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Dihydroergotamine

(Redirected from Dihydroergotamine mesylate)

Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines.[7] It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.[8]

Dihydroergotamine
Clinical data
Pronunciation/daɪˌhaɪdroʊ.ɜːrˈɡɒtəmiːn/ dy-HY-droh-ur-GOT-ə-meen
Trade namesD.H.E. 45, Migranal, Trudhesa, others
Other namesDHE; (5'α)-9,10-Dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl)-ergotaman-3',6',18-trione
AHFS/Drugs.comMonograph
MedlinePlusa603022
License data
Routes of
administration		Nasal, Subcutaneous, Intramuscular, Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability32% (nasal spray)
Elimination half-life9 hours
ExcretionBile
Identifiers
  • (2R,4R,7R)-N-[(1S,2S,4R,7S)-7-benzyl-2-hydroxy-4-methyl-5,8-dioxo-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecan-4-yl]-6-methyl-6,11-diazatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),9,12,14-tetraene-4-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.007.386 Edit this at Wikidata
Chemical and physical data
FormulaC33H37N5O5
Molar mass583.689 g·mol−1
3D model (JSmol)
  • [H][C@]56C[C@@H](C(=O)N[C@]1(C)O[C@]4(O)N(C1=O)[C@@H](Cc2ccccc2)C(=O)N3CCC[C@]34[H])CN(C)[C@]5([H])Cc7c[nH]c8cccc6c78
  • InChI=1S/C33H37N5O5/c1-32(35-29(39)21-15-23-22-10-6-11-24-28(22)20(17-34-24)16-25(23)36(2)18-21)31(41)38-26(14-19-8-4-3-5-9-19)30(40)37-13-7-12-27(37)33(38,42)43-32/h3-6,8-11,17,21,23,25-27,34,42H,7,12-16,18H2,1-2H3,(H,35,39)/t21-,23-,25-,26+,27+,32-,33+/m1/s1 checkY
  • Key:LUZRJRNZXALNLM-JGRZULCMSA-N checkY
  (verify)

It has similar actions to the triptans, acting as an agonist to the serotonin receptors and causing vasoconstriction of the intracranial blood vessels, but also interacts centrally with dopamine and adrenergic receptors. It can be used to treat acute intractable headache or withdrawal from analgesics.

Medical uses

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Subcutaneous and intramuscular injections are generally more effective than the nasal spray and can be self-administered by patients.[8] Intravenous injection is considered very effective for severe migraine or status migrainosus. DHE is also used in the treatment of medication overuse headache.[9]

Side effects

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Nausea is a common side effect of IV administration and less common in other modes.[10] Antiemetics can be given prior to DHE to counteract the nausea. Risks and contraindications are similar to the triptans. DHE and triptans should never be taken within 24 hours of each other due to the potential for coronary artery vasospasm.[11] DHE produces no dependence.[12]

Contraindications

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DHE is contraindicated with potent CYP3A4 inhibitors, like macrolide antibiotics.[13]

Pharmacology

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Pharmacodynamics

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DHE's antimigraine activity is due to its action as an agonist at the serotonin 5-HT1B, 5-HT1D, and 5-HT1F receptors. It also interacts with other serotonin, adrenergic, and dopamine receptors.[14]

DHE is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[15]

In spite of acting as an agonist of the serotonin 5-HT2A receptor, DHE has been described as non-hallucinogenic.[16] This is also the case with certain other ergoline derivatives, such as bromocriptine and pergolide.[17]

Activities of dihydroergotamine at various sites[18][14][12]
Site Affinity (Ki/IC50 [nM]) Efficacy (Emax [%]) Action
5-HT1A 0.4–1.5 ? Agonist
5-HT1B 0.006–18 ? Agonist
5-HT1D 0.13–0.5 ? Agonist
5-HT1E 1,100 ? ?
5-HT1F 180 ? Agonist
5-HT2A 9.0 ? Agonist
5-HT2B 15–33 ? Agonist
5-HT2C 1.3 ? Agonist
5-HT3 >3,700–>10,000 ? ?
5-HT4 60 ? ?
5-HT5A ? ? ?
5-HT5B ? ?
5-HT6 5.4 ? ?
5-HT7 9.1–9.2 ? ?
α1A 6.6 ? ?
α1B 8.3 ? ?
α1D ? ? ?
α2A 1.9 ? ?
α2B 3.3 ? ?
α2C 1.4 ? ?
β1 3,100 ? ?
β2 2,700 ? ?
β3 271 ? ?
D1 2,779 ? ?
D2 1.2–5.0 ? Agonist
D3 6.4–16 ? ?
D4 8.7 ? ?
D5 ? ? ?
H1 ? ? ?
mACh ? ? ?
Notes: All receptors are human except 5-HT3 (rat/mouse), 5-HT4 (guinea pig), 5-HT5B (rat—no human counterpart), α1A-adrenergic (rat/human), and α2A-adrenergic (rat/human).[18]

