autonomics/ neurotransmitters - acmt...autonomics/ neurotransmitters g. patrick daubert, md...
TRANSCRIPT
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Autonomics/Neurotransmitters
G. Patrick Daubert, MDSacramento, CA
Some (most) material plundered from various mentors and other talentedtoxicologists, with permission
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Autonomic Nervous System
ACh
CNS
ACh
NMJ
AChACh
ACh NE
Muscarinic Nicotinic
Hollow end-organs
Courtesy Cynthia Aaron, MD
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Sympatheticganglion
NEACh
CNS
ACh
ACh
ACh
Secretinghollow end-organs:HeartLungsGI
Sympatheticinnervationto heart,lungs, etc
ACh
Striatedmuscle
ACh
Muscarinic NicotinincCourtesy Cynthia Aaron, MD
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Acetylcholine
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ACh Receptors
n Nicotinic Receptorsn CNS (mainly spinal cord)n Preganglionic autonomic neurons (sympathetic and
parasympathetic)n Adrenal neuronal receptorsn Skeletal muscle neuromuscular junction
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ACh Receptors
n Muscarinic Receptorsn CNS (mainly brain)n Postganglionic parasympathetic nerve endingsn Postganglionic sympathetic receptors for most sweat
glands
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Agents that Induce ACh Release
n Aminopyridinesn Latrodectus venomn Carbacholn Guanidinen Alpha2-adrenergic antagonists (h ACh release
from parasympathetic nerve endings)
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Acetylcholinesterase Inhibitors
n h [ACh] at both nicotinic and muscarinicreceptors
n Produce a variety of CNS, sympathetic,parasympathetic, and NMJ effectsn Carbamatesn Organophosphorus compoundsn Nerve agentsn ‘Central’ AChE inhibitors (donepezil)
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Autonomic Nervous System
ACh
CNS
ACh
NMJ
AChACh
ACh NE
Muscarinic Nicotinic
Hollow end-organsDUMBBELS
HTN,tachycardia,mydriasis
Fasciculations,respiratoryparalysis
Seizures, coma
Courtesy Cynthia Aaron, MD
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Question
n Which one of the following agents inhibitsacetylcholine release?
A. BupropionB. DisulfiramC. MirtazapineD. TizanidineE. Yohimbine
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Answer
n Which one of the following agents inhibitsacetylcholine release?
A. BupropionB. DisulfiramC. MirtazapineD. TizanidineE. Yohimbine
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Agents that Block ACh Release
n Alpha2-adrenergic agonistsn Botulinum toxinn Crotalinae venomsn Elapidae beta-neurotoxinsn Hypermagnesemia
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Nicotinic Receptor Agonists
n Initial activation of receptorsn Prolonged depolarization leads to inhibition
n Initial sympathomimetic, GI distress, fasciculations,seizures
n Then i BP, i HR, paralysis, coma
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Nicotinic Receptor Agonists
n Nicotine alkaloids (nicotine, coniine)n Carbachol (mainly muscarinic effects)n Methacholine (minimal effects)n Succinylcholine (initial effects)
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Nicotinic Receptor Antagonists
n NMJ blockers: weakness, paralysisn Curare, atracurium, alpha-bungarotoxin
n Peripheral neuronal blockers: autonomicganglionic blockaden Trimethaphan (not entirely specific, may produce
NMJ blockade)
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Nicotinic Indirect Agonists
n Bind to distinct allosteric sites on the nicotinicreceptor, not ACh binding site (enhancedchannel opening)n Physostigminen Tacrinen Galantamine
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Nicotinic Indirect Antagonists
n Bind to distinct allosteric sites on the nicotinicreceptor, not ACh binding site (decreasedchannel opening)n Chlorpromazinen Ketaminen Phencyclidine (PCP)n Local anestheticsn Ethanoln Corticosteroids
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Buzzwords
n Nicotine alkaloids (nicotine, coniine)n Trick to remember the hemlocks –
n Water Gate Candidate Scandal (Water hemlock,GABA, Cicutoxin, Seizures)
n Poison Control Network (Poison hemlock,Coniine, Nicotine)
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Muscarinic Agonists
n Peripheral: DUMBBELSn Central: Sedation, dystonia, coma, seizures
n Muscarinen Bethanacholn Pilocarpine
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Question
n A 35-year-old man presents to hospital withvomiting, diarrhea, profuse sweating, and mildbradycardia. What is the most likely mushroomhe ingested
A. Amanita phalloidesB. Clitocybe dealbataC. Cortinarius orellanusD. Gyromitra esculentaE. Tricholoma equestre
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Question
n A 35-year-old man presents to hospital withvomiting, diarrhea, profuse sweating, and mildbradycardia. What is the most likely mushroomhe ingested
A. Amanita phalloidesB. Clitocybe dealbataClitocybe dealbataC. Cortinarius orellanusD. Gyromitra esculentaE. Tricholoma equestre
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Muscarinic Antagonists
n Peripheral: mydriasis, anhidrosis, tachycardia,urinary retention, ileus, dry and flushed skin
n Central: delirium, agitation, hallucinations, coman Atropinen Benztropinen Scopolaminen Phenothiazinesn Cyclic antidepressants
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Histamine
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H1 Receptor Antagonists
n 1st generationn Cross the BBBn Diphenhydramine
n 2nd generationn Classified as non-sedationn Selectively bind peripheral
