Dihydroergotamine

Dihydroergotamine (DHE) is a medication used to treat migraines and cluster headaches. It belongs to a class of drugs called ergot alkaloids, which have vasoconstrictive properties. DHE works by narrowing the blood vessels in the brain, which can help alleviate the throbbing pain associated with migraines.

DHE is often used when other migraine medications, such as triptans, are not effective or well-tolerated. It may be administered intravenously (IV), intramuscularly (IM), or as a nasal spray.

DHE’s ability to constrict blood vessels is thought to contribute to its effectiveness in relieving migraine symptoms. This vasoconstriction can reduce the dilation of blood vessels during a migraine.

The intravenous form of DHE is usually administered in a healthcare setting, such as a hospital or clinic, where the patient can be monitored for potential side effects.

Common side effects of DHE may include nausea, vomiting, dizziness, and nasal congestion. Sometimes, DHE can cause transient chest pain and tightness, so it’s essential to report any unusual sensations to a healthcare provider.

DHE is contraindicated in certain conditions, such as peripheral vascular disease, ischemic heart disease, uncontrolled hypertension, and hepatic or renal impairment. It should not be used during pregnancy.

DHE can interact with other medications, including antifungal drugs, certain antibiotics, and certain protease inhibitors. It’s essential to inform your healthcare provider about all your medications.

Due to potential side effects and the availability of alternative treatments, DHE is often reserved for cases where other migraine medications are ineffective or unsuitable.

As with any medication, it’s essential to use DHE under the guidance of a healthcare professional who can assess its appropriateness for your specific situation and monitor for potential side effects.

Pharmacokinetics

Peak plasma-dihydroergotamine concentrations have been attained within 1 to 2 hours after oral doses, 30 minutes after intramuscular injection, 15 to 45 minutes after subcutaneous injection, and 45 to 55 minutes after intranasal doses. However, the bioavailability of dihydroergotamine after oral doses is very low; values ranging from less than 0.1 to 1.5% have been reported. Although dihydroergotamine is incompletely absorbed from the gastrointestinal tract, the low bioavailability is determined primarily by extensive first-pass hepatic metabolism. Bioavailability after intranasal doses is 43%. Dihydroergotamine is 90 to 95% bound to plasma proteins.

Dihydroergotamine undergoes extensive metabolism, with the major metabolite, 8′-β-hydroxydihydroergotamine, being active. Plasma concentrations of this metabolite are greater than those of dihydroergotamine. A further oxidation step produces 8′,10′-dihydroxydihydroergotamine, which is also active. Other metabolites are also formed. Most of the dose is excreted as metabolites, mainly in the bile; 5 to 10% is excreted in the urine, of which only trace amounts are of unchanged drug. The elimination of dihydroergotamine is biphasic; half-lives of about 1 to 2 hours and 22 to 32 hours have been reported for the 2 phases, respectively.

Uses and Administration

Dihydroergotamine is a semisynthetic ergot alkaloid with weaker oxytocic and vasoconstrictor effects than ergotamine. Its activity as a 5-HT1 agonist is believed to contribute to its antimigraine action. It is used in treating migraines, cluster headaches, and orthostatic hypotension. It has also been used for venous thromboembolism prophylaxis.

Dihydroergotamine is commonly used as the mesylate by subcutaneous, intramuscular, or intravenous injection, although it may also be given as a nasal spray or orally.

For the treatment of migraine and to terminate an acute attack of cluster headache, dihydroergotamine mesylate is usually given by subcutaneous or intramuscular injection in doses of 1 mg repeated, if necessary, after 30 to 60 minutes up to a maximum daily dose of 3 mg. If a more rapid effect is desired, it may be given intravenously in doses of 0.5 or 1 mg up to a maximum daily dose of 2 mg. The total weekly dose given by any injection route should not exceed 6 mg.

