Chemical used to treat migraines
Pharmaceutical compound
Dihydroergotamine Pronunciation dy-HY -droh-ur-GOT -ə-meen Trade names D.H.E. 45, Migranal, Trudhesa, others Other names DHE; (5'α)-9,10-Dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl)-ergotaman-3',6',18-trione AHFS /Drugs.com Monograph MedlinePlus a603022 License data
Routes of administration Nasal , Subcutaneous , Intramuscular , Intravenous ATC code Legal status
Bioavailability 32% (nasal spray) Elimination half-life 9 hours Excretion Bile
(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 InfoCard 100.007.386 Formula C 33 H 37 N 5 O 5 Molar mass 583.689 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
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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]
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.[ 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
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
DHE is contraindicated with potent CYP3A4 inhibitors, like macrolide antibiotics.[ 13]
Pharmacology
Pharmacodynamics
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
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
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
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
Brand names
Brand names of DHE include Diergo, Dihydergot, D.H.E. 45, Ergont, Ikaran, Migranal, Orstanorm, and Seglor, among others.[ 7]
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.[ 22]
References
^ "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 .
^ 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 .
^ "D.H.E. 45- dihydroergotamine mesylate injection, solution" . DailyMed . Retrieved 31 October 2021 .
^ "Migranal- dihydroergotamine mesylate spray" . DailyMed . Retrieved 31 October 2021 .
^ "Dromelate- dihydroergotamine mesylate injection, solution" . DailyMed . Retrieved 31 October 2021 .
^ "Trudhesa- dihydroergotamine mesylate spray, metered" . DailyMed . Retrieved 31 October 2021 .
^ a b Index Nominum 2000: International Drug Directory . Taylor & Francis. 2000. pp. 340–. ISBN 978-3-88763-075-1 .
^ 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 .
^ 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 .
^ Hauser JM, Azzam JS, Kasi A (2024). "Antiemetic Medications" . StatPearls . Treasure Island (FL): StatPearls Publishing. PMID 30335336 . Retrieved 18 August 2024 .
^ "Dihydroergotamine (DHE) for Migraine Treatment | AMF" . American Migraine Foundation . Retrieved 18 August 2024 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ National Institute on Drug Abuse (1994). NIDA Research Monograph . DHEW publication. National Institute on Drug Abuse. p. 275. Retrieved 26 October 2024 .
^ 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 .
^ 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 .
^ 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 .
^ "Dihydroergotamine (DHE) for Migraine Relief: Are You a Good Candidate? What to Know" . MigraineAgain.com . Retrieved 18 August 2024 .
^ 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 .
^ 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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Tetracyclic antidepressants (e.g., amoxapine , mianserin , mirtazapine )
Trazodone
Typical antipsychotics (e.g., chlorpromazine )
TIK-301
Yohimbine
5-HT2C
Agonists: 2Cs (e.g., 2C-B , 2C-E , 2C-I , 2C-T-2 , 2C-T-7 , 2C-T-21 )
5-Methoxytryptamines (5-MeO-DET , 5-MeO-DiPT , 5-MeO-DMT , 5-MeO-DPT , 5-MT )
α-Alkyltryptamines (e.g., 5-Cl-αMT , 5-Fl-αMT , 5-MeO-αET , 5-MeO-αMT , α-Me-5-HT , αET , αMT )
A-372159
AL-38022A
Alstonine
CP-809101
Dimemebfe
DOx (e.g., DOB , DOC , DOI , DOM )
Ergolines (e.g., ALD-52 , cabergoline , dihydroergotamine , ergine (LSA) , ergotamine , lisuride , LA-SS-Az , LSB , LSD , LSD-Pip , LSH , LSP , pergolide )
Flumexadol
Lorcaserin
MDxx (e.g., MDA (tenamfetamine) , MDMA (midomafetamine) , MDOH , MMDA )
MK-212
ORG-12962
ORG-37684
Oxaflozane
PHA-57378
Phenethylamines (e.g., lophophine , mescaline )
Piperazines (e.g., aripiprazole , BZP , mCPP , quipazine , TFMPP )
PNU-22394
PNU-181731
