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1.5 Daubert 4.9.12 Autonomic Homeostasis

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1.5 Daubert 4.9.12 Autonomic Homeostasis Autonomics/Neurotransmitters Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA Some (most) material plundered from various mentors and other talented toxicologists, with permission 1 Autonomic Nervous System ACh ACh ACh ACh ACh NE NMJ Hollow end-organs CNS Muscarinic Nicotinic 2 Courtesy Cynthia Aaron, MD ACh ACh CNS ACh NE Sympathetic Secreting ACh innervation hollow end- ACh to heart, lungs, etc organs: Sympathetic Heart ganglion Lungs GI Striated muscle ACh Muscarinic Nicotininc 3 Courtesy Cynthia Aaron, MD 1 Autonomics/Neurotransmitters Acetylcholine 4 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 5 ACh Receptors n Muscarinic Receptors n CNS (mainly brain) n Postganglionic parasympathetic nerve endings n Postganglionic sympathetic receptors for most sweat glands 6 2 Autonomics/Neurotransmitters Agents that Induce ACh Release n Aminopyridines n Latrodectus venom n Carbachol n Guanidine n Alpha2-adrenergic antagonists ( ACh release from parasympathetic nerve endings) 7 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) 8 Autonomic Nervous System ACh ACh HTN, tachycardia, ACh ACh ACh NE mydriasis NMJ Seizures, coma Hollow end-organs DUMBBELS CNS Fasciculations, Muscarinic Nicotinic respiratory paralysis 9 Courtesy Cynthia Aaron, MD 3 Autonomics/Neurotransmitters Question n Which one of the following agents inhibits acetylcholine release? A. Bupropion B. Disulfiram C. Mirtazapine D. Tizanidine E. Yohimbine 10 Answer n Which one of the following agents inhibits acetylcholine release? A. Bupropion B. Disulfiram C. Mirtazapine D. Tizanidine E. Yohimbine 11 Agents that Block ACh Release n Alpha2-adrenergic agonists n Botulinum toxin n Crotalinae venoms n Elapidae beta-neurotoxins n Hypermagnesemia 12 4 Autonomics/Neurotransmitters 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 13 Nicotinic Receptor Agonists n Nicotine alkaloids (nicotine, coniine) n Carbachol (mainly muscarinic effects) n Methacholine (minimal effects) n Succinylcholine (initial effects) 14 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) 15 5 Autonomics/Neurotransmitters 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 16 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 17 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) 18 6 Autonomics/Neurotransmitters Muscarinic Agonists n Peripheral: DUMBBELS n Central: Sedation, dystonia, coma, seizures n Muscarine n Bethanachol n Pilocarpine 19 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 20 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 21 7 Autonomics/Neurotransmitters 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 22 Histamine 23 H1 Receptor Antagonists n 1st generation n 2nd generation n Cross the BBB n Classified as non-sedation n Diphenhydramine n Selectively bind peripheral H1 receptors n Lower binding affinity for cholinergic receptors n Reduced antimuscarinic effects and CNS depression 24 8 Autonomics/Neurotransmitters H1 Receptor Antagonists CYP3A4 Terfenadine terfenadine carboxylate CYP3A4 Astemizole desmethylastemizole n Parent compounds block Ikr n Increased risk of TdP n Withdrawn from market in 1998 25 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) 26 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 27 9 Autonomics/Neurotransmitters 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 28 Serotonin 29 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 30 10 Autonomics/Neurotransmitters Serotonin Synthesis & Metabolism Tryptophan tryptophan hydroxylase (rate limiting) 5-OH-Tryptophan l-aromatic acid decarboxylase Serotonin MAO, aldehyde dehydroxylase 5HIAA 5HIAA: 5-OH-indoleacetic acid 31 Serotonin Agonists n Enhanced synthesis n L-tryptophan (associated with eosinophilia myalgia syndrome) n 5-OH-tryptophan 32 Increased Serotonin Release n Amphetamines (MDMA) n Cocaine n Codeine derivatives n Dexfenfluramine n Fenfluramine n L-Dopa 33 11 Autonomics/Neurotransmitters Other Serotonins n Inhibit Serotonin Metabolism n MAO-I n Unknown Serotonin Effect n Lithium 34 Inhibit Serotonin Uptake Amphetamines Meperidine Cocaine Dextromethorphan Cyclic antidepressants Carbamazepine SSRIs Lamotragine St. John’s Wart (Hypericum perforatum) 35 Direct Serotonin Antagonists 5-HT1 Methysergide, cyproheptadine 5-HT2 5-HT2 Trazadone, nefazodone 5-HT2A Risperidone, olanzapine, ziprasidone, quetiapine, cyclic antidepressants 5-HT2C 5-HT3 Ondansetron, granisetron, metoclopramide 36 12 Autonomics/Neurotransmitters Adenosine 37 Adenosine Receptor Antagonists n Methylxanthines n Theophylline n Caffiene n Theobromine 38 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 39 13 Autonomics/Neurotransmitters 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) 40 Adenosine AutoReceptors and Glutamate Neurotransmission Adenosine R1 Ca Glu Ca R Glu AP A Glu Post Pre 41 Adenosine A1 Receptors - CNS n Postsynaptic n Enhances outward K+ channels n Enhances inward Cl- influx n Results in induced hyperpolarization Adenosine R 1 Pre K+ (-) A Cl - Glu Post 42 14 Autonomics/Neurotransmitters Adenosine A2 Receptors - CNS n Presynaptic n Activates adenylyl cyclase cAMP levels n Inhibits L-type & N-type calcium channels n Vasodilation n Only the A2A subtype of A2 receptors have significant activity n Effects of A1 receptors predominate over A2A n A1 receptors are more numerous n Adenosine affinity for A1 > A2A receptors 43 Adenosine A2A Receptors n Adenosine A2A receptors are prominent in endothelial cells (vasodilation) n A2A receptor activity inhibits locomotor activity by inhibiting dopamine at D2 receptors n A2A receptors serve as check-balance for A1 44 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 45 15 Autonomics/Neurotransmitters Question n Which of the following laboratory abnormalities is consistent with acute theophylline toxicity? A. Hyperchloremia B. Hypernatremia C. Hyperphosphatemia D. Hypokalemia E. Hypoglycemia 46 Question n Which of the following laboratory abnormalities is consistent with acute theophylline toxicity? A. Hyperchloremia B. Hypernatremia C. Hyperphosphatemia D. Hypokalemia E. Hypoglycemia 47 Questions? Good Luck!! 48 16 1 AUTONOMIC HOMEOSTASIS CORE CONTENT 2.1.11.4 Drugs That Affect Autonomic Homeostasis 2.1.11.4.1 Anticholinergics 2.1.11.4.2 Antihistamines 2.1.11.4.3 Antiserotinergics 2.1.11.4.4 Cholinergics (eg, nicotine) 2.1.11.4.5 Ergot and derivatives 2.1.11.4.6 Methylxanthines 2.1.11.4.7 Sympathomimetics AUTONOMIC NERVOUS SYSTEM (ANS) The ANS is a neuronal network that enables us to function without
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