The usual nasal dose of dihydroergotamine mesylate for an acute migraine attack is 500 micrograms sprayed into each nostril as a 0.4% solution, followed after 15 minutes by an additional 500 micrograms in each nostril. A total intranasal dose of 2 mg per attack should not be exceeded. In the USA, the maximum dose in 24 hours is 3 mg; in 7 days, it is 4 mg, while maximum daily doses of up to 4 mg with a maximum dose of 12 mg in 7 days have been given in other countries. In some countries, it is given orally; up to 10 mg daily has been given orally for the treatment of acute attacks of migraine. Lower oral doses have been given in some countries for migraine prevention.

Dihydroergotamine mesylate has also been used alone or with etilefrine hydrochloride (p. 1284) in treating orthostatic hypotension in usual oral doses of up to 10 mg daily in divided doses. Doses of up to 40 to 60 mg have been used in some patients.

Dihydroergotamine tartrate has been used for indications similar to those of the mesylate.

Medication-Overuse Headache

Dihydroergotamine may be used to treat medication-overuse headaches, including symptoms of ergotamine withdrawal.

Migraine and Cluster Headache

Although sumatriptan is often the treatment of choice to abort acute attacks of migraine that do not respond to simple analgesic preparations, parenteral dihydroergotamine, especially with an antiemetic, is an alternative for patients who develop severe or refractory migraine. Preparations for intranasal use are also available; it is given orally in some countries. In a comparative study, migraine relief was slower after subcutaneous dihydroergotamine than after subcutaneous sumatriptan, but headaches recurred less often. In other studies, intranasal dihydroergotamine was less effective than subcutaneous or intranasal sumatriptan. Dihydroergotamine is also used to treat cluster headaches, usually in emergency settings, where it is given to abort individual headache attacks.

Orthostatic Hypotension

Dihydroergotamine may be of use in patients with refractory orthostatic hypotension. It is sometimes used in preparations with sympathomimetics such as etilefrine. After parenteral dihydroergotamine, standing blood pressure is increased, but total peripheral resistance and supine blood pressure are also increased. It does not prevent postprandial hypotension, presumably because it does not constrict the splanchnic veins, although use with caffeine may overcome this problem. However, the main disadvantage of dihydroergotamine is that it is ineffective, or at best weakly effective, when given by mouth, although there has been some evidence that oral ergotamine tartrate may be of value.

Dihydroergotamine has been suggested to prevent hypotension associated with epidural or spinal anesthesia, the usual management of which is discussed in Treatment of Adverse Effects of Local Anaesthetics. It has also been tried in the management of hypotension associated with hemodialysis.

Venous Thromboembolism

Standard prophylaxis for surgical patients at high risk of venous thromboembolism is usually with heparin or low-molecular-weight heparin. Dihydroergotamine can reduce venous stasis by vasoconstriction of capacitance vessels and has enhanced postoperative prophylaxis when used with heparin. Doses of dihydroergotamine mesylate 500 micrograms with heparin 5000 units, both given subcutaneously 2 hours before surgery, have been used. This regimen has then been given every 8 to 12 hours for 5 to 14 days, depending on the risk of thrombosis.

Dihydroergotamine with low-molecular-weight heparin is of similar efficacy to dihydroergotamine with heparin but might offer a more convenient dosing schedule. However, although dihydroergotamine might enhance the effect of heparin, a US National Institutes of Health consensus conference warned of the potential risk associated with its vasoconstrictive effects and the contraindications to its use. In 1989, the Swedish Adverse Drug Reactions Advisory Committee recommended that dihydroergotamine with heparin should not be given for more than seven days.

Adverse Effects and Treatment

They are the same as for Ergotamine Tartrate, although vasoconstriction may be less pronounced and the frequency of nausea and vomiting lower with dihydroergotamine mesylate than with ergotamine tartrate. Dihydroergotamine does not appear to produce physical dependence.

Effects on the Cardiovascular System

There are conflicting reports on the risk of vasospasm in patients given dihydroergotamine with heparin for thromboembolism prophylaxis. Vasospastic or necrotic reactions have been reported on several occasions during such therapy. In an Austrian study of 147 290 patients given drug prophylaxis for thromboembolism, complications attributable to ergotism were seen in 142 of 61 092 (0.23%) who received dihydroergotamine and heparin.

