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

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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

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