1.5 Daubert 4.9.12 Autonomic Homeostasis

Home , Tryptophan hydroxylase

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

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

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

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)

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)

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

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

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

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

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

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)

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

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

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)

6 Autonomics/Neurotransmitters

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

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

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

Histamine

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

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

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)

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

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

Serotonin

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

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

Increased Serotonin Release

n Amphetamines (MDMA) n Cocaine n Codeine derivatives n Dexfenfluramine n Fenfluramine n L-Dopa

11 Autonomics/Neurotransmitters

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

Inhibit Serotonin Uptake

Amphetamines Meperidine

Cocaine Dextromethorphan

Cyclic antidepressants Carbamazepine

SSRIs Lamotragine

St. John’s Wart (Hypericum perforatum)

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

12 Autonomics/Neurotransmitters

Adenosine

Adenosine Receptor Antagonists n Methylxanthines n Theophylline n Caffiene n Theobromine

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

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

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

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

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

Questions?

Good Luck!!

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 consciously controlling and managing our bodies. In order to accomplish this specific neurotransmitters and neuromodulators are involved working through many different pathways. The system is also an integral part of neuroendocrine and immunomodulary systems.

LLCDoc Quit 2007 2 ACETYLCHOLINE Acetylcholine (ACh) was the first neurotransmitter (NT) discovered and is the major NT in the peripheral nervous system (PNS) • Acetylcholine o Produced from acetyl-CoA (glucose metabolism) and choline o Acetyl-CoA and choline are independently synthesized in the neuronal cell body and transported along the axon to the synapse for conjugation into ACh o Release is mediated via Ca influx and presynaptic vesicles interacting with cell membrane docking complex (process disrupted by botulinum toxin) o In order to allow repolarization, ACh must be removed rapidly (ie, AChE) o Two classes of ACh receptors . Nicotinic . Muscarinic Nicotinic Receptors (nAChRs) o CNS (mainly spinal cord) o Preganglionic autonomic neurons (sympathetic and parasympathetic) o Adrenal neuronal receptors o Skeletal muscle neuromuscular junction • Nicotinic Receptor Agonists o Initial activation of nicotinic receptors . Prolonged depolarization leads to inhibition . Initial sympathomimetic, GI distress, fasciculations, seizures . Then i BP, i HR, paralysis, coma o Nicotine alkaloids (nicotine, coniine) . Trick to remember the hemlocks – • Water Gate Candidate Scandal (Water hemlock, GABA, Cicutoxin, Seizures) • Poison Control Network (Poison hemlock, Coniine, Nicotine) o Carbachol (mainly muscarinic effects, primarily in ophthalmic use) o Methacholine (minimal effects, does not cross BBB, methacholine test in asthma) o Succinylcholine (initial effects) • Nicotinic Receptor Antagonists o Neuromuscular junction (NMJ) blockers: weakness, paralysis . Curare, atracurium, alpha-bungarotoxin (prevents AChR channel opening) o Peripheral neuronal blockers: autonomic ganglionic blockade . Trimethaphan (not entirely specific, may produce NMJ blockade) • Nicotinic Indirect Agonists o Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (enhanced channel opening) . Physostigmine . Tacrine . Galantamine 3 • Nicotinic Indirect Antagonists o Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (decreased channel opening) . Chlorpromazine . Local anesthetics . Ketamine . Ethanol . Phencyclidine (PCP) . Corticosteroids • Muscarinic Receptors o CNS (mainly brain) o Postganglionic parasympathetic nerve endings o Postganglionic sympathetic receptors for most sweat glands • Muscarinic Agonists o Peripheral: DUMBBELS o Central: Sedation, dystonia, coma, seizures o Muscarine o Bethanachol o Pilocarpine • Muscarinic Antagonists o Peripheral: mydriasis, anhidrosis, tachycardia, urinary retention, ileus, dry and flushed skin o Central: delirium, agitation, hallucinations, coma . Atropine . Phenothiazines . Benztropine . Cyclic antidepressants . Scopolamine • Agents that Induce ACh Release o Aminopyridines o Latrodectus venom (acts as a transmembrane pore and allows Ca influx into cells) o Carbachol o Guanidine o Alpha2-adrenergic antagonists (h ACh release from parasympathetic nerve endings) • Acetylcholinesterase Inhibitors o h [ACh] at both nicotinic and muscarinic receptors o Produce a variety of CNS, sympathetic, parasympathetic, and NMJ effects (DUMBBELS) o Carbamates o Organophosphorus compounds o Nerve agents o ‘Central’ AChE inhibitors (donepezil) • Agents that Block ACh Release o Alpha2-adrenergic agonists o Botulinum toxin (prevents NT vesicle from docking with cell membrane) o Crotalinae venoms o Elapidae beta-neurotoxins o Hypermagnesemia (blocks presynaptic N-subtype calcium channels) 4 HISTAMINE

