Etilefrine

Etilefrine, sold under the brand name Effortil among others, is a sympathomimetic medication used as an antihypotensive agent to treat orthostatic hypotension.^[1] It is usually used by mouth, but is also available as an injectable.^[3][4]

Etilefrine

Clinical data
Trade names	Effortil, many others[1][2]
Other names	Etilephrine; Ethylnorphenylephrine; Ethylphenephrine; Ethyladrianol; Etiladrianol; Aethyladrianol; M-I-36; 3,β-Dihydroxy-N-ethylphenethylamine; 3,β-Dihydroxy-N-ethyl-β-phenylethylamine
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral, injection[3][4]
Drug class	Adrenergic receptor agonist; Sympathomimetic
ATC code	C01CA01 (WHO)
Pharmacokinetic data
Bioavailability	Oral: 50%[3]
Protein binding	23% (8.5% to albumin)[3]
Metabolism	Conjugation (glucuronidation)[3]
Metabolites	• Conjugates[3] • Hydroxymandelic acid (3%)[3]
Elimination half-life	2.5 hours[3]
Excretion	Urine (80%; 7–28% unchanged, 44–73% as conjugates)[3]
Identifiers
IUPAC name (RS)-3-[2-(ethylamino)-1-hydroxyethyl]phenol
CAS Number	709-55-7
PubChem CID	3306
DrugBank	DB08985 Y
ChemSpider	3190 Y
UNII	ZB6F8MY53V
KEGG	D07931 Y
ChEMBL	ChEMBL86882 Y
CompTox Dashboard (EPA)	DTXSID1023029
ECHA InfoCard	100.010.829
Chemical and physical data
Formula	C10H15NO2
Molar mass	181.235 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES CCNCC(O)c1cc(O)ccc1
InChI InChI=1S/C10H15NO2/c1-2-11-7-10(13)8-4-3-5-9(12)6-8/h3-6,10-13H,2,7H2,1H3 Y Key:SQVIAVUSQAWMKL-UHFFFAOYSA-N Y
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Side effects of etilefrine include nausea, tremors, and palpitations, among others.^[5] Etilefrine is an agonist of the α- and β-adrenergic receptors.^[6] It is a substituted phenethylamine and is related to epinephrine, phenylephrine, and norfenefrine.^[2]

Etilefrine was first described and introduced for medical use by 1949.^[7][8]

Medical uses

Etilefrine is used to treat orthostatic hypotension and as a nasal decongestant.^[5][9] It has also been used off-label to treat priapism.^[6][9]

Side effects

Side effects of etilefrine include nausea, tremors, and palpitations, among others.^[5]

Pharmacology

Pharmacodynamics

Etilefrine is an agonist of the α₁-adrenergic receptor.^[5] It is a vasoconstrictor and antihypotensive agent.^[5] It has also been described as a β₁-adrenergic receptor agonist with some agonistic actions at the α- and β₂-adrenergic receptors.^[9]

Intravenous infusion of this compound increases cardiac output, stroke volume, venous return, and blood pressure in humans and animals, suggesting stimulation of both α- and β-adrenergic receptors.^{[10][11][12][13][14]} However, in vitro studies indicate that etilefrine has a much higher affinity for β₁ (cardiac) than for β₂ adrenoreceptors.^[15]

Intravenous etilefrine increases the pulse rate, cardiac output, stroke volume, central venous pressure, and mean arterial pressure of healthy individuals. Peripheral vascular resistance falls during the infusion of 1 to 8 mg etilefrine but begins to rise at higher dosage. Marked falls in pulse rate, cardiac output, stroke volume, and peripheral blood flow, accompanied by rises in mean arterial pressure, occur when etilefrine is infused after administration of intravenous propranolol 2.5 mg. These findings indicate that etilefrine has both β₁- and α₁-adrenergic receptor actions in humans.

Pharmacokinetics

Absorption

Etilefrine is rapidly absorbed with oral administration.^[3] The oral bioavailability of etilefrine is approximately 50%.^[3] Peak concentrations of etilefrine occur after 30 minutes.^[3]

Distribution

The plasma protein binding of etilefrine is 23%.^[3] About 8.5% is bound to albumin.^[3]

Etilefrine is a peripherally selective drug.^[16]

Metabolism

Etilefrine is metabolized by conjugation, for instance glucuronidation, in the liver and gastrointestinal tract.^[3] There appears to be significant first-pass metabolism.^[3] About 3% is metabolized into hydroxymandelic acid.^[3]

Elimination

The elimination of etilefrine is dependent on route of administration.^[3] Regardless of route, about 80% is excreted in urine within 24 hours.^[3] With oral administration, 7% is eliminated unchanged in urine and 73% as conjugates.^[3] Conversely, with intravenous administration, 28% is eliminated unchanged in urine and 44% as conjugates.^[3]

