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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 1 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 Nicotinic

2 Courtesy Cynthia Aaron, MD

3 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

4 ACh Receptors n Muscarinic Receptors n CNS (mainly brain) n Postganglionic parasympathetic nerve endings n Postganglionic sympathetic receptors for most sweat glands

5 Agents that Induce ACh Release n Aminopyridines n Latrodectus venom n n Guanidine n Alpha2-adrenergic antagonists ( ACh release from parasympathetic nerve endings)

6 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)

7 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

8 Courtesy Cynthia Aaron, MD Question n Which one of the following agents inhibits acetylcholine release? A. B. C. D. Tizanidine E.

9 Answer n Which one of the following agents inhibits acetylcholine release? A. Bupropion B. Disulfiram C. Mirtazapine D. Tizanidine E. Yohimbine

10 Agents that Block ACh Release n Alpha2-adrenergic n Botulinum toxin n Crotalinae venoms n Elapidae beta-neurotoxins n Hypermagnesemia

11 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

12 Nicotinic Receptor Agonists n (nicotine, coniine) n Carbachol (mainly muscarinic effects) n n Lobeline n Methacholine (minimal effects) n Succinylcholine (initial effects)

13 Nicotinic Receptor Antagonists n NMJ blockers: weakness, paralysis n , atracurium, alpha- n Peripheral neuronal blockers: autonomic ganglionic blockade n Trimethaphan (not entirely specific, may produce NMJ blockade)

14 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

15 Nicotinic Indirect Antagonists n Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (decreased channel opening) n Chlorpromazine n n (PCP) n Local anesthetics n Ethanol n Corticosteroids

16 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)

17 Muscarinic Agonists n Peripheral: DUMBBELS n Central: Sedation, dystonia, coma, seizures n Muscarine n Bethanachol n Pilocarpine

18 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

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

21 Muscarinic Antagonists n Peripheral: mydriasis, anhidrosis, tachycardia, urinary retention, ileus, dry and flushed skin n Central: delirium, agitation, hallucinations, coma n Atropine n n Benztropine n Cyclic antidepressants n n Scopolamine

22 Histamine

23 H1 Receptor Antagonists n 1st generation n 2nd generation n Cross the BBB n Classified as non-sedation n n Selectively bind peripheral H1 receptors n Lower binding affinity for receptors n Reduced antimuscarinic effects and CNS depression

24 H1 Receptor Antagonists

CYP3A4 Terfenadine  terfenadine carboxylate

CYP3A4  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 (QRS and QT prolongation) with diphenhydramine

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 Cimetidine n Only H2 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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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 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 n Prescription drug (Tryptan)

32 Increased Serotonin Release n (MDMA) n n derivatives n n n L-Dopa

33 Other n Inhibit Serotonin Metabolism n MAO-I n Unknown Serotonin Effect n Lithium

34 Inhibit Serotonin Uptake

Amphetamines Meperidine

Cocaine

Cyclic antidepressants Carbamazepine

SSRIs Lamotragine

St. John’s Wart (Hypericum perforatum)

35 Direct Serotonin Antagonists

5-HT1 Methysergide, cyproheptadine

5-HT2

5-HT2 Trazadone,

5-HT2A Risperidone, olanzapine, , , cyclic antidepressants 5-HT2C

5-HT3 Ondansetron, granisetron, metoclopramide

36 Adenosine

37 Antagonists n Methylxanthines n n Caffiene n

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 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 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

43 Question n Which of the following laboratory abnormalities is consistent with acute theophylline toxicity? A. Hyperchloremia B. Hypernatremia C. Hyperphosphatemia D. Hypokalemia E. Hypoglycemia

44 Question n Which of the following laboratory abnormalities is consistent with acute theophylline toxicity? A. Hyperchloremia B. Hypernatremia C. Hyperphosphatemia D. Hypokalemia E. Hypoglycemia

45 Questions?

Good Luck!!

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