Dihydroergotamine

Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines.[5] 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.[6]

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
IUPAC name
  • (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
Chemical and physical data
FormulaC33H37N5O5
Molar mass583.689 g·mol−1
3D model (JSmol)
SMILES
  • [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
  • 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 Y
  • Key:LUZRJRNZXALNLM-JGRZULCMSA-N Y
  (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

Subcutaneous and intramuscular injections are generally more effective than the nasal spray and can be self-administered by patients.[6] Intravenous injection is considered very effective for severe migraine or status migrainosus. DHE is also used in the treatment of medication overuse headache.[7]

Side effects

Nausea is a common side effect of IV administration and less common in other modes. 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. DHE produces no dependence.[8]

Contraindications

DHE is contraindicated with potent CYP3A4 inhibitors, like macrolide antibiotics.[9]

Pharmacology

Mechanism of action

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.[10]

DHE is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.[11]

Pharmacodynamic
Activities of dihydroergotamine at various sites[12][13][8]
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).[12]

Pharmacokinetics

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.

Contraindications

Contraindications for DHE include: pregnancy, renal or hepatic failure, coronary, cerebral, and peripheral vascular disease, hypersensitivity reactions, sepsis, and uncontrolled hypertension.[9]

History

Dihydroergotamine (DHE) is a semi-synthetic form of ergotamine approved in the US in 1946.[14]

Society and culture

Brand names

Brand names of DHE include Diergo, Dihydergot, D.H.E. 45, Ergont, Ikaran, Migranal, Orstanorm, and Seglor, among others.[5]

European Union

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.[15]

References
  1. "D.H.E. 45- dihydroergotamine mesylate injection, solution". DailyMed. Retrieved 31 October 2021.
  2. "Migranal- dihydroergotamine mesylate spray". DailyMed. Retrieved 31 October 2021.
  3. "Dromelate- dihydroergotamine mesylate injection, solution". DailyMed. Retrieved 31 October 2021.
  4. "Trudhesa- dihydroergotamine mesylate spray, metered". DailyMed. Retrieved 31 October 2021.
  5. Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 340–. ISBN 978-3-88763-075-1.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. "Ergotamine search results". PDSP Ki Database. University of North Carolina Chapel Hill. Archived from the original on 13 April 2021. Retrieved 15 January 2022.
  13. 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.
  14. 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.
  15. Restrictions on use of medicines containing ergot derivatives (EMA 2013), Retrieved 3 August 2014
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