Ro60-0175
Ro60-0213
Serotonin (5-HT)
Tryptamines (e.g., 5-BT , 5-CT , bufotenin , DET , DiPT , DMT , DPT , psilocin , psilocybin , tryptamine )
Vabicaserin
WAY-629
WAY-161503
YM-348
Antagonists: Adatanserin
Agomelatine
Atypical antipsychotics (e.g., asenapine , clorotepine , clozapine , fluperlapine , iloperidone , melperone , olanzapine , paliperidone , quetiapine , risperidone , sertindole , ziprasidone , zotepine )
Captodiame
CEPC
Cinanserin
Cyproheptadine
Deramciclane
Desmetramadol
Dotarizine
Eltoprazine
Ergolines (e.g., amesergide , bromocriptine , LY-53857 , LY-215,840 , mesulergine , metergoline , methysergide , sergolexole )
Etoperidone
Fluoxetine
FR-260010
Irindalone
Ketanserin
Ketotifen
Latrepirdine (dimebolin)
Medifoxamine
Metitepine (methiothepin)
Nefazodone
Pirenperone
Pizotifen
Propranolol
Ritanserin
RS-102221
S-14671
SB-200646
SB-206553
SB-221284
SB-228357
SB-242084
SB-243213
SDZ SER-082
Tedatioxetine
Tetracyclic antidepressants (e.g., amoxapine , aptazapine , esmirtazapine , maprotiline , mianserin , mirtazapine )
TIK-301
Tramadol
Trazodone
Tricyclic antidepressants (e.g., amitriptyline , nortriptyline )
Typical antipsychotics (e.g., chlorpromazine , loxapine , pimozide , pipamperone , thioridazine )
Xylamidine
5-HT3 –7
5-HT3
Agonists: Alcohols (e.g., butanol , ethanol (alcohol) , trichloroethanol )
m-CPBG
Phenylbiguanide
Piperazines (e.g., BZP , mCPP , quipazine )
RS-56812
Serotonin (5-HT)
SR-57227
SR-57227A
Tryptamines (e.g., 2-Me-5-HT , 5-CT , bufotenidine (5-HTQ) )
Volatiles/gases (e.g., halothane , isoflurane , toluene , trichloroethane )
YM-31636
Antagonists: Alosetron
Anpirtoline
Arazasetron
AS-8112
Atypical antipsychotics (e.g., clozapine , olanzapine , quetiapine )
Azasetron
Batanopride
Bemesetron (MDL-72222)
Bupropion
Cilansetron
CSP-2503
Dazopride
Dolasetron
Galanolactone
Granisetron
Hydroxybupropion
Lerisetron
Memantine
Ondansetron
Palonosetron
Ramosetron
Renzapride
Ricasetron
Tedatioxetine
Tetracyclic antidepressants (e.g., amoxapine , mianserin , mirtazapine )
Thujone
Tropanserin
Tropisetron
Typical antipsychotics (e.g., loxapine )
Volatiles/gases (e.g., nitrous oxide , sevoflurane , xenon )
Vortioxetine
Zacopride
Zatosetron
5-HT4
5-HT5A
5-HT6
Agonists: Ergolines (e.g., dihydroergocryptine , dihydroergotamine , ergotamine , lisuride , LSD , mesulergine , metergoline , methysergide )
Hypidone
Serotonin (5-HT)
Tryptamines (e.g., 2-Me-5-HT , 5-BT , 5-CT , 5-MT , Bufotenin , E-6801 , E-6837 , EMD-386088 , EMDT , LY-586713 , N-Me-5-HT , ST-1936 , tryptamine )
WAY-181187
WAY-208466
Antagonists: ABT-354
Atypical antipsychotics (e.g., aripiprazole , asenapine , clorotepine , clozapine , fluperlapine , iloperidone , olanzapine , tiospirone )
AVN-101
AVN-211
AVN-322
AVN-397
BGC20-760
BVT-5182
BVT-74316
Cerlapirdine
EGIS-12,233
GW-742457
Idalopirdine
Ketanserin
Landipirdine
Latrepirdine (dimebolin)
Masupirdine
Metitepine (methiothepin)
MS-245
PRX-07034
Ritanserin
Ro 04-6790
Ro 63-0563
SB-258585
SB-271046
SB-357134
SB-399885
SB-742457
Tetracyclic antidepressants (e.g., amoxapine , mianserin )
Tricyclic antidepressants (e.g., amitriptyline , clomipramine , doxepin , nortriptyline )
Typical antipsychotics (e.g., chlorpromazine , loxapine )
5-HT7
Antagonists: Atypical antipsychotics (e.g., amisulpride , aripiprazole , asenapine , brexpiprazole , clorotepine , clozapine , fluperlapine , olanzapine , risperidone , sertindole , tiospirone , ziprasidone , zotepine )
Butaclamol
DR-4485
EGIS-12,233
Ergolines (e.g., 2-Br-LSD (BOL-148) , amesergide , bromocriptine , cabergoline , dihydroergotamine , ergotamine , LY-53857 , LY-215,840 , mesulergine , metergoline , methysergide , sergolexole )
JNJ-18038683
Ketanserin
LY-215,840
Metitepine (methiothepin)
Ritanserin
SB-258719
SB-258741
SB-269970
SB-656104
SB-656104A
SB-691673
SLV-313
SLV-314
Spiperone
SSR-181507
Tetracyclic antidepressants (e.g., amoxapine , maprotiline , mianserin , mirtazapine )
Tricyclic antidepressants (e.g., amitriptyline , clomipramine , imipramine )
Typical antipsychotics (e.g., acetophenazine , chlorpromazine , chlorprothixene , fluphenazine , loxapine , pimozide )
Vortioxetine