Ergotamine Derivatives: Uses, Mechanisms, and Global Trade Dynamics
How do ergotamine derivatives work to treat migraines. What are the key pharmacological targets of dihydroergotamine and ergotamine. Which countries dominate the global trade of ergot alkaloids.
Pharmacological Properties of Ergotamine Derivatives
Ergotamine derivatives are a class of medications primarily used in the treatment of migraine headaches. The two main drugs in this category are dihydroergotamine and ergotamine. These compounds exert their therapeutic effects through multiple mechanisms of action, targeting several receptor systems in the body.
Key Pharmacological Targets
- 5-HT receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4)
- Alpha-adrenergic receptors (α1 and α2 subtypes)
- Dopamine receptors (D2, D3, D4)
The complex pharmacology of ergotamine derivatives contributes to their effectiveness in treating migraines, but also accounts for their potential side effects and contraindications.
Dihydroergotamine: A Potent Antimigraine Agent
Dihydroergotamine (DHE) is a semisynthetic ergot alkaloid widely used for acute migraine treatment. It offers several advantages over other antimigraine medications.
Mechanism of Action
DHE primarily acts as a potent agonist at 5-HT1B and 5-HT1D receptors, leading to vasoconstriction of cranial blood vessels and inhibition of neuropeptide release. This dual action helps alleviate migraine pain and associated symptoms.
Pharmacokinetics and Administration
DHE can be administered through various routes, including intranasal, subcutaneous, and intravenous. Its relatively long half-life contributes to sustained therapeutic effects.
Clinical Applications
Besides acute migraine treatment, DHE has shown efficacy in managing cluster headaches and medication-overuse headaches. How does DHE compare to triptans in terms of efficacy? While both drug classes are effective, DHE may be particularly useful in patients who do not respond well to triptans or have contraindications to their use.
Ergotamine: The Classical Antimigraine Medication
Ergotamine has been used for migraine treatment for nearly a century. Despite newer alternatives, it remains a valuable option for some patients.
Receptor Profile
Ergotamine exhibits high affinity for 5-HT1B/1D receptors, as well as α-adrenergic and dopamine receptors. This broad receptor profile contributes to its antimigraine effects but also increases the risk of side effects.
Formulations and Administration
Ergotamine is available in various formulations, including tablets, sublingual preparations, and suppositories. It is often combined with caffeine to enhance absorption and efficacy.
Precautions and Contraindications
Due to its potent vasoconstrictive properties, ergotamine use requires careful consideration. It is contraindicated in patients with cardiovascular diseases, peripheral vascular disorders, and during pregnancy.
Long-term Use of Ergotamine Derivatives: Benefits and Risks
While ergotamine derivatives can be highly effective for migraine management, their long-term use raises concerns about potential complications.
Potential Complications
- Ergotism: A rare but serious condition characterized by severe vasoconstriction
- Medication overuse headache: Paradoxical increase in headache frequency with frequent use
- Fibrotic complications: Rare cases of retroperitoneal, pleural, and cardiac valve fibrosis
Can long-term ergotamine use lead to neurological complications? In rare cases, prolonged use of ergotamine derivatives has been associated with pachymeningitis and cranial nerve palsies, as highlighted in some case reports.
Global Trade Dynamics of Ergot Alkaloids
The international market for ergot alkaloids and their derivatives plays a crucial role in ensuring the availability of these important medications worldwide.
Major Exporting Countries
In 2020, the global export landscape for ergot alkaloids (excluding ergometrine, ergotamine, and lysergic acid) was dominated by:
- Czech Republic: US$44.7 million
- Italy: US$27.1 million
- India: US$3.71 million
These figures underscore the significance of European and Asian manufacturers in the global supply chain of ergot alkaloids.
Leading Importing Nations
The main importers of ergot alkaloids in 2020 were:
- China: US$20.3 million
- Japan: US$10.6 million
- Romania: US$6.9 million
The substantial import volumes in Asian countries reflect the growing pharmaceutical industries and increasing demand for migraine treatments in these regions.
