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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!!