Embed Size (px)
Citation preview
22
OverviewOverview
Ergot alkaloids -- produced by Claviceps purpurea, a grain Ergot alkaloids -- produced by Claviceps purpurea, a grain (rye, especially) fungus (rye, especially) fungus
This fungus synthesizes many biologically active agents This fungus synthesizes many biologically active agents including: including: acetylcholine acetylcholine histamine histamine tyramine and tyramine and many unique ergot alkaloids -- which effect: many unique ergot alkaloids -- which effect:
alpha-adrenergic receptors alpha-adrenergic receptors dopamine receptorsdopamine receptors Serotonin receptors Serotonin receptors
33
Ergot poisoning (ergotism, Ergot poisoning (ergotism, St. Anthony's fire)St. Anthony's fire)
dementia dementia florid hallucinations florid hallucinations persistent vasospasm (gangrene may persistent vasospasm (gangrene may
develop) develop) uterine muscle stimulation (may cause uterine muscle stimulation (may cause
abortion in pregnancy) abortion in pregnancy) Ergot poisoning specific manifestations Ergot poisoning specific manifestations
depend on the alkaloids mixturedepend on the alkaloids mixture
44
Chemistry and Chemistry 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) ergonovine ergonovine methysergide (Sansert) methysergide (Sansert) 6-methylergoline 6-methylergoline lysergic acid lysergic acid
Peptide alkaloids: Examples -- Peptide alkaloids: Examples -- ergotamine ergotamine alpha-ergocryptine alpha-ergocryptine
bromocriptine (Parlodel) bromocriptine (Parlodel)
55
Ergot alkaloids -variably absorbed from the Ergot alkaloids -variably absorbed from the GI tract GI tract
Absorption following oral administration: Absorption following oral administration: improved by caffeine improved by caffeine
Bromocriptine (Parlodel): well absorbed from Bromocriptine (Parlodel): well absorbed from the GI tract the GI tract
Metabolism: Metabolism:
extensively metabolizedextensively metabolized
66
PharmacodynamicsPharmacodynamics
Mechanism of ActionMechanism of Action Targets: several receptor types Targets: several receptor types
agonist effects agonist effects
partial agonist effects partial agonist effects
antagonist effects antagonist effects
Pre- and post-synaptic sites Pre- and post-synaptic sites
77
Ergot Ergot AlkaloidsAlkaloids
Alpha-Alpha-adrenergadrenerg
ic ic receptorreceptor
DopaminDopamine e
receptorreceptor
SerotoniSerotonin n
receptorreceptor(5 HT(5 HT22))
Uterine Uterine smooth smooth muscle muscle
stimulatistimulationon
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
88
Organ Systems:Organ Systems: CNS: CNS:
hallucinogenic-- LSD: hallucinogenic-- LSD: peripheral (5 HT2) serotonin receptor peripheral antagonist peripheral (5 HT2) serotonin receptor peripheral antagonist
behavioral effects: agonist presynaptic or behavioral effects: agonist presynaptic or postsynaptic 5 HT2 effects. postsynaptic 5 HT2 effects.
99
Dopamine Receptor Interactions: Dopamine Receptor Interactions:
Extrapyramidal system Extrapyramidal system
Prolactin release regulation: Prolactin release regulation:
bromocriptine (Parlodel) and pergolide (Permax)}specificity bromocriptine (Parlodel) and pergolide (Permax)}specificity
for pituitary dopamine receptors for pituitary dopamine receptors
1.suppression of pituitary prolactin secretion: by activating 1.suppression of pituitary prolactin secretion: by activating
regulatory dopamine receptors regulatory dopamine receptors
2.Bromocriptine (Parlodel) and pergolide (Permax) are 2.Bromocriptine (Parlodel) and pergolide (Permax) are
competitive with dopamine and other dopamine agonists competitive with dopamine and other dopamine agonists
(apomorphine) (apomorphine)
1010
Vascular Smooth Muscle: Vascular Smooth Muscle: Ergotamine are mainly vasoconstriction. Ergotamine are mainly vasoconstriction.