Mexico’s Role in the Ergot Alkaloid Trade
Mexico’s involvement in the international trade of ergot alkaloids provides insights into regional market dynamics and pharmaceutical needs.
Import Trends
In 2022, Mexico’s imports of ergot alkaloids were primarily concentrated in:
- Ciudad de México: US$110,000
This centralization of imports in the capital city suggests a concentrated pharmaceutical industry or distribution network.
Major Supplying Countries
Mexico’s main sources of ergot alkaloids in 2022 were:
- Czech Republic: US$33,500
- India: US$30,000
- Italy: US$29,000
- Germany: US$16,600
- France: US$1,000
The diversity of supplying countries indicates Mexico’s strategy to ensure a stable supply chain for these critical pharmaceutical ingredients.
Future Perspectives and Research Directions
As our understanding of migraine pathophysiology evolves, so does the potential for developing new ergotamine derivatives or optimizing existing formulations.
Novel Delivery Systems
Research is ongoing to develop innovative delivery systems for ergotamine derivatives, aiming to enhance bioavailability and reduce side effects. These include nasal powders, transdermal patches, and targeted nanoparticle formulations.
Combination Therapies
Exploring synergistic combinations of ergotamine derivatives with other antimigraine agents could lead to more effective treatment options. For instance, combining DHE with CGRP antagonists might provide enhanced efficacy in refractory cases.
Personalized Medicine Approaches
Advances in pharmacogenomics may allow for more tailored use of ergotamine derivatives based on individual patient profiles. This could optimize treatment outcomes while minimizing adverse effects.
How might artificial intelligence contribute to optimizing ergotamine derivative therapy? AI algorithms could potentially analyze patient data to predict responsiveness to different formulations or dosing regimens, enabling more personalized treatment strategies.
Regulatory Landscape and Market Outlook
The regulatory environment surrounding ergotamine derivatives continues to evolve, impacting their availability and use in different regions.
Regulatory Challenges
Due to their potential for misuse and side effects, ergotamine derivatives face stringent regulatory scrutiny. This has led to restricted availability in some countries and ongoing debates about their risk-benefit profile.
Market Trends
Despite competition from newer antimigraine medications, ergotamine derivatives maintain a significant market presence. Factors contributing to their continued use include:
- Cost-effectiveness compared to some newer treatments
- Established efficacy in certain patient populations
- Availability of generic formulations
Will the market for ergotamine derivatives expand or contract in the coming years? While newer antimigraine drugs may capture market share, the unique properties of ergotamine derivatives suggest they will likely retain a place in migraine management, particularly for refractory cases or as part of combination therapies.
In conclusion, ergotamine derivatives remain an important class of medications in the treatment of migraines and cluster headaches. Their complex pharmacology, coupled with a long history of clinical use, positions them as valuable tools in the neurologist’s arsenal. As research continues and global trade dynamics evolve, these compounds are likely to play a continuing role in addressing the significant burden of migraine disorders worldwide.
