Abstract

Ergotamine, a notable member of the ergot alkaloid family, is recognized by its various commercial names such as Cafergot (when combined with caffeine) and Ergomar, among other designations. This ergopeptine compound shares a striking structural and biochemical affinity with ergoline. This piece delves into a comprehensive exploration of Ergotamine, encompassing its fundamental characteristics, physico-chemical traits, pharmacological applications, observed effects and accompanying symptoms, market pricing and approximate dosages, potential hazardous interactions, legal standings, the intricate process of Ergotamine synthesis, conclusions.

Ergot: the story of a parasitic fungus (1958).

General Information About Ergotamin [1-6]

Other synonyms names of Ergotamin are: Gynergen; Ergonsvine; Ergostat; ergotaminum; Ergotamina; Ergomar; Cornutamine; Lingraine; Rigetamin; Wigrettes; Temigran; 12′-Hydroxy-2′-methyl-5’alpha-(phenylmethyl)ergotaman-3′,6′,18-trione; N-[(2R,5S,10aS,10bS)-5-benzyl-10b-hydroxy-2-methyl-3,6-dioxo-8,9,10,10a-tetrahydro-5H-oxazolo[[?]]pyrrolo[[?]]pyrazin-2-yl]-methyl-[?]carboxamide

IUPAC Name of Ergotamin: (6aR,9R)-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]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide

CAS numbers are 113-15-5; 379-79-3

Related CAS is 379-79-3 (2:1 tartrate salt)

International/Other Brands are Anervan (Recip) / Antimigraine (Ta Fong) / Enxak (Cazi) / Ergam (Gedeon Richter) / Ergo-Kranit (Krewel Meuselbach) / Gynaemine (Sriprasit Dispensary) / Gynergen / Wigrettes

Physico-Chemical Properties of Ergotamin [1-6]

• Molecular Formula C₃₃H₃₅N₅O₅
• Molar Weight 581.7 g/mol
• Melting Point 213-214 ℃
• Decomposes Point 212-214 ℃
• Solubility: In water, 2.91 mg/L at 25 °C (est); Soluble in about 70 parts methanol, 150 parts acetone, 300 parts alcohol; freely soluble in chloroform, pyridine, glacial acetic acid; moderately soluble in ethyl acetate; slightly soluble in benzene; almost insoluble in petroleum ether
• Color/Form: Very hygroscopic. Darkens and decomposes on exposure to air, heat and light. Needles from alcohol; prisms from benzene; plates from acetone
• Specific optical rotation: -160 deg at 20 °C/D (chloroform)

Structural formula present on Figure 1.

Tablet and commercial product of the Ergotamin can be seen in the pictures provided in Figure 2 and Figure 3.

General Information of Ergotamin and Pharmacology [7, 8]

Ergotamine, a multifaceted organic compound, exhibits an intricate array of attributes, including its classification as an amine, ether, amide, and drug. Beyond its medicinal utility, it takes on roles as a mycotoxin, adrenergic alpha-agonist, non-narcotic analgesic, sympatholytic agent, vasoconstrictor, and even a metabolite. As a fungal toxin and natural compound toxin, it intricately targets specific receptors and processes within living organisms.

Focusing on the specific iteration of Ergotamine known as Ergotamine D-tartrate, its place within the realm of nonsteroidal anti-inflammatory drugs becomes evident. With its application in the treatment of migraines and various headaches, Ergotamine D-tartrate exerts its effects through the inhibition of nitric oxide production, a key factor in angiogenesis. Notably, its affinity for alpha2 adrenergic receptors on brain blood vessels underpins its anti-migraine efficacy, a distinct characteristic absent in other nonsteroidal anti-inflammatory drugs.

Yet, Ergotamine’s journey through the body is complex. Subject to substantial first-pass metabolism by the liver following oral administration, its bioavailability remains low. However, the biologically active metabolites of Ergotamine and its counterpart DHE persist, surpassing parent compound concentrations. Sequestration within tissues contributes to the prolonged physiological effects, even beyond plasma detection limits.