Others, however, observed only 1 case of vasospasm in 5100 trauma patients (0.02%) given the combination. In 1989, the Swedish Adverse Drug Reactions Advisory Committee reported that up to the end of September 1987, the manufacturer had received 201 reports of vasospastic reactions associated with using Orstanorm (dihydroergotamine + lidocaine) with heparin. Permanent damage occurred in 59% of these patients.

Vasospastic reactions had occurred more frequently in patients who had undergone surgery for trauma, and the prognosis for such patients was generally poorer than for others. Since the risk of permanent damage appeared to be related to treatment duration, the Committee recommended that this preparation should not be given for more than seven days. The possibility of such reactions and the contra-indications of dihydroergotamine should be considered when using this form of prevention.

Precautions

Dihydroergotamine (DHE) requires careful consideration of certain precautions to ensure its safe and effective use. Here are some necessary precautions:

1. Cardiovascular Conditions: DHE can cause vasoconstriction (narrowing of blood vessels), which may pose a risk for individuals with cardiovascular conditions such as ischemic heart disease, angina, peripheral vascular disease, and uncontrolled hypertension. It’s crucial to inform your healthcare provider if you have a history of cardiovascular problems.
2. Liver and Kidney Function: DHE is metabolized in the liver and excreted through the kidneys. Individuals with impaired liver or kidney function may require dose adjustments or alternative treatments. Inform your healthcare provider about any pre-existing liver or kidney conditions.
3. Pregnancy and Breastfeeding: DHE is generally not recommended during pregnancy due to its vasoconstrictive effects, which could affect blood flow to the developing fetus. It may also pass into breast milk. Discuss the potential risks and benefits with your healthcare provider if you are pregnant or breastfeeding.
4. Drug Interactions: DHE can interact with other medications, including some antifungal drugs, antibiotics, and protease inhibitors. To avoid potential interactions, it’s essential to provide your healthcare provider with a complete list of all medications, including over-the-counter drugs and supplements.
5. Allergies: Inform your healthcare provider of any known allergies, especially if you are sensitive to ergot alkaloids.
6. Monitoring: If you are receiving DHE intravenously or in a healthcare setting, your vital signs and overall condition may be monitored due to the potential for side effects. Be attentive to any unusual sensations, chest pain, or other symptoms, and report them promptly.
7. Limitations on Use: DHE is typically used when other migraine treatments are not effective or are not well-tolerated. It is not a first-line treatment and is reserved for specific situations.

Always follow your healthcare provider’s instructions regarding the use of dihydroergotamine, and promptly report any concerns or side effects. Individual responses to medications can vary, and a healthcare professional can help determine if DHE is a suitable option based on your medical history and current health status.

Porphyria

Dihydroergotamine is associated with acute porphyria attacks and is considered unsafe in patients with porphyric.

Interactions

Dihydroergotamine (DHE) can interact with various medications, potentially affecting their efficacy or increasing the risk of side effects. You must inform your healthcare provider about all your medications, supplements, and over-the-counter drugs. Here are some notable interactions:

1. Other Ergot Alkaloids: Using DHE with other ergot alkaloids, such as ergotamine, should be avoided, as it may increase the risk of vasoconstriction and other adverse effects.
2. CYP3A4 Inhibitors: DHE is metabolized by the liver enzyme CYP3A4. Medications that inhibit CYP3A4 can increase DHE levels in the blood, potentially leading to toxicity. Examples of CYP3A4 inhibitors include certain antifungal drugs (ketoconazole, itraconazole) and macrolide antibiotics (clarithromycin, erythromycin).
3. CYP3A4 Inducers: Drugs that induce CYP3A4 may decrease the effectiveness of DHE. Examples of CYP3A4 inducers include rifampin and certain anticonvulsant medications.
4. Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): There have been reports of serotonin syndrome, a potentially life-threatening condition when DHE is used concurrently with SSRIs or SNRIs. Close monitoring is essential if these medications are used together.
5. Protease Inhibitors: Some protease inhibitors used in the treatment of HIV, such as ritonavir, may increase DHE levels and should be used cautiously.
6. Beta-Blockers: Concurrent use of beta-blockers with DHE may increase the risk of peripheral ischemia (reduced blood flow to extremities). Monitoring is recommended in such cases.
7. Antihypertensive Medications: DHE can cause vasoconstriction, and its use with antihypertensive medications may lead to additive effects on blood pressure. Blood pressure should be closely monitored.
8. Other Migraine Medications: Combining DHE with other migraine medications, such as triptans, may increase the risk of vasospasm and ischemia. The use of these medications together should be carefully monitored.