Vasoconstriction: partially blocked by alpha adrenergic Vasoconstriction: partially blocked by alpha adrenergic
receptor blocking drugs–receptor blocking drugs– suggesting vasoconstriction by ergot alkaloids may be due suggesting vasoconstriction by ergot alkaloids may be due
to partial agonist effects at alpha adrenergic receptors to partial agonist effects at alpha adrenergic receptors
Vasoconstriction: long-lasting-- Vasoconstriction: long-lasting-- alpha adrenergic receptor effects alpha adrenergic receptor effects 5 HT receptor-mediated effects 5 HT receptor-mediated effects
1111
Vasoconstriction: differential vascular sensitivity to Vasoconstriction: differential vascular sensitivity to ergot alkaloids ergot alkaloids
most sensitive: cerebral arteriovenous anastomotic most sensitive: cerebral arteriovenous anastomotic vessels to: vessels to:
ergotamine ergotamine dihydroergotamine dihydroergotamine sumatriptan (Imitrex) sumatriptan (Imitrex)
Antimigraine specificity: mediated by Antimigraine specificity: mediated by neuronal or vascular serotonin receptorsneuronal or vascular serotonin receptors
1212
Uterine Smooth Muscle Uterine Smooth Muscle Stimulant action: involves serotonergic, alpha-Stimulant action: involves serotonergic, alpha-
adrenergic, and other effects adrenergic, and other effects Uterine sensitivity changes during pregnancy Uterine sensitivity changes during pregnancy
(possibly due to progressively increasing (possibly due to progressively increasing numbers of alpha1 receptors numbers of alpha1 receptors
Small doses: rhythmic uterine contraction and Small doses: rhythmic uterine contraction and relaxation relaxation
Larger doses: substantial, prolonged contractions Larger doses: substantial, prolonged contractions Ergonovine: more uterine selective (agent of Ergonovine: more uterine selective (agent of
choice for obstetric uses)choice for obstetric uses)
1313
Migraine Migraine
Clinical PresentationsClinical Presentations
Often accompanied by brief aura(prodromal Often accompanied by brief aura(prodromal phase) phase)
Severe, throbbing, usually unilateral Severe, throbbing, usually unilateral headache (few hours to a few days in headache (few hours to a few days in duration)duration)
1414
Familial diseaseFamilial disease
more common in women more common in women
onset: early adolescence; less common in older patients onset: early adolescence; less common in older patients
Migraine associated with stress Migraine associated with stress
Headache frequency: Range --1 to or more per week to once a Headache frequency: Range --1 to or more per week to once a
yearyear
1515
Migraine Migraine PathophysiologyPathophysiology
Vasomotor mechanism -- inferred from: Vasomotor mechanism -- inferred from: increased temporal artery pulsation magnitude increased temporal artery pulsation magnitude pain relief (by ergotamine) occurs with decreased artery pain relief (by ergotamine) occurs with decreased artery
pulsations pulsations Migraine attack associated with (based on histological Migraine attack associated with (based on histological
studies): studies): sterile neurogenic perivascular edema sterile neurogenic perivascular edema
inflammation (clinically effective antimigraine inflammation (clinically effective antimigraine medication reduce perivascular inflammation)medication reduce perivascular inflammation)
1616
Serotonin involvement (evidence for)Serotonin involvement (evidence for)
Throbbing headache: associated with decreased Throbbing headache: associated with decreased serum and platelet serotonin serum and platelet serotonin
Presence of serotonergic nerve terminals at Presence of serotonergic nerve terminals at meningeal blood vessels meningeal blood vessels
Antimigraine drugs influence serotonergic Antimigraine drugs influence serotonergic neurotransmitter neurotransmitter
1717
Some migraine chemical triggers may work Some migraine chemical triggers may work
through serotonin pathways, i.e. decreasing through serotonin pathways, i.e. decreasing
estrogen (associated with the menstrual estrogen (associated with the menstrual
cycle) and increased prostaglandin E1cycle) and increased prostaglandin E1
1818
Drug Treatment Drug Treatment (migraine)(migraine)
Ergotamine: best results when drug administered prior to Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack the attack (prodromal phase) -- less effective as attack progresses progresses
Ergotamine may be combined with caffeine; caffeine promotes Ergotamine may be combined with caffeine; caffeine promotes ergot alkaloid absorption ergot alkaloid absorption
Vasoconstriction associated with excessive ergotamine use may Vasoconstriction associated with excessive ergotamine use may be long-lasting and potentially severe. be long-lasting and potentially severe.