Human understanding of Ergotamine’s tissue odyssey remains veiled, yet it finds its path into the cerebrospinal fluid. Rats divulge its predilections, casting it in higher amounts within liver and lung domains, with subdued presence in kidney, heart, and brain. The liver, a master conductor of metabolism, commands the transformation of ergotamine. Following oral introduction, hepatic metabolism swiftly dismantles it from the bloodstream, with remnants mainly exiled through fecal biliary routes. Urine bears but a trace of the original essence. A secondary plasma crescendo, some studies attest, graces the scene around the 48-hour mark, hinting at the cyclical dance of enterohepatic recirculation. Ergotamine’s finale adheres to a dual-phase choreography, with half-lives averaging 10 minutes and 3.4 hours.

Effects and symptoms of Ergotamin Use [8]

Undesirable outcomes stemming from ergotamine encompass the unsettling duet of nausea and vomiting. When traversing higher dosages, the stage transforms, spotlighting elevated arterial blood pressure, a tapestry of vasoconstriction weaving through, encompassing coronary vasospasm, and orchestrating the rhythm of the heart as bradycardia or tachycardia. The grand production of severe vasoconstriction unfurls its effects, potentially casting intermittent claudication as its star performer.

Ergotism, a spectral consequence of prolonged ergot exposure, takes its cues from the historical script of ergot poisoning. Traditionally, this narrative was spun from the alkaloids birthed by Claviceps purpurea—the very essence of “club” or “nail” as evoked by ‘clava’ and ‘clavus’, and crowned by the headiness of ‘-ceps’. This purple-hued club-headed fungus, an infiltrator of rye and kin cereals, penned this tale. In modern chapters, the roles of protagonist have expanded to include a cast of ergoline-based drugs. This saga also dons aliases like ergotoxicosis, ergot poisoning, and the blaze of Saint Anthony.

Prices and Approximate Dosage

Ergotamine tartrate exhibits rapid, albeit incomplete and variable, absorption after being taken orally (approximately 1%), rectally (1% to 2%), or through intramuscular injection (47%). The zenith of plasma concentrations is reached approximately one hour subsequent to oral or rectal administration, with the highest levels observed after rectal intake. The presence of caffeine augments the absorption of ergotamine tartrate following oral ingestion. Dosage variations span from 1 mg to 5 mg.

An excessive dose could precipitate sensations of lethargy, emesis, throbbing sensations in the cervical region or auditory organs, as well as paresthesia or discomfort in the extremities, cyanotic digits, loss of consciousness, or convulsions.

Commercial product prices stand at $108 for 5 mg, $540 for 500 mg, and $820 for 1000 mg. A caffeine/ergotamine oral tablet (100 mg caffeine – 1 mg ergotamine) is available at an approximate cost of $1,189 for a quantity of 100 tablets.

Dangerous interactions

Ergotamine usage is contraindicated in cases of allergy to the compound or the presence of the following conditions:

• Peripheral vascular disease causing circulation problems
• Hypertension (high blood pressure)
• Coronary heart disease marked by arterial blockage
• Impaired liver or kidney function
• Sepsis, denoting a severe response to an infection
• Numerous medications possess the potential to interact with ergotamine, yielding hazardous consequences. There are specific drugs that should not be combined with ergotamine:
• Nefazodone
• Antibiotics like clarithromycin, erythromycin, and telithromycin
• Antifungal agents such as itraconazole, ketoconazole, posaconazole, and voriconazole
• Antiviral drugs utilized to manage HIV or hepatitis C, including boceprevir, cobicistat, dasabuvir, elvitegravir, indinavir, lopinavir/ritonavir, nelfinavir, ombitasvir, paritaprevir, saquinavir, telaprevir, and tipranavir
• Specific cancer medications like ceritinib, idelalisib, ribociclib, and tucatinib

Combining these medications with ergotamine can lead to diminished blood circulation in the extremities, potentially resulting in lasting tissue impairment or even amputation in certain cases.

Ergotamine also holds the capacity to influence blood circulation in the uterus. Consequently, its use is not advised during pregnancy. Furthermore, breastfeeding should be avoided while employing ergotamine.

