Ergotamine Derivatives: Uses, Mechanisms, and Global Trade Analysis
What are the main uses of ergotamine derivatives. How do these compounds work to treat migraines. Which countries dominate the global trade of ergot alkaloids. What are the key drug targets of dihydroergotamine and ergotamine.
Overview of Ergotamine Derivatives
Ergotamine derivatives are a class of compounds derived from ergot alkaloids, which are produced by fungi of the genus Claviceps. These compounds have important medical applications, particularly in the treatment of migraines and cluster headaches. The two most prominent ergotamine derivatives used clinically are ergotamine and dihydroergotamine.
Ergotamine was first isolated in 1918 and has been used to treat migraines since the 1920s. Dihydroergotamine is a semisynthetic derivative of ergotamine that was developed later to improve upon the pharmacological properties of ergotamine. Both compounds act as vasoconstrictors and have complex pharmacological profiles involving multiple neurotransmitter systems.
Key Properties of Ergotamine Derivatives
- Potent vasoconstrictors
- Agonists at multiple serotonin receptor subtypes
- Interact with adrenergic and dopaminergic receptors
- Highly effective for acute treatment of migraines
- Can cause significant side effects due to widespread activity
Pharmacological Mechanisms of Ergotamine Derivatives
The therapeutic effects of ergotamine derivatives in treating migraines are primarily attributed to their vasoconstrictor properties and interactions with serotonin receptors. However, these compounds have complex pharmacological profiles involving multiple receptor systems.
Key Drug Targets of Dihydroergotamine
- 5-HT1B/1D receptors (primary antimigraine targets)
- 5-HT1A, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT2C receptors
- Alpha-1 and alpha-2 adrenergic receptors
- Dopamine D2, D3, and D4 receptors
Key Drug Targets of Ergotamine
- 5-HT1B/1D receptors
- 5-HT2A and 5-HT2C receptors
- Alpha-1A, alpha-1B, and alpha-2A adrenergic receptors
- Dopamine D2 receptor
How do ergotamine derivatives alleviate migraine symptoms? These compounds act by constricting cranial blood vessels and inhibiting the release of neuropeptides involved in neurogenic inflammation. The activation of 5-HT1B/1D receptors is particularly important for their antimigraine effects.
Clinical Uses of Ergotamine Derivatives
Ergotamine derivatives are primarily used in the acute treatment of migraines and cluster headaches. They are particularly effective for severe migraines that do not respond to other treatments.
Indications for Ergotamine Derivatives
- Acute treatment of migraine with or without aura
- Management of cluster headaches
- Treatment of menstrual migraines
Are ergotamine derivatives suitable for all migraine patients? While these drugs can be highly effective, their use is limited due to the risk of side effects and the potential for medication overuse headaches. They are typically reserved for patients who do not respond to or cannot tolerate other acute migraine treatments like triptans or NSAIDs.
Side Effects and Precautions
The wide-ranging pharmacological activity of ergotamine derivatives contributes to their efficacy but also leads to a significant side effect profile. Proper use and monitoring are crucial to minimize risks.
Common Side Effects
- Nausea and vomiting
- Dizziness
- Paresthesias
- Muscle pain
- Chest tightness
Serious Adverse Effects
- Ergotism (severe peripheral vasoconstriction)
- Fibrosis of cardiac valves or retroperitoneal tissues
- Medication overuse headaches
Can long-term use of ergotamine derivatives lead to complications? Prolonged or excessive use of these drugs can result in serious complications, including the development of fibrotic changes in various tissues. A rare but severe complication is ergotism, characterized by severe vasoconstriction that can lead to tissue ischemia and gangrene.
Global Trade of Ergot Alkaloids and Derivatives
The international trade of ergot alkaloids and their derivatives, including ergotamine, is a significant component of the pharmaceutical industry. Analysis of trade data provides insights into the global market for these compounds.
Top Exporting Countries (2020)
- Czech Republic ($44.7 million)
- Italy ($27.1 million)
- India ($3.71 million)
Top Importing Countries (2020)
- China ($20.3 million)
- Japan ($10.6 million)
- Romania ($6.9 million)
Why does the Czech Republic dominate ergot alkaloid exports? The Czech Republic has a long history of ergot alkaloid production, dating back to the early 20th century. The country’s pharmaceutical industry has developed significant expertise in the cultivation of ergot fungi and the extraction and synthesis of ergot derivatives, giving it a competitive advantage in the global market.
Mexican Trade in Ergot Alkaloids
Mexico plays a role in the international trade of ergot alkaloids and their derivatives, primarily as an importer. Analysis of recent trade data provides insights into Mexico’s position in this market.
Key Points on Mexican Trade (2022)
- Primary importing region: Ciudad de México ($110,000)
- Main sources of imports:
- Czech Republic ($33,500)
- India ($30,000)
- Italy ($29,000)
- Germany ($16,600)
- France ($1,000)
How has Mexico’s trade in ergot alkaloids changed over time? While comprehensive historical data is not provided, the current import figures suggest that Mexico relies on imports to meet its domestic needs for ergot alkaloids and their derivatives. The diversity of import sources indicates that Mexico maintains trade relationships with multiple major producers of these compounds.
Future Perspectives and Research Directions
Despite their long history of use, ergotamine derivatives continue to be an active area of research and development in the field of migraine treatment. Current research focuses on improving their efficacy and safety profile.
