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Autonomics/
Neurotransmitters
G. Patrick Daubert, MD
Sacramento, CA
Some (most) material plundered from various mentors and other talented
toxicologists, 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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Sympathetic
ganglion
NEACh
CNS
ACh
ACh
ACh
Secreting
hollow end-
organs:
Heart
Lungs
GI
Sympathetic
innervation
to heart,
lungs, etc
ACh
Striated
muscle
ACh
Muscarinic Nicotininc
Courtesy Cynthia Aaron, MD
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Acetylcholine
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ACh Receptors
n Nicotinic Receptors
n CNS (mainly spinal cord)
n Preganglionic autonomic neurons (sympathetic and
parasympathetic)
n Adrenal neuronal receptors
n Skeletal muscle neuromuscular junction
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ACh Receptors
n Muscarinic Receptors
n CNS (mainly brain)
n Postganglionic parasympathetic nerve endings
n Postganglionic sympathetic receptors for most sweat
glands
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Agents that Induce ACh Release
n Aminopyridines
n Latrodectus venom
n Carbachol
n Guanidine
n Alpha2-adrenergic antagonists (h ACh release
from parasympathetic nerve endings)
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Acetylcholinesterase Inhibitors
n h [ACh] at both nicotinic and muscarinic
receptors
n Produce a variety of CNS, sympathetic,
parasympathetic, and NMJ effects
n Carbamates
n Organophosphorus compounds
n Nerve agents
n ‘Central’ AChE inhibitors (donepezil)
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Autonomic Nervous System
ACh
CNS
ACh
NMJ
AChACh
ACh NE
Muscarinic Nicotinic
Hollow end-organs
DUMBBELS
HTN,
tachycardia,
mydriasis
Fasciculations,
respiratory
paralysis
Seizures, coma
Courtesy Cynthia Aaron, MD
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Question
n Which one of the following agents inhibits
acetylcholine release?
A. Bupropion
B. Disulfiram
C. Mirtazapine
D. Tizanidine
E. Yohimbine
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Answer
n Which one of the following agents inhibits
acetylcholine release?
A. Bupropion
B. Disulfiram
C. Mirtazapine
D. Tizanidine
E. Yohimbine
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Agents that Block ACh Release
n Alpha2-adrenergic agonists
n Botulinum toxin
n Crotalinae venoms
n Elapidae beta-neurotoxins
n Hypermagnesemia
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Nicotinic Receptor Agonists
n Initial activation of receptors
n 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, paralysis
n Curare, atracurium, alpha-bungarotoxin
n Peripheral neuronal blockers: autonomic
ganglionic blockade
n Trimethaphan (not entirely specific, may produce
NMJ blockade)
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Nicotinic Indirect Agonists
n Bind to distinct allosteric sites on the nicotinic
receptor, not ACh binding site (enhanced
channel opening)
n Physostigmine
n Tacrine
n Galantamine
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Nicotinic Indirect Antagonists
n Bind to distinct allosteric sites on the nicotinic
receptor, not ACh binding site (decreased
channel opening)
n Chlorpromazine
n Ketamine
n Phencyclidine (PCP)
n Local anesthetics
n Ethanol
n 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: DUMBBELS
n Central: Sedation, dystonia, coma, seizures
n Muscarine
n Bethanachol
n Pilocarpine
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Question
n A 35-year-old man presents to hospital with
vomiting, diarrhea, profuse sweating, and mild
bradycardia. What is the most likely mushroom
he ingested
A. Amanita phalloides
B. Clitocybe dealbata
C. Cortinarius orellanus
D. Gyromitra esculenta
E. Tricholoma equestre
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Question
n A 35-year-old man presents to hospital with
vomiting, diarrhea, profuse sweating, and mild
bradycardia. What is the most likely mushroom
he ingested
A. Amanita phalloides
B. Clitocybe dealbataClitocybe dealbata
C. Cortinarius orellanus
D. Gyromitra esculenta
E. 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, coma
n Atropine
n Benztropine
n Scopolamine
n Phenothiazines
n Cyclic antidepressants
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Histamine
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H1 Receptor Antagonists
n 1st generation
n Cross the BBB
n Diphenhydramine
n 2nd generation
n Classified as non-sedation
n Selectively bind peripheral
H1 receptors
n Lower binding affinity for
cholinergic receptors
n Reduced antimuscarinic
effects and CNS
depression
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H1 Receptor Antagonists
Terfenadine g terfenadine carboxylate
Astemizole g desmethylastemizole
n Parent compounds block Ikr
n Increased risk of TdP
n Withdrawn from market in 1998
CYP3A4
CYP3A4
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H1 Receptor Antagonists
n Clinical manifestations
n CNS depression
n Antimuscarinic effects
n Cardiac
n Na and Ikr blockade with diphenhydramine (QRS and QT
prolongation)
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H2 Receptor Antagonists
n Hydrophilic – poor access to CNS
n Alter gastric pH
n May impact absorption of acid-labile drugs
n e.g., ketoconazole
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Cimetidine
n Only H2 receptor antagonist to inhibit P450
isozymes (specifically CPY3A4)
n Useful in dapsone-induced methemoglobinemia
n Useful in toxicity from Gyromitra esculenta
n Associated with myelosuppression if taken with
drugs 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 alkylamine
n Synthesis from tryptophan
n Central neurotransmitter
n Precursor for melatonin
n Serotonergic neurons lie in or near midline nuclei
in brainstem and project to various parts of
cerebrum
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 synthesis
n L-tryptophan (associated with eosinophilia myalgia
syndrome)
n 5-OH-tryptophan
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Increased Serotonin Release
n Amphetamines (MDMA)
n Cocaine
n Codeine derivatives
n Dexfenfluramine
n Fenfluramine
n L-Dopa
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Other Serotonins
n Inhibit Serotonin Metabolism
n MAO-I
n Unknown Serotonin Effect
n Lithium
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Inhibit Serotonin Uptake
St. John’s Wart (Hypericum
perforatum)
LamotragineSSRIs
CarbamazepineCyclic antidepressants
DextromethorphanCocaine
MeperidineAmphetamines
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Direct Serotonin Antagonists
Risperidone, olanzapine, ziprasidone,
quetiapine, cyclic antidepressants
5-HT2A
5-HT2C
Trazadone, nefazodone5-HT2
Ondansetron, granisetron, metoclopramide5-HT3
Methysergide, cyproheptadine5-HT1
5-HT2
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Adenosine
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Adenosine Receptor Antagonists
n Methylxanthines
n Theophylline
n Caffiene
n Theobromine
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Normal Adenosine Accumulation
and Physiologic Response
n Adenosine accumulates in the extracellular space
during conditions of fatigue
n ATP utilization > ATP synthesis
n Seizures, hypoxia or ischemia promotes
accumulation
n Hypoxia i adenosine kinase activity
n h Adenosine promotes sleepiness
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Adenosine A1 Receptors - CNS
n Presynaptic
n InhibitsInhibits adenylyl cyclase g i cAMP levels
n InhibitsInhibits presynaptic N-type Ca2+ channels
n i Neurotransmitter release
n GABA, NE, 5-HT and Ach
n Strongest inhibition on glutamate release
Neuroscience. 112(2):319-329
(2002)
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Ca
Glu
Glu
Glu
Ca
Adenosine AutoReceptors and
Glutamate Neurotransmission
A
Adenosine
R1
Ca R
Glu
Glu
Glu
AP
PrePost
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Cl
-
K
+
Adenosine A1 Receptors - CNS
n Postsynaptic
n EnhancesEnhances out