Legal Status

Ergotamine is classified as a List I precursor according to United States regulations, primarily due to its widespread utilization as a precursor in the synthesis of LSD (lysergic acid diethylamide), a potent hallucinogenic compound. This classification signifies that the production, distribution, and acquisition of ergotamine are subject to strict legal controls and restrictions.

Synthesis of Ergotamin [8, 9]

Novel strains of Claviceps purpurea, unveiled through investigations conducted at Sandoz Laboratories and Farmitalia, introduce an additional avenue for generating medically valuable ergot alkaloids. These strains exhibit the capacity to synthesize ergot alkaloids of the peptide category, including noteworthy compounds like ergotamine, or alternatively, the distinctive alkaloids belonging to the ergotoxine family. Illustrated in Figure 4 is the ergot fungus, a visual representation of this intriguing organism’s structure and characteristics.

The process of synthesizing ergotamine presents substantial challenges, with comprehensive insights extensively elaborated in reference [9]. The procedure for creating ergotamine commences from a specific point and meticulously follows the sequence outlined in the schematic diagram depicted in Figure 5.

Conclusion

Ergotamine stands as a compound of significant importance due to its diverse applications and intricate synthesis process. With its origins in the Claviceps purpurea fungus, ergotamine has found utility in various medical contexts, particularly as a treatment for migraines and cluster headaches. Its vasoconstrictive properties have proven valuable in managing these conditions, although its usage is often limited due to potential side effects and interactions with other medications.

The synthesis of ergotamine is a complex endeavor, requiring intricate chemical transformations and expertise. Detailed procedures and methodologies have been explored in scientific literature, shedding light on the challenges and intricacies involved in creating this valuable compound. The development of novel strains of Claviceps purpurea has also expanded the possibilities for producing ergot alkaloids, broadening the potential sources for their synthesis.

Despite its medical applications and potential benefits, ergotamine’s usage must be approached with caution due to its potential adverse effects and interactions, especially with other drugs. Moreover, its inclusion as a precursor in the synthesis of LSD has led to its classification and regulation in various jurisdictions, reflecting the complex interplay between its therapeutic potential and its role in illicit activities.

In essence, ergotamine’s intricate synthesis, diverse applications, and regulatory considerations underscore the multifaceted nature of this compound within the realms of medicine, chemistry, and legal frameworks. The potential for more refined applications and controlled synthesis processes may pave the way for its continued contributions to medical science and beyond.

Bibliography

1. https://en.wikipedia.org/wiki/Ergotamine
2. https://pubchem.ncbi.nlm.nih.gov/compound/8223
3. https://www.chemspider.com/Chemical-Structure.7930.html
4. https://go.drugbank.com/drugs/DB00696
5. https://www.musechem.com/product/ergotamine-r000379/
6. https://www.biosynth.com/p/FE30656/379-79-3-ergotamine-d-tartrate
7. Stephen D. Silberstein MD, FACP, Douglas C. McCrory MD. Ergotamine and Dihydroergotamine: History, Pharmacology, and Efficacy. Headache: the journal of head and face pain, Volume 43, Issue 2, pp. 144-166, 2003. https://doi.org/10.1046/j.1526-4610.2003.03034.x https://headachejournal.onlinelibrary.wiley.com/doi/abs/10.1046/j.1526-4610.2003.03034.x
8. A. Stoll, A. Hofmann Die Alkaloide der Ergotoxingruppe: Ergocristin, Ergokryptin und Ergocornin. (7. Mitteilung über Mutterkornalkaloide). Helvetica Chimica Acta, Volume 26, Issue 5, pp. 1570-1601, 1943. https://doi.org/10.1002/hlca.19430260522 https://onlinelibrary.wiley.com/doi/abs/10.1002/hlca.19430260522
9. A. Hofmann Historical View on Ergot Alkaloids. Pharmacology, 16, Suppl. 1, pp. 1–11, 1978. https://doi.org/10.1159/000136803 https://karger.com/pha/article-abstract/16/Suppl.%201/1/268147/Historical-View-on-Ergot-Alkaloids?redirectedFrom=PDF