This list is not exhaustive, and individual responses to medications can vary. Always provide a comprehensive list of your medications to your healthcare provider to ensure safe and effective use of DHE. They can help assess potential interactions and adjust your treatment plan accordingly.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Dihidroergotamina; Dihydroergotamiini; Dihydroergotamin; Dihydroergotaminum

BAN: Dihydroergotamine

INN: Dihydroergotamine [rINN (en)]

INN: Dihidroergotamina [rINN (es)]

INN: Dihydroergotamine [rINN (fr)]

INN: Dihydroergotaminum [rINN (la)]

INN: Дигидроэрготамин [rINN (ru)]

Chemical name: (5’S,8R)-5´-Benzyl-9,10-dihydro-12´-hydroxy-2´-methyl-3′,6′,18-trioxoergotaman

Molecular formula: C33H37N5O5 =583.7

CAS: 511-12-6

ATC code: N02CA01

Read code: y0CdZ

Dihydroergotamine Mesilate

(British Approved Name Modified, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: Dihidroergotamin-mezilát; Dihidroergotamina, mesilato de; Dihidroergotamino mesilatas; Dihydroergotamiinimesilaatti; Dihydroergotamin-mesylát; Dihydroergotamine Mesylate; Dihydroergotamine Methanesulphonate; Dihydroergotamini Mesilas; Dihydroergotaminmesilat

BAN: Dihydroergotamine Mesilate [BANM]

USAN: Dihydroergotamine Mesylate

INN: Dihydroergotamine Mesilate [rINNM (en)]

INN: Mesilato de dihidroergotamina [rINNM (es)]

INN: Dihydroergotamine, Mésilate de [rINNM (fr)]

INN: Dihydroergotamini Mesilas [rINNM (la)]

INN: Дигидроэрготамина Мезилат [rINNM (ru)]

Molecular formula: C33H37N5O5,CH4O3S =679.8

CAS: 6190-39-2

ATC code: N02CA01

Read code: y00JL

Pharmacopoeias. In Europe , Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Dihydroergotamine Mesylate). Colorless crystals or a white or almost white crystalline powder. Slightly soluble in water and alcohol; sparingly soluble in methyl alcohol. A 0.1% solution in water has a pH of 4.4 to 5.4. Protect from light.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Dihydroergotamine Mesylate). A white to slightly yellowish powder, or off-white to faintly red powder, having a faint odor. Soluble 1 in 125 of water, 1 in 90 of alcohol, 1 in 175 of chloroform, and 1 in 2600 of ether. pH of a 0.1% solution in water is between 4.4 and 5.4. Protect from light.

Dihydroergotamine Tartrate

(British Approved Name Modified, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: Dihidroergotamin-tartarát; Dihidroergotamina, tartrato de; Dihidroergotamino tartratas; Dihydroergotamiinitartraatti; Dihydroergotamin-tartarát; Dihydroergotamini Tartras; Dihydroergotamintartrat

BAN: Dihydroergotamine Tartrate [BANM]

INN: Dihydroergotamine Tartrate [rINNM (en)]

INN: Tartrato de dihidroergotamina [rINNM (es)]

INN: Dihydroergotamine, Tartrate de [rINNM (fr)]

INN: Dihydroergotamini Tartras [rINNM (la)]

INN: Дигидроэрготамина Тартрат [rINNM (ru)]

Molecular formula: (C33H37N5O5)2,C4H6O6 =1317.4

CAS: 5989-77-5

ATC code: N02CA01

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Dihydroergotamine Tartrate). Colorless crystals or a white or almost white crystalline powder. Very slightly soluble in water; sparingly soluble in alcohol. A 0.1 % suspension in water has a pH of 4.0 to 5.5. Protect from light.