Pharmacokinetics

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Oral bioavailability is poor and it is not available in oral form in the US. DHE is available as a nasal spray and in ampules for subcutaneous, intramuscular and intravenous injection. Efficacy is variable in the nasal spray form with relative bioavailability of 32% compared to injection.[19]

Contraindications

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chemical structure of dihydroergotamine

Contraindications for DHE include: pregnancy, renal or hepatic failure, coronary, cerebral, and peripheral vascular disease, hypersensitivity reactions, sepsis, and uncontrolled hypertension.[13]

History

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Dihydroergotamine (DHE) is a semi-synthetic form of ergotamine approved in the US in 1946.[19] Dihydroergotamine is derived from ergot, a fungus that grows on rye and other grains.[20][21]

Society and culture

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Brand names

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Brand names of DHE include Diergo, Dihydergot, D.H.E. 45, Ergont, Ikaran, Migranal, Orstanorm, and Seglor, among others.[7]

European Union

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In 2013 the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that medicines containing ergot derivatives no longer be used to treat several conditions involving problems with memory, sensation or blood circulation, or to prevent migraine headaches because the risks (increased risk of fibrosis and ergotism) were said to be greater than the benefits in these indications.[22]

References

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  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 15 August 2023.
  3. ^ "D.H.E. 45- dihydroergotamine mesylate injection, solution". DailyMed. Retrieved 31 October 2021.
  4. ^ "Migranal- dihydroergotamine mesylate spray". DailyMed. Retrieved 31 October 2021.
  5. ^ "Dromelate- dihydroergotamine mesylate injection, solution". DailyMed. Retrieved 31 October 2021.
  6. ^ "Trudhesa- dihydroergotamine mesylate spray, metered". DailyMed. Retrieved 31 October 2021.
  7. ^ a b Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 340–. ISBN 978-3-88763-075-1.
  8. ^ a b Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH (April 2005). "Parenteral dihydroergotamine for acute migraine headache: a systematic review of the literature". Annals of Emergency Medicine. 45 (4): 393–401. doi:10.1016/j.annemergmed.2004.07.430. PMID 15795718.
  9. ^ Saper JR, Silberstein S, Dodick D, Rapoport A (November 2006). "DHE in the pharmacotherapy of migraine: potential for a larger role". Headache. 46 (Suppl 4): S212–S220. doi:10.1111/j.1526-4610.2006.00605.x. PMID 17078853. S2CID 34332034.
  10. ^ Hauser JM, Azzam JS, Kasi A (2024). "Antiemetic Medications". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30335336. Retrieved 18 August 2024.
  11. ^ "Dihydroergotamine (DHE) for Migraine Treatment | AMF". American Migraine Foundation. Retrieved 18 August 2024.
  12. ^ a b Schaerlinger B, Hickel P, Etienne N, Guesnier L, Maroteaux L (September 2003). "Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy". British Journal of Pharmacology. 140 (2): 277–284. doi:10.1038/sj.bjp.0705437. PMC 1574033. PMID 12970106.
  13. ^ a b Bigal ME, Tepper SJ (February 2003). "Ergotamine and dihydroergotamine: a review". Current Pain and Headache Reports. 7 (1): 55–62. doi:10.1007/s11916-003-0011-7. PMID 12525272. S2CID 23124461.
  14. ^ a b Silberstein SD, McCrory DC (February 2003). "Ergotamine and dihydroergotamine: history, pharmacology, and efficacy". Headache. 43 (2): 144–166. doi:10.1046/j.1526-4610.2003.03034.x. PMID 12558771. S2CID 21356727.
  15. ^ Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods. 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
  16. ^ National Institute on Drug Abuse (1994). NIDA Research Monograph. DHEW publication. National Institute on Drug Abuse. p. 275. Retrieved 26 October 2024.
  17. ^ Gumpper RH, Roth BL (January 2024). "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology. 49 (1): 119–127. doi:10.1038/s41386-023-01567-7. PMID 36932180.
  18. ^ a b "Ergotamine search results". PDSP Ki Database. University of North Carolina Chapel Hill. Archived from the original on 13 April 2021. Retrieved 15 January 2022.
  19. ^ a b Silberstein SD, Shrewsbury SB, Hoekman J (January 2020). "Dihydroergotamine (DHE) - Then and Now: A Narrative Review". Headache. 60 (1): 40–57. doi:10.1111/head.13700. PMC 7003832. PMID 31737909.
  20. ^ "Dihydroergotamine (DHE) for Migraine Relief: Are You a Good Candidate? What to Know". MigraineAgain.com. Retrieved 18 August 2024.
  21. ^ Shafqat R, Flores-Montanez Y, Delbono V, Nahas SJ (2020). "Updated Evaluation of IV Dihydroergotamine (DHE) for Refractory Migraine: Patient Selection and Special Considerations". Journal of Pain Research. 13: 859–864. doi:10.2147/JPR.S203650. PMC 7200221. PMID 32431533.
  22. ^ Restrictions on use of medicines containing ergot derivatives (EMA 2013) Archived 20 June 2018 at the Wayback Machine, Retrieved 3 August 2014
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