Ergotamine Derivative | DrugBank Online
All categories
- Name
- Ergotamine Derivative
- Accession Number
- DBCAT003327
- Description
Not Available
- Drugs
Drug Drug Description Dihydroergotamine An ergot alkaloid used in the acute treatment of migraine headache and cluster headache. Ergotamine An alpha-1 selective adrenergic agonist vasoconstrictor used to treat migraines with or without aura and cluster headaches. Dihydroergotoxine Not Annotated - Drugs & Drug Targets
Drug Target Type Dihydroergotamine 5-hydroxytryptamine receptor 1D target Dihydroergotamine 5-hydroxytryptamine receptor 1B target Dihydroergotamine Cytochrome P450 3A4 enzyme Dihydroergotamine Alpha-2A adrenergic receptor target Dihydroergotamine 5-hydroxytryptamine receptor 2B target Dihydroergotamine P-glycoprotein 1 transporter Dihydroergotamine 5-hydroxytryptamine receptor 1A target Dihydroergotamine 5-hydroxytryptamine receptor 1E target Dihydroergotamine 5-hydroxytryptamine receptor 2A target Dihydroergotamine 5-hydroxytryptamine receptor 2C target Dihydroergotamine Alpha-1 adrenergic receptors target Dihydroergotamine Alpha-2 adrenergic receptors target Dihydroergotamine Dopamine D2 receptor target Dihydroergotamine Dopamine D3 receptor target Dihydroergotamine Dopamine D4 receptor target Dihydroergotamine 5-hydroxytryptamine receptor 1F target Dihydroergotamine 5-hydroxytryptamine receptor 4 target Dihydroergotamine Beta-3 adrenergic receptor target Ergotamine Alpha-1A adrenergic receptor target Ergotamine 5-hydroxytryptamine receptor 1D target Ergotamine 5-hydroxytryptamine receptor 1B target Ergotamine 5-hydroxytryptamine receptor 2A target Ergotamine Alpha-2A adrenergic receptor target Ergotamine Dopamine D2 receptor target Ergotamine Cytochrome P450 3A4 enzyme Ergotamine Alpha-1B adrenergic receptor target Ergotamine Alpha-1D adrenergic receptor target Ergotamine P-glycoprotein 1 transporter Ergotamine D(1) dopamine receptor target Ergotamine 5-hydroxytryptamine receptor 1A target Ergotamine 5-hydroxytryptamine receptor 1F target Ergotamine 5-hydroxytryptamine receptor 2C target Ergotamine 5-hydroxytryptamine receptor 2B target Ergotamine Alpha-2C adrenergic receptor target
Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl.
Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof): Commercial exchange, international purchases and sales, market and specialization
About
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The states with the most international purchases in 2022 were Ciudad de México (US$110k).
The main commercial origins of Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) in 2022 were Czech Republic (US$33.5k), India (US$30k), Italy (US$29k), Germany (US$16.6k), and France (US$1k).
In the global context, the main exporting countries of Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) in 2020 were Czech Republic (US$44.7M), Italy (US$27.1M), and India (US$3.71M). In the same year, the main importing countries of Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) were China (US$20.
3M), Japan (US$10.6M), and Romania (US$6.9M).
Trade Balance of Mexico
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Net Trade Balance
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Year20222021202020192018201720162015201420132012201120102009200820072006
The visualizations show the net balance of Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) at the level of states and countries. Colors more similar to blue, indicate that the territory presented a higher level of international sales. Colors more similar to red, indicate that the territory presented a higher level of international purchases.
Net International Trade
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June, 2020: US$5.74M, International Purchases
In June 2020, international sales of Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) were US$0, while international purchases reached US$5.
74M. The above results in a trade balance of -US$5.74M.
Exchange by Territory
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International Purchases
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Year20222021202020192018201720162015201420132012201120102009200820072006
In 2022, the states with the highest international in Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) were Ciudad de México (US$110k).
The countries with the most international sales to Mexico in 2022 were Czech Republic (US$33.5k), India (US$30k), Italy (US$29k), Germany (US$16.6k), and France (US$1k).
Specialization
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Specialization by State
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The RCA-Complexity diagram compares the Revelead Comparative Advantages of states in Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) and the Economic Complexity Index of each state.
RCA values greater than 1 indicate that the state has comparative advantages in Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof). On the other hand, high levels of complexity (ECI) are associated with higher levels of income, potential for economic growth, lower income inequality and lower emissions.
Global Market
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Origins and Trade Destinations
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20202019201820172016201520142013
The visualizations show the global market for Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof). In both charts, Mexico stands out in order to identify its participation in the export and import market.
In 2020, the main exporting countries of Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl.
Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) were Czech Republic (US$44.7M), Italy (US$27.1M), and India (US$3.71M). In the same year, the main importing countries for Ergot Alkaloids of Rye and its Derivatives; Salts Thereof (Excl. Ergometrine, Ergotamine, Lysergic Acid and Salts Thereof) were China (US$20.3M), Japan (US$10.6M), and Romania (US$6.9M).