Ergotamine: available by oral, IV ,or Ergotamine: available by oral, IV ,or intramuscular routes of administrationintramuscular routes of administration
1919
Dihydroergotamine (IV administration mainly): may be Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine (nasal or oral appropriate for intractable migraine (nasal or oral formulations ) formulations )
Sumatriptan (Imitrex): alternative to ergotamine for Sumatriptan (Imitrex): alternative to ergotamine for acute migraine treatment; not recommended for acute migraine treatment; not recommended for patients with coronary vascular disease risk. patients with coronary vascular disease risk. formulations: subcutaneous injection, oral, nasal spray formulations: subcutaneous injection, oral, nasal spray
selective serotonin-receptor agonist (short selective serotonin-receptor agonist (short duration of action)duration of action)
probably more effective than ergotamine for management of probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal acute migraine attacks (relief: 10 to 15 minutes following nasal spray) spray)
subcutaneous injection: relief within two hours subcutaneous injection: relief within two hours
2020
New Triptans: New Triptans:
Zolmitriptan--more rapid onset than oral Zolmitriptan--more rapid onset than oral
sumatriptan (Imitrex) sumatriptan (Imitrex) Naratriptan-- Naratriptan--
slower onset; longer half-life slower onset; longer half-life Rizatriptan-- more rapid onset than oral Rizatriptan-- more rapid onset than oral
sumatriptan sumatriptan
2121
Analgesics:-- may be sufficient for model/moderate migraine Analgesics:-- may be sufficient for model/moderate migraine Aspirin Aspirin Aspirin combination (aspirin + caffeine + butalbital) Aspirin combination (aspirin + caffeine + butalbital) Acetaminophen Acetaminophen Acetaminophen combinations (acetaminophen + Acetaminophen combinations (acetaminophen +
dichloralphenazone) dichloralphenazone) Excedrin Migraine: acetaminophen + aspirin +caffeine Excedrin Migraine: acetaminophen + aspirin +caffeine Oral opioids: usual systemic opioid adverse effects Oral opioids: usual systemic opioid adverse effects Butorphanol nasal spray --opioid agonist-antagonist Butorphanol nasal spray --opioid agonist-antagonist
effective for moderate/severe migraine; effective for moderate/severe migraine; psychiatric reactions/drug abuse have been psychiatric reactions/drug abuse have been reportedreported
2222
All triptans except naratriptan are contraindicated in All triptans except naratriptan are contraindicated in
patients taking MAO inhibitors (or within two weeks of patients taking MAO inhibitors (or within two weeks of
discontinuation of MAO inhibitors)discontinuation of MAO inhibitors)
2323
Migraine ProphylaxisMigraine Prophylaxis
Ergonovine Ergonovine Methysergide (Sansert) Methysergide (Sansert)
effective in about 60% of patients effective in about 60% of patients 40%: frequency of toxicity 40%: frequency of toxicity NOT effective in treating an active migraine attack or even preventing an NOT effective in treating an active migraine attack or even preventing an
impending attack. impending attack. Methysergide toxicity: Methysergide toxicity:
retroperitoneal fibroplasia retroperitoneal fibroplasia
subendocardial fibrosissubendocardial fibrosis The side effects are the basis of recommending a 3-4 The side effects are the basis of recommending a 3-4
week drug holiday every six months week drug holiday every six months
2424
Propranolol (Inderal) -- prophylaxis- Most Propranolol (Inderal) -- prophylaxis- Most common for continuous prophylaxis common for continuous prophylaxis
propranolol (Inderal) and timolol propranolol (Inderal) and timolol
BEWARE THAT all beta-blockers are BEWARE THAT all beta-blockers are contraindicated in asthmatics contraindicated in asthmatics
2525
Best established drug for Best established drug for migraine attack preventionmigraine attack prevention
Amitriptyline -- prophylaxis-- most frequently used among Amitriptyline -- prophylaxis-- most frequently used among the tricyclic antidepressants the tricyclic antidepressants
Valproic acid --effective in decreasing migraine Valproic 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
2626
Other uses of ergotsOther uses of ergots
Postpartum Hemorrhage:Postpartum Hemorrhage: Ergot Derivatives: used to control late uterine Ergot Derivatives: used to control late uterine
bleeding (NEVER given before delivery, given bleeding (NEVER given before delivery, given before delivery an increase in internal and fetal before delivery an increase in internal and fetal mortality occur) mortality occur)
Ergot alkaloids cause uterine contractions Ergot alkaloids cause uterine contractions (prolonged, powerful spasms, unlike natural labor)(prolonged, powerful spasms, unlike natural labor)
2727
Ergot ToxicityErgot Toxicity
Most common: Most common: gastrointestinal -- diarrhea, vomiting, nausea gastrointestinal -- diarrhea, vomiting, nausea
Mechanism of Action: Mechanism of Action: medullary vomiting center stimulation medullary vomiting center stimulation activation of gastrointestinal serotonergic receptors activation of gastrointestinal serotonergic receptors
Use of methysergide (prophylactic migraine agent) limited by GI Use of methysergide (prophylactic migraine agent) limited by GI
toxicitiestoxicities
2828
Other toxicities: Other toxicities: Vasospasm -- overdosage with drugs such as: Vasospasm -- overdosage with drugs such as:
ergotamine and ergonovine ergotamine and ergonovine
Dangerous toxic effect Dangerous toxic effect gangrene, possible amputation gangrene, possible amputation
most vasospastic reactions involves the extremities most 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-dose Serious vasospastic reactions may be reversible by high-dose nitroprusside or nitroglycerin nitroprusside or nitroglycerin
2929
Chronic toxicitiesChronic toxicities
Methysergide Methysergide -- retroperitoneal fibroplasia, subendocardial -- retroperitoneal fibroplasia, subendocardial
fibrosisfibrosis
Slowly developing Slowly developing
Presenting symptoms: Presenting symptoms:
hydronephrosis (ureter obstruction) hydronephrosis (ureter obstruction)
cardiac murmur (valve deformation) cardiac murmur (valve deformation)
3030
Contraindications for Contraindications for Ergot Alkaloids UseErgot Alkaloids Use
Presence of vascular or collagen diseasePresence of vascular or collagen disease
