Dihydroergotamine

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Dihydroergotamine
Dihydroergotamine.svg
Clinical data
Pronunciation /daɪˌhaɪdroʊ.ɜːrˈɡɒtəmiːn/ dy-HY-droh-ur-GOT-ə-meen
Trade names D.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.com Monograph
MedlinePlus a603022
License data
Routes of
administration 		Nasal, Subcutaneous, Intramuscular, Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 32% (nasal spray)
Elimination half-life 9 hours
Excretion Bile
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 InfoCard 100.007.386 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C33H37N5O5
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 Yes check.svgY
  • Key:LUZRJRNZXALNLM-JGRZULCMSA-N Yes check.svgY
   (verify)

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]

Contents

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]
SiteAffinity (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 Dihydroergotamine.png
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]

Related Research Articles

<span class="mw-page-title-main">Sumatriptan</span> Medication used for migraines & cluster headaches

Sumatriptan, sold under the brand name Imitrex among others, is a medication used to treat migraine headaches and cluster headaches. It is taken orally, intranasally, or by subcutaneous injection. Therapeutic effects generally occur within three hours.

<span class="mw-page-title-main">Ergoline</span> Chemical compound

Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of these are implicated in the condition ergotism, which can take a convulsive form or a gangrenous form. Even so, many ergoline alkaloids have been found to be clinically useful. Annual world production of ergot alkaloids has been estimated at 5,000–8,000 kg of all ergopeptines and 10,000–15,000 kg of lysergic acid, used primarily in the manufacture of semi-synthetic derivatives.

<span class="mw-page-title-main">Ergotamine</span> Chemical compound in the ergot family of alkaloids

Ergotamine, sold under the brand name Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It is structurally similar to several neurotransmitters, and it acts as a vasoconstrictor. It is used for acute migraines, sometimes with caffeine as the combination ergotamine/caffeine.

<span class="mw-page-title-main">Triptan</span> Class of pharmaceutical drugs

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, they do not provide preventive treatment and are not considered a cure. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain.

<span class="mw-page-title-main">Ergoloid</span> Chemical compound

Ergoloid mesylates (USAN), co-dergocrine mesilate (BAN) or dihydroergotoxine mesylate, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids.

<span class="mw-page-title-main">Rizatriptan</span> Medication used for the treatment of migraine headaches

Rizatriptan, sold under the brand name Maxalt among others, is a medication used for the treatment of migraine headaches. It is taken by mouth. It can also be applied on the tongue. It is a serotonin (5-HT) 1B/1D receptor agonist (triptan).

<span class="mw-page-title-main">Zolmitriptan</span> Medication used in treatment of migraines

Zolmitriptan, sold under the brand name Zomig among others, is a serotonergic medication which is used in the acute treatment of migraine attacks with or without aura and cluster headaches. It is taken by mouth as a swallowed or disintegrating tablet or as a nasal spray.

<span class="mw-page-title-main">Ergometrine</span> Lysergamide

Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used either by mouth, by injection into a muscle, or injection into a vein. It begins working within 15 minutes when taken by mouth and is faster in onset when used by injection. Effects last between 45 and 180 minutes.

<span class="mw-page-title-main">Methylergometrine</span> Chemical compound

Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.

<span class="mw-page-title-main">Methysergide</span> Chemical compound

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.

<span class="mw-page-title-main">Almotriptan</span> Chemical compound

Almotriptan is a triptan medication discovered and developed by Almirall for the treatment of heavy migraine headache.

<span class="mw-page-title-main">Eletriptan</span> Chemical compound

Eletriptan, sold under the brand name Relpax and used in the form of eletriptan hydrobromide, is a second-generation triptan medication intended for treatment of migraine headaches. It is used as an abortive medication, blocking a migraine attack which is already in progress. Eletriptan is marketed and manufactured by Pfizer Inc.

<span class="mw-page-title-main">Lisuride</span> Chemical compound

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

<span class="mw-page-title-main">Nicergoline</span> Chemical compound

Nicergoline, sold under the brand name Sermion among others, is an ergot derivative used to treat senile dementia and other disorders with vascular origins. Internationally it has been used for frontotemporal dementia as well as early onset in Lewy body dementia and Parkinson's dementia. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs. Unlike many other ergolines, such as ergotamine, nicergoline is not associated with cardiac fibrosis.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

<span class="mw-page-title-main">Naratriptan</span> Chemical compound

Naratriptan (trade names include Amerge) is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. It is a selective 5-HT1 receptor subtype agonist.

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. They are selective 5-hydroxytryptamine/serotonin1B/1D (5-HT1B/1D) agonists. Migraine is a complex disease which affects about 15% of the population and can be highly disabling. Triptans have advantages over ergotamine and dihydroergotamine, such as selective pharmacology, well established safety record and evidence-based prescribing instructions. Triptans are therefore often preferred treatment in migraine.

Migraine may be treated either prophylactically (preventive) or abortively (rescue) for acute attacks. Migraine is a complex condition; there are various preventive treatments which disrupt different links in the chain of events that occur during a migraine attack. Rescue treatments also target and disrupt different processes occurring during migraine.

<span class="mw-page-title-main">Donitriptan</span> Chemical compound

Donitriptan (INN) is a triptan drug which was investigated as an antimigraine agent but ultimately was never marketed. It acts as a high-affinity, high-efficacy/near-full agonist of the 5-HT1B and 5-HT1D receptors, and is among the most potent of the triptan series of drugs. Donitriptan was being developed in France by bioMérieux-Pierre Fabre and made it to phase II clinical trials in Europe before development was discontinued.

References

  1. ↑ 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.
  2. ↑ "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.
  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. 1 2 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 340–. ISBN   978-3-88763-075-1.
  8. 1 2 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. 1 2 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. 1 2 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. 1 2 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. 1 2 "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. 1 2 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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