Consequences of misuse of painkillers
Pain medications (non-steroidal anti-inflammatory drugs – NSAIDs, ergotamine derivatives, analgesics) are the most popular and widely used over-the-counter drugs.
Pain medications (non-steroidal anti-inflammatory drugs – NSAIDs, ergotamine derivatives, analgesics) are the most popular and widely used OTC drugs. At the same time, headaches (cephalgia) are very often the cause of their use. Most often it is the so-called tension headache and migraine.
The possibility of buying a drug without a doctor’s prescription in Ukraine leads to the fact that many people decide on their own which drug, at what dose and with what frequency to take.
And therein lies the danger, since for each drug there are certain contraindications and restrictions for use.
First, the uncontrolled use of analgesics and NSAIDs often leads to the development of various side effects, including changes in blood composition, gastrointestinal bleeding, erosions and ulcers in the digestive tract.
And secondly, irrational (too frequent or exceeding the recommended dosage) use of painkillers for cephalalgia, including migraine, often causes the so-called drug-induced or abuse headache. Most often, such a headache occurs in chronic migraine as a result of chronic abuse of drugs for the treatment of attacks of cephalalgia. The development of overuse headache is indicated by the use of painkillers more than 2-3 times a week (10 times a month) for 3 or more months. At the same time, the severity of headache attacks and the frequency of their occurrence can progress against the background of excessive drug intake.
Interestingly, analgesic-associated headache occurs only in patients with primary headache (80% of overbusy headache patients are migraine patients) and never develops as a result of taking the same drugs, but according to different indications (for example, osteoarthritis).
Theoretically, too frequent use of any migraine medications, including analgesics, NSAIDs, ergotamine derivatives, opioids, triptans, can lead to the development of “abuses”. However, since the fact of abuse (i.e., excessive frequency of use) of the drug is of greatest importance here, this problem most often occurs when taking NSAIDs and analgesics, given their greater availability and less effectiveness in moderate and severe forms of migraine. As for the mechanisms of development of abusus cephalgia, it is assumed that it is based on changes in the parts of the brain responsible for conducting pain impulses that arise as a result of regular use of headache medications.
Diagnosis of overuse headache is not difficult – it is enough to analyze the entries in the headache diary of a patient who has addressed a doctor with complaints of progression of migraine or other primary headache, in which the time of onset of headache attacks and the number of pain medications taken for at least 3 months.
The superimposition of drug-induced headache on migraine symptoms significantly worsens the patient’s condition and requires proper treatment, the effectiveness of which depends on the patience and discipline of the patient. First of all, the doctor studies the treatment regimen, finds and cancels the “guilty” drug. Usually the complete withdrawal of such pain medication is sufficient intervention, however, in severe cases, inpatient treatment with antidepressants and detoxification therapy may be required. At the second stage, a correction of the migraine treatment regimen is carried out in order to effectively prevent attacks and most sparing pain relief in the event of the development of cephalalgia. Treatment regimens with alternating periods of frequent use of the drug and relatively long periods without treatment are preferred, since the regular use of painkillers is a major risk factor for the development of abuse headaches. A necessary condition for the effective treatment of “abuses” is the refusal to take the analgesic that caused the development of abuses headache, since any therapy will be much less effective if the patient continues to use such a drug on a regular basis.
Prevention of the development of drug-induced headaches in people with migraine and other primary cephalalgias consists in refusing self-medication and strictly following the doctor’s recommendations. In particular, it is of great importance to abandon the uncontrolled increase in the doses and frequency of taking NSAIDs and analgesics, in case of their ineffectiveness, in favor of switching to triptans.
Sources:
- https://www.webmd.com/pain-management/pain-medication-side-effects#1
- https://www.healthline.com/health/opioids-and-related-disorders#symptoms
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Ergotamine (INN) and its salts
HS position
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Products of the chemical and related industries (Chapters 28-38)
.. Position OKPD 2
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Customs fees
Import
| Basic rate of customs duty | 3% sol.  |