Histamine interacts with four types of receptors H1-4. H1 receptors use G-protein second messenger systems. H1 receptors are diverse and have the most clinical toxicity in overdose. They are located in the CNS, heart and vasculature, airways, sensory nerves, Gastrointestinal smooth muscles cells, immune cells, and adrenal medulla. H2 receptors are located mainly in the gastric mucosa, but also exist in the heart, lungs, CNS, uterus, and immune cells. H3 receptors serve as neuromodulators for the release of other NT, including histamine. H4 receptors are involved in hematopoietic functions and eosinophil chemotaxis. • Antihistamines o 1st generation . Cross the BBB . Diphenhydramine most clinically relevant for boards o 2nd generation . Classified as non-sedating . Selectively bind peripheral H1 receptors . Lower binding affinity for cholinergic receptors . Reduced antimuscarinic effects and CNS depression • H1 Receptor Antagonists o Historical perspective . Terfenadine gCYP3A4g terfenadine carboxylate . Astemizole gCYP3A4gdesmethylastemizole • Parent compounds block Ikr • Increased risk of TdP • Withdrawn from market in 1998 o Clinical manifestations . Rapid onset with potential for long duration . CNS depression . Antimuscarinic effects . Cardiac • Sodium channel and Ikr blockade with diphenhydramine (QRS and QT prolongation) o H2 Receptor Antagonists . Hydrophilic – poor access to CNS . Alter gastric pH . May impact absorption of acid-labile drugs • e.g., ketoconazole . Cimetidine • Only H2 receptor antagonists to inhibit P450 isozymes (specifically CPY3A4) • Useful in dapsone-induced methemoglobinemia • Useful in toxicity from Gyromitra esculenta • Associated with myelosuppression if taken with drugs associated with BM suppression • Rapid IV dosing has resulted in bradycardia, hypotension, and cardiac arrest 5 ADENOSINE Adenosine is a neuromodulator primarily involved in the reduction of excitatory NT release including glutamate, GABA, norepinephrine, serotonin, and ACh. Its greatest effect is in the inhibition of glutamate release and neuronal excitation. • Adenosine receptor antagonism o CNS: excitation due to sustained and unmodulated release of glutamate and other excitatory neurotransmitters (A1 receptors) o Cardiac: tachycardia due to an increase rate of signaling in pacemaker cells (A1 receptors) o Vasculature: vasoconstriction of CNS, cardiac, and peripheral vascular (A2 receptors) • Adenosine A1 Receptors - CNS o Postsynaptic o Enhances outward potassium channels o Enhances inward Chloride influx o Results in induced hyperpolarization • Adenosine A2 Receptors - CNS o Presynaptic o Activates adenylyl cyclase increasing cAMP levels o Inhibits L-type & N-type calcium channels o Vasodilation o Only the A2A subtype of A2 receptors have significant activity • Effects of A1 receptors predominate over A2A o A1 receptors are more numerous o Adenosine affinity for A1 > A2A receptors o Adenosine A2A Receptors o Adenosine A2A receptors are prominent in endothelial cells (vasodilation) o A2A receptor activity inhibits locomotor activity by inhibiting dopamine at D2 receptors o A2A receptors serve as check-balance for A1 • Adenosine A1 Antagonism o Cardiac . h HR . h Atrial inotropicity . h Response to epinephrine o CNS . h Excitatory amino acid (EAA) release o Renal . Diuresis • Other methylxanthine effects o Increased catecholamine release o Phosphodiesterase (PDE) inhibition: results in increased levels of cyclic adenosine monophosphate (cAMP) that serves to augment adrenergic effects o Increased intracellular calcium uptake and storage: clinical significance is unknown 6 SEROTONIN Serotonin is an indole alkylamine synthesized from tryptophan. Serotonergic neurons lie in or near midline nuclei in brainstem and project to various parts of cerebrum. There are 7 current serotonin receptor classes (5-HT1-7) with at least 15 subtypes. Serotonin has a wide variety of functions including vasoconstriction, inhibition of gastric secretion, enhanced platelet aggregation, stimulation of smooth muscle, and is naturally present in the central nervous system (CNS) as a neurotransmitter. Hallucinogenic drugs produce their electrophysiologic effects primarily through partial agonism at 5-HT2 receptors. Serotonin syndrome involves 5-HT1A and 5-HT2A receptors. • Serotonin synthesis and metabolism Tryptophan