H1 receptorsn Lower binding affinity for
cholinergic receptorsn Reduced antimuscarinic
effects and CNSdepression
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H1 Receptor Antagonists
Terfenadine g terfenadine carboxylate
Astemizole g desmethylastemizole
n Parent compounds block Ikr
n Increased risk of TdPn Withdrawn from market in 1998
CYP3A4
CYP3A4
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H1 Receptor Antagonists
n Clinical manifestationsn CNS depressionn Antimuscarinic effectsn Cardiac
n Na and Ikr blockade with diphenhydramine (QRS and QTprolongation)
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H2 Receptor Antagonists
n Hydrophilic – poor access to CNSn Alter gastric pH
n May impact absorption of acid-labile drugsn e.g., ketoconazole
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Cimetidine
n Only H2 receptor antagonist to inhibit P450isozymes (specifically CPY3A4)n Useful in dapsone-induced methemoglobinemian Useful in toxicity from Gyromitra esculenta
n Associated with myelosuppression if taken withdrugs associated with BM suppression
n Rapid IV dosing has resulted in bradycardia,hypotension, and cardiac arrest
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Serotonin
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Serotonin
n Indole alkylaminen Synthesis from tryptophann Central neurotransmittern Precursor for melatoninn Serotonergic neurons lie in or near midline nuclei
in brainstem and project to various parts ofcerebrum
n 7 classes of receptors with at least 15 subtypes
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Serotonin Synthesis & Metabolism
Tryptophan
5-OH-Tryptophan
Serotonin
5HIAA
tryptophan hydroxylase (rate limiting)
l-aromatic acid decarboxylase
MAO, aldehyde dehydroxylase
5HIAA: 5-OH-indoleacetic acid
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Serotonin Agonists
n Enhanced synthesisn L-tryptophan (associated with eosinophilia myalgia
syndrome)n 5-OH-tryptophan
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Increased Serotonin Release
n Amphetamines (MDMA)n Cocainen Codeine derivativesn Dexfenfluraminen Fenfluraminen L-Dopa
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Other Serotonins
n Inhibit Serotonin Metabolismn MAO-I
n Unknown Serotonin Effectn Lithium
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Inhibit Serotonin Uptake
St. John’s Wart (Hypericumperforatum)
LamotragineSSRIs
CarbamazepineCyclic antidepressants
DextromethorphanCocaine
MeperidineAmphetamines
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Direct Serotonin Antagonists
Risperidone, olanzapine, ziprasidone,quetiapine, cyclic antidepressants
5-HT2A5-HT2C
Trazadone, nefazodone5-HT2
Ondansetron, granisetron, metoclopramide5-HT3
Methysergide, cyproheptadine5-HT15-HT2
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Adenosine
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Adenosine Receptor Antagonists
n Methylxanthinesn Theophyllinen Caffienen Theobromine
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Normal Adenosine Accumulationand Physiologic Response
n Adenosine accumulates in the extracellular spaceduring conditions of fatiguen ATP utilization > ATP synthesis
n Seizures, hypoxia or ischemia promotesaccumulation
n Hypoxia i adenosine kinase activityn h Adenosine promotes sleepiness
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Adenosine A1 Receptors - CNS
n Presynapticn InhibitsInhibits adenylyl cyclase g i cAMP levelsn InhibitsInhibits presynaptic N-type Ca2+ channels
n i Neurotransmitter releasen GABA, NE, 5-HT and Achn Strongest inhibition on glutamate release
Neuroscience. 112(2):319-329(2002)
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Ca
Glu
Glu
Glu
Ca
Adenosine AutoReceptors andGlutamate Neurotransmission
A
AdenosineR1
Ca R
Glu
Glu
Glu
AP
PrePost
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Cl-
K+
Adenosine A1 Receptors - CNS
n Postsynapticn EnhancesEnhances outward K+ channelsn EnhancesEnhances inward Cl- influxn Results in induced hyperpolarizationhyperpolarization
(-) A
AdenosineR1
Glu
Pre
Post
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Adenosine A2 Receptors - CNS
n Presynapticn ActivatesActivates adenylyl cyclase g h cAMP levels
n Inhibits L-type & N-type calcium channelsn Vasodilation
n Only the A2A subtype of A2 receptors havesignificant activity
n Effects of A1 receptors predominate over A2An A1 receptors are more numerousn Adenosine affinity for A1 > A2A receptors
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Adenosine A2A Receptors
n Adenosine A2A receptors are prominent inendothelial cells (vasodilation)
n A2A receptor activity inhibits locomotor activityby inhibiting dopamine at D2 receptors
n A2A receptors serve as check-balance for A1
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Adenosine A1 Antagonism
n Cardiacn h HRn h Atrial inotropicityn h Response to epinephrine
n CNSn h Excitatory amino acid (EAA) release
n Renaln Diuresis
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Question
n Which of the following laboratory abnormalities isconsistent with acute theophylline toxicity?
A. HyperchloremiaB. HypernatremiaC. HyperphosphatemiaD. HypokalemiaE. Hypoglycemia
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Question
n Which of the following laboratory abnormalities isconsistent with acute theophylline toxicity?
A. HyperchloremiaB. HypernatremiaC. HyperphosphatemiaD. HypokalemiaE. Hypoglycemia
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Questions?
Good Luck!!