Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD...

48
0 Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists, with permission

Transcript of Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD...

Page 1: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Autonomics/Neurotransmitters

G. Patrick Daubert, MDSacramento, CA

Some (most) material plundered from various mentors and other talentedtoxicologists, with permission

Page 2: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Autonomic Nervous System

ACh

CNS

ACh

NMJ

AChACh

ACh NE

Muscarinic Nicotinic

Hollow end-organs

Courtesy Cynthia Aaron, MD

Page 3: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Sympatheticganglion

NEACh

CNS

ACh

ACh

ACh

Secretinghollow end-organs:HeartLungsGI

Sympatheticinnervationto heart,lungs, etc

ACh

Striatedmuscle

ACh

Muscarinic NicotinincCourtesy Cynthia Aaron, MD

Page 4: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Acetylcholine

Page 5: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

ACh Receptors

n Nicotinic Receptorsn CNS (mainly spinal cord)n Preganglionic autonomic neurons (sympathetic and

parasympathetic)n Adrenal neuronal receptorsn Skeletal muscle neuromuscular junction

Page 6: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

ACh Receptors

n Muscarinic Receptorsn CNS (mainly brain)n Postganglionic parasympathetic nerve endingsn Postganglionic sympathetic receptors for most sweat

glands

Page 7: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Agents that Induce ACh Release

n Aminopyridinesn Latrodectus venomn Carbacholn Guanidinen Alpha2-adrenergic antagonists (h ACh release

from parasympathetic nerve endings)

Page 8: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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)

Page 9: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 10: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Question

n Which one of the following agents inhibitsacetylcholine release?

A. BupropionB. DisulfiramC. MirtazapineD. TizanidineE. Yohimbine

Page 11: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Answer

n Which one of the following agents inhibitsacetylcholine release?

A. BupropionB. DisulfiramC. MirtazapineD. TizanidineE. Yohimbine

Page 12: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Agents that Block ACh Release

n Alpha2-adrenergic agonistsn Botulinum toxinn Crotalinae venomsn Elapidae beta-neurotoxinsn Hypermagnesemia

Page 13: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 14: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Nicotinic Receptor Agonists

n Nicotine alkaloids (nicotine, coniine)n Carbachol (mainly muscarinic effects)n Methacholine (minimal effects)n Succinylcholine (initial effects)

Page 15: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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)

Page 16: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Nicotinic Indirect Agonists

n Bind to distinct allosteric sites on the nicotinicreceptor, not ACh binding site (enhancedchannel opening)n Physostigminen Tacrinen Galantamine

Page 17: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 18: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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)

Page 19: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Muscarinic Agonists

n Peripheral: DUMBBELSn Central: Sedation, dystonia, coma, seizures

n Muscarinen Bethanacholn Pilocarpine

Page 20: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 21: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 22: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 23: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Histamine

Page 24: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 25: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 26: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

H1 Receptor Antagonists

n Clinical manifestationsn CNS depressionn Antimuscarinic effectsn Cardiac

n Na and Ikr blockade with diphenhydramine (QRS and QTprolongation)

Page 27: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

H2 Receptor Antagonists

n Hydrophilic – poor access to CNSn Alter gastric pH

n May impact absorption of acid-labile drugsn e.g., ketoconazole

Page 28: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 29: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Serotonin

Page 30: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 31: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 32: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Serotonin Agonists

n Enhanced synthesisn L-tryptophan (associated with eosinophilia myalgia

syndrome)n 5-OH-tryptophan

Page 33: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Increased Serotonin Release

n Amphetamines (MDMA)n Cocainen Codeine derivativesn Dexfenfluraminen Fenfluraminen L-Dopa

Page 34: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Other Serotonins

n Inhibit Serotonin Metabolismn MAO-I

n Unknown Serotonin Effectn Lithium

Page 35: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Inhibit Serotonin Uptake

St. John’s Wart (Hypericumperforatum)

LamotragineSSRIs

CarbamazepineCyclic antidepressants

DextromethorphanCocaine

MeperidineAmphetamines

Page 36: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Direct Serotonin Antagonists

Risperidone, olanzapine, ziprasidone,quetiapine, cyclic antidepressants

5-HT2A5-HT2C

Trazadone, nefazodone5-HT2

Ondansetron, granisetron, metoclopramide5-HT3

Methysergide, cyproheptadine5-HT15-HT2

Page 37: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Adenosine

Page 38: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Adenosine Receptor Antagonists

n Methylxanthinesn Theophyllinen Caffienen Theobromine

Page 39: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 40: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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)

Page 41: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Ca

Glu

Glu

Glu

Ca

Adenosine AutoReceptors andGlutamate Neurotransmission

A

AdenosineR1

Ca R

Glu

Glu

Glu

AP

PrePost

Page 42: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 43: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 44: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 45: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

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

Page 46: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Question

n Which of the following laboratory abnormalities isconsistent with acute theophylline toxicity?

A. HyperchloremiaB. HypernatremiaC. HyperphosphatemiaD. HypokalemiaE. Hypoglycemia

Page 47: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Question

n Which of the following laboratory abnormalities isconsistent with acute theophylline toxicity?

A. HyperchloremiaB. HypernatremiaC. HyperphosphatemiaD. HypokalemiaE. Hypoglycemia

Page 48: Autonomics/ Neurotransmitters - ACMT...Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists,

0

Questions?

Good Luck!!