Ergot alkaloids

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  • 1. 11 Ergot alkaloidsErgot alkaloids By Dr. Shah MuradBy Dr. Shah Murad

2. 2 OverviewOverview Ergot alkaloids -- produced by Claviceps purpurea, a grainErgot alkaloids -- produced by Claviceps purpurea, a grain (rye, especially) fungus(rye, especially) fungus This fungus synthesizes many biologically active agentsThis fungus synthesizes many biologically active agents including:including: acetylcholineacetylcholine histaminehistamine tyramine andtyramine and many unique ergot alkaloids -- which effect:many unique ergot alkaloids -- which effect: alpha-adrenergic receptorsalpha-adrenergic receptors dopamine receptorsdopamine receptors Serotonin receptorsSerotonin receptors 3. 3 Ergot poisoningErgot poisoning (ergotism, St. Anthony's(ergotism, St. Anthony's fire)fire) dementiadementia florid hallucinationsflorid hallucinations persistent vasospasm (gangrene maypersistent vasospasm (gangrene may develop)develop) uterine muscle stimulation (may causeuterine muscle stimulation (may cause abortion in pregnancy)abortion in pregnancy) Ergot poisoning specific manifestationsErgot poisoning specific manifestations depend on the alkaloids mixturedepend on the alkaloids mixture 4. 4 Chemistry andChemistry and pharmacokinetics:pharmacokinetics: Two Major Families:Two Major Families: Tetracyclic Ergoline Nucleus: Examples --Tetracyclic Ergoline Nucleus: Examples -- lysergic acid diethylamide (LSD)lysergic acid diethylamide (LSD) ergonovineergonovine methysergide (Sansert)methysergide (Sansert) 6-methylergoline6-methylergoline lysergic acidlysergic acid Peptide alkaloids: Examples --Peptide alkaloids: Examples -- ergotamineergotamine alpha-ergocryptinealpha-ergocryptine bromocriptine (Parlodel)bromocriptine (Parlodel) 5. 5 Ergot alkaloids -variably absorbed from theErgot alkaloids -variably absorbed from the GI tractGI tract Absorption following oral administration:Absorption following oral administration: improved by caffeineimproved by caffeine Bromocriptine (Parlodel): well absorbed fromBromocriptine (Parlodel): well absorbed from the GI tractthe GI tract Metabolism:Metabolism: extensively metabolizedextensively metabolized 6. 6 PharmacodynamicsPharmacodynamics Mechanism of ActionMechanism of Action Targets: several receptor typesTargets: several receptor types agonist effectsagonist effects partial agonist effectspartial agonist effects antagonist effectsantagonist effects Pre- and post-synaptic sitesPre- and post-synaptic sites 7. 7 ErgotErgot AlkaloidsAlkaloids Alpha-Alpha- adrenergicadrenergic receptorreceptor DopamineDopamine receptorreceptor SerotoninSerotonin receptorreceptor (5 HT(5 HT22)) UterineUterine smoothsmooth musclemuscle stimulationstimulation BromocryptineBromocryptine -- ++++++ -- 00 ErgonovineErgonovine ++ ++ -- (partial agonist)(partial agonist) ++++++ ErgonovineErgonovine ---- (partial agonist)(partial agonist) 00 ++ (partial agonist)(partial agonist) ++++++ LSDLSD 00 ++++++ ---- ++ MethysergideMethysergide +/0+/0 +/0+/0 ------ (partial agonist)(partial agonist) +/0+/0 8. 8 Organ Systems:Organ Systems: CNS:CNS: hallucinogenic-- LSD:hallucinogenic-- LSD: peripheral (5 HT2) serotonin receptor peripheral antagonistperipheral (5 HT2) serotonin receptor peripheral antagonist behavioral effects: agonist presynaptic orbehavioral effects: agonist presynaptic or postsynaptic 5 HT2 effects.postsynaptic 5 HT2 effects. 9. 9 Dopamine Receptor Interactions:Dopamine Receptor Interactions: Extrapyramidal systemExtrapyramidal system Prolactin release regulation:Prolactin release regulation: bromocriptine (Parlodel) and pergolide (Permax)}specificitybromocriptine (Parlodel) and pergolide (Permax)}specificity for pituitary dopamine receptorsfor pituitary dopamine receptors 1.suppression of pituitary prolactin secretion: by activating1.suppression of pituitary prolactin secretion: by activating regulatory dopamine receptorsregulatory dopamine receptors 2.Bromocriptine (Parlodel) and pergolide (Permax) are2.Bromocriptine (Parlodel) and pergolide (Permax) are competitive with dopamine and other dopamine agonistscompetitive with dopamine and other dopamine agonists (apomorphine)(apomorphine) 10. 10 Vascular Smooth Muscle:Vascular Smooth Muscle: Ergotamine are mainly vasoconstriction.Ergotamine are mainly vasoconstriction. Vasoconstriction: partially blocked by alpha adrenergicVasoconstriction: partially blocked by alpha adrenergic receptor blocking drugsreceptor blocking drugs suggesting vasoconstriction by ergot alkaloids may be duesuggesting vasoconstriction by ergot alkaloids may be due to partial agonist effects at alpha adrenergic receptorsto partial agonist effects at alpha adrenergic receptors Vasoconstriction: long-lasting--Vasoconstriction: long-lasting-- alpha adrenergic receptor effectsalpha adrenergic receptor effects 5 HT receptor-mediated effects5 HT receptor-mediated effects 11. 