tryptophan hydroxylase (rate limiting) 5-OH-Tryptophan

l-aromatic acid decarboxylase Serotonin

MAO, aldehyde dehydroxylase 5HIAA

• Serotonin Agonists o Enhanced synthesis . L-tryptophan (associated with Eosinophilia Myalgia Syndrome – see Pharmaceutical Additives handout) . 5-OH-tryptophan • Direct Serotonin Agonists

5-HT1A Buspirone

5-HT1B Triptans 5-HT1D

Ergot alkaloids, LSD, mescaline, 5-HT2A psylocibin

Metoclopramide 5-HT4 Cisapride

• Increased Serotonin Release o Amphetamines (MDMA) o Dexfenfluramine o Cocaine o Fenfluramine o Codeine derivatives o L-Dopa 7 • Inhibit Serotonin Metabolism o MAO-I • Unknown Serotonin Effect o Lithium • Inhibit Serotonin Uptake

Amphetamines Meperidine

Cocaine Dextromethorphan

Cyclic antidepressants Carbamazepine

SSRIs Lamotragine

St. John’s Wart

(Hypericum perforatum)

• 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

8 BUZZWORDS AND KEYPOINTS – AUTONOMIC HOMEOSTASIS

• Nicotine and similar alkaloids first stimulate then inactive nAChRs • Botulinum toxin prevents release of ACh • Alpha-latrotoxin (black widow) stimulates release of ACh and NE • Cimetidine CYP3A4 inhibitor o Useful in dapsone-induced methemoglobinemia o Useful in toxicity from Gyromitra esculenta • Terfendine and astemizole withdrawn for increased risk of TdP • Hallucinogenic drugs produce their effects primarity through 5-HT2 receptors • Serotonin syndrome primarily involves 5-HT1A and 5-HT2A receptors • Methysergide (serotonin antagonist) linked to retroperitoneal fibrosis • Fenfluramine and phentermine: weight loss drugs linked thickening of the leaflet and chordae tendineae of aortic and mitral valves, withdrawn from U.S. market in 1997 • Nicotine alkaloids (nicotine, coniine) o Trick to remember the hemlocks – . Water Gate Candidate Scandal (Water hemlock, GABA, Cicutoxin, Seizures) . Poison Control Network (Poison hemlock, Coniine, Nicotine)

9 QUESTIONS 1. A 22-year-old woman with resistant depression discontinued her phenelzine (Nardil) last week and arrives to hospital after using crack cocaine with complaints of abdominal pain. The medical resident prescribes the patient meperidine. She becomes agitated, hyperthermic, rigid, and hyperreflexic with a profound startle response. What best explains her reaction? A. Excessive GABA release from the meperidine B. Excessive glutamate stimulation in the cerebellum from cocaine C. Excessive serotonin release from the cocaine and meperidine D. Serotonin antagonism from the phenelzine E. Probable concomitant methamphetamine abuse

This patient’s symptoms are consistent with excessive serotonin or serotonin syndrome. The recent use of phenelzine along with the exposure to cocaine and administration of meperidine likely lead to significant amounts of serotonin in the CNS.

