID: 30692891]
[11] Radiloff D,Zhao Y,Boico A,Blueschke G,Palmer G,Fontanella A,Dewhirst M,Piantadosi CA,Noveck R,Irwin D,Hamilton K,Klitzman B,Schroeder T, Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude. PloS one. 2014;     [PubMed PMID: 24960187]
[12] Becker DE, Basic and clinical pharmacology of autonomic drugs. Anesthesia progress. 2012 Winter;     [PubMed PMID: 23241039]
[13] Kobayashi S,Endou M,Sakuraya F,Matsuda N,Zhang XH,Azuma M,Echigo N,Kemmotsu O,Hattori Y,Gando S, The sympathomimetic actions of l-ephedrine and d-pseudoephedrine: direct receptor activation or norepinephrine release? Anesthesia and analgesia. 2003 Nov     [PubMed PMID: 14570629]
[14] Piascik MT,Perez DM, Alpha1-adrenergic receptors: new insights and directions. The Journal of pharmacology and experimental therapeutics. 2001 Aug;     [PubMed PMID: 11454900]
[15] Casella M,Dello Russo A,Izzo G,Pieroni M,Andreini D,Russo E,Colombo D,Bologna F,Bolognese L,Zeppilli P,Tondo C, Ventricular arrhythmias induced by long-term use of ephedrine in two competitive athletes. Heart and vessels. 2015 Mar     [PubMed PMID: 24390726]
[16] Santiveri X,Mansilla R,Pardina B,Navarro J,Alvarez JC,Castillo J, [Ephedrine shortens the onset of action of rocuronium but not atracurium]. Revista espanola de anestesiologia y reanimacion. 2003 Apr;     [PubMed PMID: 12825305]
[17] Leykin Y,Pellis T,Lucca M,Gullo A, Effects of ephedrine on intubating conditions following priming with rocuronium. Acta anaesthesiologica Scandinavica. 2005 Jul;     [PubMed PMID: 15954961]
[18] Willson C, Sympathomimetic amine compounds and hepatotoxicity: Not all are alike-Key distinctions noted in a short review. Toxicology reports. 2019;     [PubMed PMID: 30581759]
[19] Dingemanse J,Guentert T,Gieschke R,Stabl M, Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide. Journal of cardiovascular pharmacology. 1996 Dec;     [PubMed PMID: 8961085]
[20] Hassani V,Movaseghi G,Safaeeyan R,Masghati S,Ghorbani Yekta B,Farahmand Rad R, Comparison of Ephedrine vs. Norepinephrine in Treating Anesthesia-Induced Hypotension in Hypertensive Patients: Randomized Double-Blinded Study. Anesthesiology and pain medicine. 2018 Aug;     [PubMed PMID: 30271750]
[21] Heesen M,Rijs K,Hilber N,Ngan Kee WD,Rossaint R,van der Marel C,Klimek M, Corrigendum to     [PubMed PMID: 31178233]
[22] Almustafa MM,Al-Oweidi AS,Al-Zaben KR,Qudaisat IY,Abu-Halaweh S,Alghanem SM,Massad IM,Samarah W,Al-Shaer RA,Ismail S,Khazawla F, Ephedrine requirements during spinal anesthesia for cesarean delivery in Jordanian parturients: association with b2 adrenoceptor gene variants. Annals of Saudi medicine. 2016 Jan-Feb;     [PubMed PMID: 26922685]
[23] Skeldon SC,Goldenberg SL, Urological complications of illicit drug use. Nature reviews. Urology. 2014 Mar;     [PubMed PMID: 24535583]
[24] Daudon M,Frochot V,Bazin D,Jungers P, Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment. Drugs. 2018 Feb;     [PubMed PMID: 29264783]