Chapter 23:  Ergot Alkaloids

Ergot Alkaloids

• Overview:
  • Ergot alkaloids -- produced by Claviceps purpurea, a grain (rye, especially) fungus
  • This fungus synthesizes many biologically active agents including:
    • acetylcholine
    • histamine
    • tyramine and
    • many unique ergot alkaloids -- which effect:
      •  alpha-adrenergic receptors
      •  dopamine receptors
      •  serotonin receptors
  •   Ergot poisoning (ergotism, St. Anthony's fire)-- symptoms:
    • dementia
    • florid hallucinations
    • persistent vasospasm (gangrene may develop)
    • uterine muscle stimulation (may cause abortion in pregnancy)
    • Ergot poisoning specific manifestations depend on the alkaloids mixture
• Chemistry and pharmacokinetics:
  • Two Major Families:
    • Tetracyclic Ergoline Nucleus: Examples --
      •  lysergic acid diethylamide (LSD)
      •  ergonovine 
      •  methysergide (Sansert) 
      • 6-methylergoline
      • lysergic acid
    • Peptide alkaloids: Examples --
      •  ergotamine 
      • alpha-ergocryptine
      •  bromocriptine (Parlodel) 
  • Ergot alkaloids -variably absorbed from the GI tract
  • Absorption following oral administration: improved by caffeine
  • Bromocriptine (Parlodel): well absorbed from the GI tract
  • Metabolism:
    • extensively metabolized
• Pharmacodynamics:
  • Mechanism of Action:
    • Targets: several receptor types
      • agonist effects
      • partial agonist effects
      • antagonist effects
      • Pre- and post-synaptic sites

-- {based on Table 16-6,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, p 279.}

• Organ Systems:

  • CNS:

    •   hallucinogenic-- LSD:

      • peripheral (5 HT₂) serotonin receptor peripheral antagonist

      • behavioral effects: agonist presynaptic or postsynaptic 5 HT₂ effects.

    •   Dopamine Receptor Interactions:

      • Extrapyramidal system

      • Prolactin release regulation:

        • bromocriptine (Parlodel) and pergolide (Permax)}specificity for pituitary dopamine receptors

          1. suppression of pituitary prolactin secretion: by activating regulatory dopamine receptors

          2. Bromocriptine (Parlodel) and pergolide (Permax) are competitive with dopamine and other dopamine agonists (apomorphine) before the these binding sites

  • Vascular Smooth Muscle:

    •  Ergotamine (unrelated compounds) are mainly vasoconstricting.

      • Vasoconstriction: partially blocked by alpha adrenergic receptor blocking drugs--

        • suggesting vasoconstriction by ergot alkaloids may be due to partial agonist effects at alpha adrenergic receptors

      • Vasoconstriction: long-lasting--

        • alpha adrenergic receptor effects

        • 5 HT receptor-mediated effects

      • Vasoconstriction: differential vascular sensitivity to ergot alkaloids

        • most sensitive: cerebral arteriovenous anastomotic vessels to:

          1.  ergotamine

          2.  dihydroergotamine 

          3.  sumatriptan (Imitrex) 

        • Antimigraine specificity: mediated by neuronal or vascular serotonin receptors

      • Most-common drugs used for migraine treatment:

        • ergotamine

        • ergonovine

        •  methysergide (Sansert)

      •   Overdosage (ergotamine and related agents)

        • Severe, long-lasting vasospasm --

          • not reversible by alpha-antagonists

          • not reversible by serotonin antagonists

  • Uterine Smooth Muscle

    • Stimulant action: involves serotonergic, alpha-adrenergic, and other effects

    • Uterine sensitivity changes during pregnancy (possibly due to progressively increasing numbers of alpha₁ receptors

    • Small doses: rhythmic uterine contraction and relaxation

    • Larger doses: substantial, prolonged contractions

    • Ergonovine: more uterine selective (agent of choice for obstetric uses)

  • Other Smooth Muscle:

    • Bronchiolar smooth muscle: no effect

    • Gastrointestinal smooth muscle: variable sensitivity {nausea, diarrhea, and vomiting -- occurs with variability in required dosage probation impatient}

      •  Mechanism of Action:

        1. activation of gastrointestinal serotonin receptors

        2. CNS emetic centers

Ergot Alkaloids: Clinical Pharmacology

• Migraine

  • Clinical Presentations:

    • Often accompanied by brief aura (visual scotomas, hemianopia, beach abnormalities

    • Severe, throbbing, usually unilateral headache (few hours to a few days in duration)

    • Familial disease:

      1. more common in women

      2. onset: early adolescence; less common in older patients

      3. Migraine associated with stress

      4. Headache frequency: Range -- to or more per week to once a year

  • Migraine Pathophysiology:

    •  Vasomotor mechanism -- inferred from:

      1. increased temporal artery pulsation magnitude

      2. pain relief (by ergotamine) occurs with decreased artery pulsations

    • Migraine attack associated with (based on histological studies):

      • sterile neurogenic perivascular edema

      • inflammation (clinically effective antimigraine medication reduce perivascular inflammation)

    • Serotonin involvement (evidence for):

      • Throbbing headache: associated with decreased serum and platelet serotonin

      • Presence of serotonergic nerve terminals at meningeal blood vessels

      • Antimigraine drugs influence serotonergic neurotransmitter

      • Some migraine chemical triggers may work through serotonin pathways, i.e. decreasing estrogen (associated with the menstrual cycle) and increased prostaglandin E₁.

  • Drug Treatment (migraine):

    • Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- 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: availableby 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): 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

    • New Triptans:

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

      •  Naratriptan--

        • slower onset; longer half-life

      •  Rizatriptan-- 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) -- prophylaxis- Most common for continuous prophylaxis

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

      • note all beta-blockers: contraindicated in asthmatics

      • best established drug for migraine attack prevention.

    •  Amitriptyline (Elavil, Endep) -- prophylaxis-- most frequently used among the tricyclic antidepressants

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

    •  Nonsteroidal antiinflammatory drugs (NSAIDs) -- naproxen sodium; flurbiprofen -- used for attack prevention and aborting acute attack

• Hyperprolactinemia:(amenorrhea, infertility inwomen, 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

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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