11 Vasoconstriction: differential vascular sensitivity toVasoconstriction: differential vascular sensitivity to ergot alkaloidsergot alkaloids most sensitive: cerebral arteriovenous anastomoticmost sensitive: cerebral arteriovenous anastomotic vessels to:vessels to: ergotamineergotamine dihydroergotaminedihydroergotamine sumatriptan (Imitrex)sumatriptan (Imitrex) Antimigraine specificity: mediated byAntimigraine specificity: mediated by neuronal or vascular serotonin receptorsneuronal or vascular serotonin receptors 12. 12 Uterine Smooth MuscleUterine Smooth Muscle Stimulant action: involves serotonergic, alpha-Stimulant action: involves serotonergic, alpha- adrenergic, and other effectsadrenergic, and other effects Uterine sensitivity changes during pregnancyUterine sensitivity changes during pregnancy (possibly due to progressively increasing(possibly due to progressively increasing numbers of alpha1 receptorsnumbers of alpha1 receptors Small doses: rhythmic uterine contraction andSmall doses: rhythmic uterine contraction and relaxationrelaxation Larger doses: substantial, prolonged contractionsLarger doses: substantial, prolonged contractions Ergonovine: more uterine selective (agent ofErgonovine: more uterine selective (agent of choice for obstetric uses)choice for obstetric uses) 13. 13 MigraineMigraine Clinical PresentationsClinical Presentations Often accompanied by brief aura(prodromalOften accompanied by brief aura(prodromal phase)phase) Severe, throbbing, usually unilateralSevere, throbbing, usually unilateral headache (few hours to a few days inheadache (few hours to a few days in duration)duration) 14. 14 Familial diseaseFamilial disease more common in womenmore common in women onset: early adolescence; less common in older patientsonset: early adolescence; less common in older patients Migraine associated with stressMigraine associated with stress Headache frequency: Range --1 to or more per week to once aHeadache frequency: Range --1 to or more per week to once a yearyear 15. 15 MigraineMigraine PathophysiologyPathophysiology Vasomotor mechanism -- inferred from:Vasomotor mechanism -- inferred from: increased temporal artery pulsation magnitudeincreased temporal artery pulsation magnitude pain relief (by ergotamine) occurs with decreased arterypain relief (by ergotamine) occurs with decreased artery pulsationspulsations Migraine attack associated with (based on histologicalMigraine attack associated with (based on histological studies):studies): sterile neurogenic perivascular edemasterile neurogenic perivascular edema inflammation (clinically effective antimigraineinflammation (clinically effective antimigraine medication reduce perivascular inflammation)medication reduce perivascular inflammation) 16. 16 Serotonin involvement (evidence for)Serotonin involvement (evidence for) Throbbing headache: associated with decreasedThrobbing headache: associated with decreased serum and platelet serotoninserum and platelet serotonin Presence of serotonergic nerve terminals atPresence of serotonergic nerve terminals at meningeal blood vesselsmeningeal blood vessels Antimigraine drugs influence serotonergicAntimigraine drugs influence serotonergic neurotransmitterneurotransmitter 17. 17 Some migraine chemical triggers may workSome migraine chemical triggers may work through serotonin pathways, i.e. decreasingthrough serotonin pathways, i.e. decreasing estrogen (associated with the menstrualestrogen (associated with the menstrual cycle) and increased prostaglandin E1cycle) and increased prostaglandin E1 18. 18 Drug TreatmentDrug Treatment (migraine)(migraine) Ergotamine: best results when drug administered prior toErgotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attackthe attack (prodromal phase) -- less effective as attack progressesprogresses Ergotamine may be combined with caffeine; caffeine promotesErgotamine may be combined with caffeine; caffeine promotes ergot alkaloid absorptionergot alkaloid absorption Vasoconstriction associated with excessive ergotamine use mayVasoconstriction associated with excessive ergotamine use may be long-lasting and potentially long-lasting and potentially severe. Ergotamine: available by oral, IV ,orErgotamine: available by oral, IV ,or intramuscular routes of administrationintramuscular routes of administration 19. 19 Dihydroergotamine (IV administration mainly): may beDihydroergotamine (IV administration mainly): may be appropriate for intractable migraine (nasal or oralappropriate for intractable migraine (nasal or oral formulations )formulations ) Sumatriptan (Imitrex): alternative to ergotamine forSumatriptan (Imitrex): alternative to ergotamine for acute migraine treatment; not recommended foracute migraine treatment; not recommended for patients with coronary vascular disease risk.patients with coronary vascular di