Chemistry

Etilefrine, also known as 3,β-dihydroxy-N-ethylphenethylamine, is a substituted phenethylamine derivative.^[2] It is an analogue of epinephrine (3,4,β-trihydroxy-N-methylphenethylamine), of phenylephrine ((R)-β,3-dihydroxy-N-methylphenethylamine), of metaterol (3,β-dihydroxy-N-isopropylphenethylamine), and of norfenefrine (3,β-dihydroxyphenethylamine), as well as of metaraminol ((1R,2S)-3,β-dihydroxy-α-methylphenethylamine).^[2]

Etilefrine pivalate (K-30052) is the 3-pivalyl ester of etilefrine.^[2] In contrast to etilefrine, etilefrine pivalate was never marketed.^[2][1]

History

Etilefrine was first described and introduced for medical use by 1949.^[7][8]

Society and culture

Names

Etilefrine is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while étiléfrine is its DCFTooltip Dénomination Commune Française and etilefrina is its DCITTooltip Denominazione Comune Italiana.^[2][1] In the case of the hydrochloride salt, its generic name is etilefrine hydrochloride and this is its BANMTooltip British Approved Name and JANTooltip Japanese Accepted Name.^[2][1] Synonyms of etilefrine include ethylnorphenylephrine, ethylphenephrine, etiladrianol, aethyladrianol, and M-I-36.^[2][1][9] Brand names of the drug include Effortil, Circupon, Apocretin, Palsamin, Kertasin, Pressoton, Effoless, and Sanlephrin.^[2][1]

References

1. Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 480. ISBN 978-3-88763-101-7. Retrieved 2024-08-31.
2. Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 61. ISBN 978-1-4757-2085-3. Retrieved 2024-08-31.
3. Aviado D, Bowman W, Burnstock G, Greven J, Hannappel J, Juul P, et al. (2012). Adrenergic Activators and Inhibitors: Part II. Handbook of Experimental Pharmacology. Springer Berlin Heidelberg. pp. 364–366. ISBN 978-3-642-67584-3. Retrieved 31 August 2024.
4. Wein A, Kavoussi L, Novick A, Partin A, Peters C (2011). Campbell-Walsh Urology. Elsevier Health Sciences. pp. 758–761. ISBN 978-1-4557-2298-3. Retrieved 2024-08-31.
5. Skylynn T, Abel T, Christopher L, Suliman G, Dominic R, Joel V, et al. (January 2024). "Benefits and Risks of Medications Used in the Management of Hypotension: A Review". Cureus. 16 (1): e51608. doi:10.7759/cureus.51608. PMC 10837047. PMID 38313995.
6. Graham BA, Wael A, Jack C, Rohan MA, Wayne HJ (August 2022). "An overview of emergency pharmacotherapy for priapism". Expert Opin Pharmacother. 23 (12): 1371–1380. doi:10.1080/14656566.2022.2099271. PMID 35815373.
7. "Neue Spezialitäten". Klinische Wochenschrift (in German). 28 (19–20): 350. 1950. doi:10.1007/BF01485958. ISSN 0023-2173.
8. Spitzbarth H (December 1950). "[Results with effortil in arterial hypotension]". Medizinische Klinik (in German). 45 (50): 1593–1596. PMID 14815173.
9. Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". Br J Pharmacol. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527. PMID 18500382.
10. Nusser E, Donath H, Russ W (August 1965). "[On the circulatory action of depot-Effortil in patients with hypotonic regulation circulator disorders]". Die Medizinische Welt (in German). 32: 1824–7. PMID 5320529.
11. Mellander S (1966). "Comparative effects of acetylcholine, butyl-nor-synephrine (Vasculat), noradrenaline, and ethyl-adrainol (Effonti) on resistance, capacitance, and precapillary sphincter vessels and capillary filtration in cat skeletal muscle". Angiologica. 3 (2): 77–99. doi:10.1159/000157650. PMID 4380206.
12. von Limbourg P, Just H, Lang KF (1973). "Positive inotrope Wirkung von Etilefrinhydrochlorid (EffortilR)". Kardiol. 586: 1.
13. Tarnow J, Brückner JB, Eberlein HG, Patschke D, Reinecke A, Schmicke P (1973). "Experimentelle Untersuchungen zur Beeinflussung der Hämodynamik in tiefer Halothannarkose durch Dopamin, Glucagon, Effortil, Noradrenalin und Dextran". Der Anaesthesist. 22: 8–15.
14. Carrera AL, Aguilera AM (1973). "Algunos effectos circulatorios de la m− oxifenil etanol etilmaina y sus modificaciones por el bloqueo α y β adrenergico". Arch. Inst. Cardiol. 43. Mexico: 279–287.
15. Offermeier J, Dreyer AC (March 1971). "A comparison of the effects of noradrenaline, adrenaline and some phenylephrine derivatives on alpha-, beta₁- and beta₂- adrenergic receptors" (PDF). South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde. 45 (10): 265–267. PMID 4396765.
16. Calkins H (October 1999). "Pharmacologic approaches to therapy for vasovagal syncope". Am J Cardiol. 84 (8A): 20Q–25Q. doi:10.1016/s0002-9149(99)00626-8. PMID 10568557.