Ergot alkaloids


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Ergot alkaloids

  1. 1. 11 Ergot alkaloidsErgot alkaloids By Dr. Shah MuradBy Dr. Shah Murad
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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 drugs–receptor 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 disease risk.  formulations: subcutaneous injection, oral, nasal sprayformulations: subcutaneous injection, oral, nasal spray  selective serotonin-receptor agonist (shortselective serotonin-receptor agonist (short duration of action)duration of action)  probably more effective than ergotamine for management ofprobably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasalacute migraine attacks (relief: 10 to 15 minutes following nasal spray)spray)  subcutaneous injection: relief within two hourssubcutaneous injection: relief within two hours
  20. 20. 20 New Triptans:New Triptans:  Zolmitriptan--more rapid onset than oralZolmitriptan--more rapid onset than oral sumatriptan (Imitrex)sumatriptan (Imitrex)  Naratriptan--Naratriptan--  slower onset; longer half-lifeslower onset; longer half-life  Rizatriptan-- more rapid onset than oralRizatriptan-- more rapid onset than oral sumatriptansumatriptan
  21. 21. 21  Analgesics:-- may be sufficient for model/moderateAnalgesics:-- may be sufficient for model/moderate migrainemigraine  AspirinAspirin  Aspirin combination (aspirin + caffeine + butalbital)Aspirin combination (aspirin + caffeine + butalbital)  AcetaminophenAcetaminophen  Acetaminophen combinations (acetaminophen +Acetaminophen combinations (acetaminophen + dichloralphenazone)dichloralphenazone)  Excedrin Migraine: acetaminophen + aspirin +caffeineExcedrin Migraine: acetaminophen + aspirin +caffeine  Oral opioids: usual systemic opioid adverse effectsOral opioids: usual systemic opioid adverse effects  Butorphanol nasal spray --opioid agonist-antagonistButorphanol nasal spray --opioid agonist-antagonist  effective for moderate/severe migraine;effective for moderate/severe migraine; psychiatric reactions/drug abuse have beenpsychiatric reactions/drug abuse have been reportedreported
  22. 22. 22   All triptans except naratriptan are contraindicated inAll triptans except naratriptan are contraindicated in patients taking MAO inhibitors (or within two weeks ofpatients taking MAO inhibitors (or within two weeks of discontinuation of MAO inhibitors)discontinuation of MAO inhibitors)
  23. 23. 23 Migraine ProphylaxisMigraine Prophylaxis  ErgonovineErgonovine  Methysergide (Sansert)Methysergide (Sansert)  effective in about 60% of patientseffective in about 60% of patients  40%: frequency of toxicity40%: frequency of toxicity  NOT effective in treating an active migraine attack or even preventing anNOT effective in treating an active migraine attack or even preventing an impending attack.impending attack.  Methysergide toxicity:Methysergide toxicity: retroperitoneal fibroplasiaretroperitoneal fibroplasia  subendocardial fibrosissubendocardial fibrosis  The side effects are the basis of recommending a 3-4The side effects are the basis of recommending a 3-4 week drug holiday every six monthsweek drug holiday every six months
  24. 24. 24  Propranolol (Inderal) -- prophylaxis- MostPropranolol (Inderal) -- prophylaxis- Most common for continuous prophylaxiscommon for continuous prophylaxis  propranolol (Inderal) and timololpropranolol (Inderal) and timolol BEWARE THAT all beta-blockers areBEWARE THAT all beta-blockers are contraindicated in asthmaticscontraindicated in asthmatics
  25. 25. 25 Best established drug forBest established drug for migraine attackmigraine attack preventionprevention  Amitriptyline -- prophylaxis-- most frequently used amongAmitriptyline -- prophylaxis-- most frequently used among the tricyclic antidepressantsthe tricyclic antidepressants  Valproic acid --effective in decreasing migraineValproic acid --effective in decreasing migraine frequencyfrequency  Nonsteroidal antiinflammatory drugs (NSAIDs)Nonsteroidal antiinflammatory drugs (NSAIDs) -- naproxen sodium; flurbiprofen -- used for-- naproxen sodium; flurbiprofen -- used for attack prevention and aborting acute attackattack prevention and aborting acute attack
  26. 26. 26 Other uses of ergotsOther uses of ergots  Postpartum Hemorrhage:Postpartum Hemorrhage:  Ergot Derivatives: used to control late uterineErgot Derivatives: used to control late uterine bleeding (NEVER given before delivery, givenbleeding (NEVER given before delivery, given before delivery an increase in internal and fetalbefore delivery an increase in internal and fetal mortality occur)mortality occur)  Ergot alkaloids cause uterine contractionsErgot alkaloids cause uterine contractions (prolonged, powerful spasms, unlike natural labor)(prolonged, powerful spasms, unlike natural labor)
  27. 27. 27 Ergot ToxicityErgot Toxicity  Most common:Most common:  gastrointestinal -- diarrhea, vomiting, nauseagastrointestinal -- diarrhea, vomiting, nausea  Mechanism of Action:Mechanism of Action:  medullary vomiting center stimulationmedullary vomiting center stimulation  activation of gastrointestinal serotonergic receptorsactivation of gastrointestinal serotonergic receptors  Use of methysergide (prophylactic migraine agent) limited by GIUse of methysergide (prophylactic migraine agent) limited by GI toxicitiestoxicities
  28. 28. 28  Other toxicities:Other toxicities:  Vasospasm -- overdosage with drugs such as:Vasospasm -- overdosage with drugs such as: ergotamine and ergonovineergotamine and ergonovine Dangerous toxic effectDangerous toxic effect  gangrene, possible amputationgangrene, possible amputation  most vasospastic reactions involves the extremitiesmost vasospastic reactions involves the extremities  Bowel infarction (secondary to mesenteric artery vasospasm)Bowel infarction (secondary to mesenteric artery vasospasm) may also occurmay also occur  Serious vasospastic reactions may be reversible by high-doseSerious vasospastic reactions may be reversible by high-dose nitroprusside or nitroglycerinnitroprusside or nitroglycerin
  29. 29. 29 Chronic toxicitiesChronic toxicities MethysergideMethysergide -- retroperitoneal fibroplasia,-- retroperitoneal fibroplasia, subendocardial fibrosissubendocardial fibrosis  Slowly developingSlowly developing  Presenting symptoms:Presenting symptoms:  hydronephrosis (ureter obstruction)hydronephrosis (ureter obstruction)  cardiac murmur (valve deformation)cardiac murmur (valve deformation)
  30. 30. 30 Contraindications forContraindications for Ergot Alkaloids UseErgot Alkaloids Use  Presence of vascular or collagen diseasePresence of vascular or collagen disease