Emerging Research Areas
- Development of novel ergotamine derivatives with improved selectivity
- Investigation of long-term safety profiles
- Exploration of new delivery methods to enhance bioavailability and reduce side effects
- Combination therapies with other antimigraine drugs
What potential improvements in ergotamine derivatives are researchers pursuing? Scientists are working on developing new compounds that maintain the potent antimigraine effects of ergotamine derivatives while reducing their tendency to cause side effects. This involves designing molecules with greater selectivity for specific serotonin receptor subtypes involved in migraine pathophysiology.
Additionally, researchers are exploring novel drug delivery systems, such as nasal sprays and transdermal patches, to improve the bioavailability of these drugs and potentially reduce systemic side effects. The goal is to enhance the therapeutic index of ergotamine derivatives, making them safer and more tolerable for long-term use in migraine management.
Another area of interest is the potential synergistic effects of combining ergotamine derivatives with other antimigraine medications. By targeting multiple pathways involved in migraine pathophysiology, these combination therapies could potentially offer more effective relief with lower doses of individual drugs, thereby reducing the risk of adverse effects.
Challenges in Ergotamine Derivative Research
- Balancing efficacy and safety
- Overcoming the risk of medication overuse headaches
- Addressing the complex pharmacology of these compounds
- Developing personalized treatment approaches
How can the risk of medication overuse headaches be mitigated? One of the primary challenges in ergotamine derivative research is finding ways to maintain their effectiveness while reducing the risk of medication overuse headaches. Strategies being explored include:
- Developing formulations with built-in limits on frequency of use
- Investigating biomarkers that could predict individual susceptibility to medication overuse headaches
- Exploring combination therapies that could allow for lower doses of ergotamine derivatives
- Researching novel compounds that retain the antimigraine efficacy but have a lower propensity for causing medication overuse headaches
The complex pharmacology of ergotamine derivatives presents both challenges and opportunities for researchers. While their interactions with multiple receptor systems contribute to their efficacy, they also increase the risk of side effects. Future research aims to unravel these complex interactions and potentially develop more targeted therapies that retain the benefits of ergotamine derivatives while minimizing their drawbacks.
Regulatory Landscape and Access to Ergotamine Derivatives
The potent effects and potential for misuse of ergotamine derivatives have led to strict regulatory controls on their production, distribution, and use in many countries. Understanding the regulatory landscape is crucial for healthcare providers, patients, and stakeholders in the pharmaceutical industry.
Key Regulatory Considerations
- Prescription requirements
- Manufacturing and quality control standards
- Import/export regulations
- Monitoring and reporting of adverse effects
How do regulatory requirements impact patient access to ergotamine derivatives? The strict regulatory controls on ergotamine derivatives can sometimes create barriers to access for patients who could benefit from these medications. In many countries, these drugs are only available with a prescription from a specialist, which can delay treatment initiation. Additionally, concerns about potential abuse or misuse have led some regulatory agencies to impose restrictions on the quantity that can be prescribed or dispensed at one time.
Manufacturers of ergotamine derivatives must adhere to stringent quality control standards to ensure the safety and consistency of their products. These requirements, while necessary for patient safety, can contribute to higher production costs and potentially limit the number of manufacturers willing to produce these drugs.
International Variations in Regulation
Regulatory approaches to ergotamine derivatives can vary significantly between countries, reflecting differences in healthcare systems, cultural attitudes towards drug use, and historical experiences with these compounds. For example:
- In the United States, ergotamine derivatives are classified as Schedule IV controlled substances, requiring special prescribing and record-keeping practices.
- The European Union has harmonized regulations for ergot alkaloids in food products but individual member states may have varying approaches to medical use of ergotamine derivatives.
- In some developing countries, access to ergotamine derivatives may be limited due to cost or availability issues, rather than strict regulatory controls.
These regulatory differences can impact global trade patterns and patient access to ergotamine derivatives. Countries with more permissive regulations may become hubs for production and export, while those with stricter controls may rely more heavily on imports to meet domestic needs.
Balancing Regulation and Access
Regulatory agencies face the challenge of balancing the need for strict controls on ergotamine derivatives with ensuring that patients who could benefit from these medications have appropriate access. Strategies to address this balance include:
- Implementing risk evaluation and mitigation strategies (REMS) to ensure safe use
- Providing clear guidelines for healthcare providers on appropriate prescribing practices
- Encouraging research into safer formulations or delivery methods
- Promoting international cooperation to combat illicit trade while facilitating legitimate medical use
As research continues to refine our understanding of the benefits and risks of ergotamine derivatives, regulatory approaches may evolve to reflect new evidence. The goal is to maintain a regulatory framework that protects public health while supporting the development and appropriate use of these important medications.
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
#permalink to section
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
#permalink to section
Net Trade Balance
#permalink to section
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
#permalink to section
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
#permalink to section
International Purchases
#permalink to section
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
#permalink to section
Specialization by State
#permalink to section
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
#permalink to section
Origins and Trade Destinations
#permalink to section
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
to the list of articlesFind a doctor
TN VED code 2939620000. Online service
TN VED
Online service
Ergotamine (INN) and its salts
HS position
|
Products of the chemical and related industries (Chapters 28-38)
.. Position OKPD 2
|
Customs fees
Import
| Basic rate of customs duty | 3% sol.  |