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

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