2. Which of the following statements is correct regarding neurotransmitters? A. Acetylcholine release is mediated via transmembrane pores unlike other neurotransmitters that use synaptic vesicles B. Adenosine antagonism leads to reduction in glutamate transmission C. Hallucinogenic drugs produce their effects primarily through partial agonism at 5-HT4 receptors D. Nicotine first stimulates but then blocks nicotinic receptors both in the CNS and in skeletal muscle E. Norepinephrine is the neurotransmitter of preganglionic sympathetic neurons

Nicotine first stimulates but then blocks nicotinic receptors both in the CNS and in skeletal muscle. Acetylcholine uses synaptic vesicles primarily for its release. Adenosine antagonism leads to an increase glutamate transmission. Hallucinogenic drugs primarily stimulate 5-HT2 receptors. Norepinephrine is a neurotransmitter of postganglionic sympathetic neurons.

3. Which of the following systems is involved with an organophosphate poisoning but not encountered in a diphenhydramine overdose? A. Central nervous system B. Glands (salivary, sweat, lacrimal) C. Skeletal muscle D. Stomach and intestines E. Urinary (bladder)

All of the organ systems listed except skeletal muscles contain muscarinic receptors. The nicotinic receptors of skeletal muscles would no be effected with an exposure to a drug with antimuscarinic properties such as diphenhydramine.

4. The antagonism of adenosine A1 receptors is most likely to result in which of the following clinical manifestations? A. Bradycardia B. Diaphoresis C. Hyperkalemia D. Hypotension 10 E. Seizures

Adenosine is primarily involved in the reduction of excitatory neurotransmitter release including glutamate, GABA, norepinephrine, serotonin, and acetylcholine. Its greatest effect is in the inhibition of glutamate release and neuronal excitation. Seizures are a manifestation of this excitation and may occur with adenosine A1 antagonism.

5. Which of the following best explains the mechanism of action for the botulinum toxin? A. Blockes presynaptic N-subtype calcium channels B. Inhibits magnesium binding at the NMDA receptor C. Phosphodiesterase (PDE) inhibition with increase cyclic adenosine monophosphate (cAMP) D. Prevents neurotransmitter vesicle from docking with cell membrane E. Sodium channel and Ikr blockade The botulinum toxin enters the presynaptic terminal as two chains. Its primary mechanism of action is preventing synaptic vesicles containing acetylcholine from binding to the terminal membrane. This results in a reduction of acetylcholine release and post-synaptic acetylcholine receptor changes.

