Medical Pharmacology Chapter 23:  Ergot Alkaloids

• Drug Treatment (migraine)

  • Ergotamine exhibits best results when the drug is administered prior to the attack (prodromal phase) but less effective as attack progresses.

    • Ergotamine may be combined with caffeine; caffeine promotes ergot alkaloid absorption

    • Vasoconstriction associated with excessive ergotamine use may be long-lasting and potentially severe.

    • Ergotamine: available by oral, IV,or intramuscular routes of administration

  • Dihydroergotamine (IV administration mainly) may be appropriate for intractable migraine (nasal or oral formulations dihydroergotamine are being assessed)

  • Sumatriptan (Imitrex)  is an alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk.

    • Formulations: subcutaneous injection, oral, nasal spray

    • Selective serotonin-receptor agonist (short duration of action)

    • Probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray)

    • Subcutaneous injection: relief within two hours for 70% -- 80% of patients

  • Newer Triptans

    •  Zolmitriptan exhibits more rapid onset than oral sumatriptan (Imitrex)

    •  Naratriptan

      • Slower onset; longer half-life

    •  Rizatriptan administration is associated with a more rapid onset than oral sumatriptan

  • Analgesics may be sufficient for model/moderate migraine

    • Aspirin

    • Aspirin combination (Fiorinal --aspirin + caffeine + butalbital)

    • Acetaminophen

    • Acetaminophen combinations (Midrin-- acetaminophen + isometheptene + dichloralphenazone)

    • Excedrin Migraine: acetaminophen + aspirin +caffeine

    • Oral opioids: usual systemic opioid adverse effects

    • Butorphanol nasal spray --opioid agonist-antagonist

      • effective for moderate/severe migraine; psychiatric reactions/drug abuse have been reported

  •  Drug-Drug interactions:

    •  A triptan should not be used within one-day following another triptan or any ergotamine-containing drug (vasoconstriction may be additive)

    •  Ergot derivatives should not be taken or until 24 hours or more following a triptan

    •  "Serotonin Syndrome": weakness, hyperreflexia, incoordination following use of a selective serotonin reuptake inhibitor (SSRIs) with a triptan

    •  All triptans except naratriptan are contraindicated in patients taking MAO inhibitors (or within two weeks of discontinuation of MAO inhibitors)

• Migraine Prophylaxis

  •  Ergonovine

  •  Methysergide (Sansert)

    • Effective in about 60% of patients

    • 40%: frequency of toxicity

    • NOT effective in treating an active migraine attack or even preventing an impending attack.

    • Methysergide toxicity:

      • Retroperitoneal fibroplasia

      • Subendocardial fibrosis

      • The side effects are the basis of recommending a 3-4 week drug holiday every six months

  •  Propranolol (Inderal)  is  used for continuous prophylaxis

    • Propranolol (Inderal) and  timolol (Blocadren) FDA approval for this indication

    • Note all β-blockers are typically contraindicated in asthmatics

    • Best established drug for migraine attack prevention.

  •  Amitriptyline (Elavil, Endep)  may be used for prophylaxis.

  •  Valproic acid (Depakene, Depakote) appears effective in decreasing migraine frequency; FDA approval for this indication;

  •  Nonsteroidal antiinflammatory drugs (NSAIDs) e.g. naproxen sodium; flurbiprofen may be used for attack prevention and aborting acute attack

• Hyperprolactinemia:(amenorrhea, infertility in women, galactorrhea)

  • May be caused by:

    • Prolactin-secreting anterior pituitary tumors

    • Centrally-acting anti-dopaminergic drugs (antipsychotic drugs)

  • Drug treatment: hyperprolactinemia

    •  Bromocriptine (Parlodel) -- very effective

      • Occasional postpartum cardiotoxicity

    •  Pergolide (Permax): lactation suppression

• Postpartum Hemorrhage

  • Ergot Derivatives: used to control late uterine bleeding (NEVER given before delivery, given before delivery an increase in internal and fetal mortality occur)

  • Ergot alkaloids cause uterine contractions (prolonged, powerful spasms, unlike natural labor)

•   Ergot Toxicity

  • Most common:

    • Gastrointestinal:  diarrhea, vomiting, nausea

      • Mechanism of Action:

        1. Medullary vomiting center stimulation

        2. Activation of gastrointestinal serotonergic receptors

      • Use of methysergide (Sansert) (prophylactic migraine agent) any limited by GI toxicities

  • Other toxicities:

    • Vasospasm -- overdosage with drugs such as: ergotamine and ergonovine

    • Dangerous toxic effect

    • Gangrene, possible amputation

      • Most vasospastic reactions involves the extremities

      • Bowel infarction (secondary to mesenteric artery vasospasm) may also occur

    • Serious vasospastic reactions may be reversible by high-dose  nitroprusside or   nitroglycerin

  • Chronic toxicities:

    • Methysergide (Sansert): -- retroperitoneal fibroplasia, subendocardial fibrosis, fibroplastic changes in the pleural cavity.

      • Slowly developing

      • Presenting symptoms:

        1. Hydronephrosis (ureter obstruction)

        2. Cardiac murmur (valve deformation)

    • Methysergide (Sansert) CNS effects (stimulation/loose nations)

  • Contraindications for Ergot Alkaloids Use:

    • Presence of vascular or collagen disease

Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.;  New "Triptans" and Other Drugs for Migraine, The Medical Letter, Vol. 40 (Issue 1037); October 9, 1998