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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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Sympathetic ganglion

NE ACh

CNS ACh

ACh

ACh

Secreting hollow end-organs: Heart Lungs GI

Sympathetic innervation to heart, lungs, etc

ACh

Striated muscle

ACh

Muscarinic Nicotinic 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 ( ACh release

from parasympathetic nerve endings)

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Acetylcholinesterase Inhibitors

n  [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

ACh ACh

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 BP, HR, paralysis, coma

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Nicotinic Receptor Agonists

n  Nicotine alkaloids (nicotine, coniine) n  Carbachol (mainly muscarinic effects) n  Cytisine n  Lobeline 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, Nicotinic)

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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 dealbata C.  Cortinarius orellanus D.  Gyromitra esculenta E.  Tricholoma equestre

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Buzzwords

n  Mushrooms n  Clitocybe Inocybe Muscarinic n  (California international marathon) – sweat like crazy

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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  Antihistamines n  Benztropine n  Cyclic antidepressants n  Phenothiazines n  Scopolamine

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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 terfenadine carboxylate

Astemizole 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 (QRS and QT prolongation) with diphenhydramine

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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 may result 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 n  Prescription drug (Tryptan)

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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

Amphetamines Meperidine

Cocaine Dextromethorphan

Cyclic antidepressants Carbamazepine

SSRIs Lamotragine

St. John’s Wart (Hypericum perforatum)

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Direct Serotonin Antagonists

5-HT1

5-HT2

Methysergide, cyproheptadine

5-HT2 Trazadone, nefazodone

5-HT2A

5-HT2C

Risperidone, olanzapine, ziprasidone, quetiapine, cyclic antidepressants

5-HT3 Ondansetron, granisetron, metoclopramide

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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 adenosine kinase activity

n  Adenosine promotes sleepiness

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Adenosine A1 Receptors - CNS

n  Presynaptic

n  Inhibits adenylyl cyclase cAMP levels

n  Inhibits presynaptic N-type Ca2+ channels n  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

Pre Post

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Cl-

K+

Adenosine A1 Receptors - CNS n  Postsynaptic n  Enhances outward K+ channels

n  Enhances inward Cl- influx

n  Results in induced hyperpolarization

(-) A

Adenosine R1

Glu

Pre

Post

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Adenosine A1 Antagonism

n  Cardiac n  HR n  Atrial inotropicity n  Response to epinephrine

n  CNS n  Excitatory amino acid (EAA) release

n  Renal n  Diuresis

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Question

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

A.  Hyperchloremia B.  Hypernatremia C.  Hyperphosphatemia D.  Hypokalemia E.  Hypoglycemia

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Question

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

A.  Hyperchloremia B.  Hypernatremia C.  Hyperphosphatemia D.   Hypokalemia E.  Hypoglycemia

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Questions?

Good Luck!!