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Ergot alkaloidsErgot alkaloids
By Dr. Shah MuradBy Dr. Shah Murad
shahmurad65@yahoo.comshahmurad65@yahoo.com

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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

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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

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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)

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 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

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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

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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

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 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.

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 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)

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 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

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 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

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 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)

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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)

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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

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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)

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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

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 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

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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 severe.be long-lasting and potentially severe.
 Ergotamine: available by oral, IV ,orErgotamine: available by oral, IV ,or
intramuscular routes of administrationintramuscular routes of administration

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 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

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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

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 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

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
 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)

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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

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 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

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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

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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)

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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

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 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

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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)

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Contraindications forContraindications for
Ergot Alkaloids UseErgot Alkaloids Use
 Presence of vascular or collagen diseasePresence of vascular or collagen disease