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Ergot alkaloids






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Ergot alkaloids Ergot alkaloids Presentation Transcript

  • Ergot alkaloids By Dr. Shah Murad [email_address]
  • 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)
        • 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
  • +/0 --- (partial agonist) +/0 +/0 Methysergide + -- +++ 0 LSD +++ + (partial agonist) 0 -- (partial agonist) Ergonovine +++ - (partial agonist) + + Ergonovine 0 - +++ - Bromocryptine Uterine smooth muscle stimulation Serotonin receptor (5 HT 2 ) Dopamine receptor Alpha-adrenergic receptor Ergot Alkaloids
    • 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)
      • Vascular Smooth Muscle:
        •  Ergotamine are mainly vasoconstriction.
          • 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:
            •   ergotamine
            •   dihydroergotamine 
            •   sumatriptan (Imitrex) 
    • Antimigraine specificity: mediated by neuronal or vascular serotonin receptors
      • 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)
  • Migraine
      • Clinical Presentations
        • Often accompanied by brief aura(prodromal phase)
        • Severe, throbbing, usually unilateral headache (few hours to a few days in duration)
  • Familial disease
          • more common in women
          • onset: early adolescence; less common in older patients
          • Migraine associated with stress
          • Headache frequency: Range --1 to or more per week to once a year
  • Migraine Pathophysiology
        •   Vasomotor mechanism -- inferred from:
          • increased temporal artery pulsation magnitude
          • 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: available by oral, IV ,or intramuscular routes of administration
        • Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine (nasal or oral formulations )
        • 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
        • 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 (aspirin + caffeine + butalbital)
          • Acetaminophen
          • Acetaminophen combinations (acetaminophen + 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
    •   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
          • BEWARE THAT all beta-blockers are contraindicated in asthmatics
  • Best established drug for migraine attack prevention
        • Amitriptyline -- prophylaxis-- most frequently used among the tricyclic antidepressants
        •   Valproic acid --effective in decreasing migraine frequency
    •   Nonsteroidal antiinflammatory drugs (NSAIDs) -- naproxen sodium; flurbiprofen -- used for attack prevention and aborting acute attack
  • Other uses of ergots
    • 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:
            • medullary vomiting center stimulation
            • activation of gastrointestinal serotonergic receptors
          • Use of methysergide (prophylactic migraine agent) 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 -- retroperitoneal fibroplasia, subendocardial fibrosis
          • Slowly developing
          • Presenting symptoms:
            • hydronephrosis (ureter obstruction)
            • cardiac murmur (valve deformation)
  • Contraindications for Ergot Alkaloids Use
    • Presence of vascular or collagen disease