1C 2D 3C 4E 5D

ANTICONVULSANTS

G. Patrick Daubert, MD; Michelle Burns-Ewald, MD CORE CONTENT 2.1.11.2 Anticonvulsants ANTICONVULSANTS

• Traditional Anticonvulsants o Phenobarbital (Luminol) o Clonazepam (Klonopin) o Phenytoin (Dilantin) o Ethosuximide (Zarontin) o Carbamazepine (Tegretol) o Primidone (Mysoline) o Valproic acid (Depakote, Depakene) o Trimethadione (Tridione) • Mechanisms of Action o Sodium channel inhibition . Inhibit Na+ influx g i rate of firing . PHT, CBZ, OxCBZ, VPA, lamotragine, felbamate o GABA-A receptor augmentation . Increase inhibition g i neuronal activity . PHB, benzos, VPA, gapapentin, vigabatrin o Calcium channel (T-type) inhibition . Inhibit Ca2+ mediated NT release . Ethosuximide, VPA, trimethadione • Phenytoin (PHT) o Na+ channel blocker (Class IB) o Delayed absorption, highly protein bound o Therapeutic level 10-20 mg/L o Propylene glycol diluent in IV forms o P450 inducer/inhibitor o Saturation kinetics (Michaelis-Menton) • Oral Phenytoin Overdose o Toxic effects common at levels > 30 mg/L o Nystagmus, ataxia, slurred speech, confusion o Oral PHT does not cause cardiac toxicity o Supportive care in most cases o Multidose AC may help eliminate PHT faster but outcome data is lacking o Paradoxical seizures and death are rare • Fetal hydantoin syndrome o Microcephaly, developmental delay, telecanthus, short nose and flat nasal bridge, anteverted nares, long shallow filtrum, thin upper lip, hypoplastic nails 2

• Carbamazepine (CBZ) o Structurally similar to imipramine o Only given orally o Erratic absorption common o Therapeutic level 8-12 mcg/ml o Estimated toxic dose 5-10 mg/kg o Active metabolite – 10,11 epoxide . Less anticonvulsant activity but equally as toxic o CBZ Receptor Promiscuity . Type 1A antidysrhythmic • Prolonged QRS g seizures, VT/Vfib . Cardiac K+ channel blocker • Prolonged QT g TdP . Antimuscarinic • Classic toxidrome with hHR and AMS . Adenosine type 1 blockade • Seizures o CBZ Treatment . Cardiac monitor - . NaHCO3 for wide QRS and > 3mm terminal R wave in aVR . Lidocaine for VT/Vfib . Magnesium for wide QTc and TdP . BZD for seizures . Multidose AC – be aware of gut motility . Hemodialysis/Hemoperfusion may be effective • Valproic Acid o Branched chain fatty acid o It is available as Depakene (sodium VPA) or an enteric coated form of two molecules of VPA linked (divalproex or Depakote) o Therapeutic level 50 – 100 mg/L o Highly protein bound o Onset and peak levels often delayed in overdose o Saturation kinetics above 90 mg/L o Metabolism . Many of the VPA metabolites (hydroxyvalproate, 2-propylgluturate, 2- propylpent-4-enoate, 5-hydroxyvalproate, and 4-hydroxyvalproate) contribute to toxicity without having any therapeutic benefit. Most of the toxicity can be linked to carnitine depletion and increase ω-oxidation. Carnitine is necessary for transport of fatty acids into the mitochondria and to maintain the ratio of acyl CoA to CoA across the mitochondria. Without this balance, toxic acyl groups accumulate in the cell and destabilize the membrane, which can impair several enzymatic processes. Hepatotoxicity and hyperammonemia also occur due to carnitine depletion and increase ω-oxidation. ω-oxidation increases levels of 4-en- VPA which inhibits carbamyl phosphate synthetase (CPS1) and enzyme necessary in converting ammonia to urea. As the metabolism shifts from β to ω-oxidation, there is a decrease in acetyl-CoA and ATP. Acetyl- 3

CoA is needed to synthesize N-acetyl glutamic acid (NAGA). NAGA activates CPS1, which again is an enzyme necessary in converting ammonia to urea. • Clinical Presentation o CNS depression/coma . Common with ingestions > 30 mg/kg . Ataxia, nystagmus, slurred speech generally do not occur o Other less common findings . Hypernatremia, hypoglycemia, hypoglycemia, QT prolongation . Pancreatitis . Bone marrow suppression days 3-5 after ingestion • VPA Hepatitis o Transient elevation of enzymes o Reversible elevation of ammonia o Frank hepatitis o Reye-like steatosis • Treatment o Supportive care for CNS depression o Multi-dose charcoal o Hemodialysis for levels 800-1000 mg/L o L-carnitine o Probably not beneficial in CNS depression alone o Children < 2, multiple anticonvulsants, ketogenic diet, malnourished o Elevated ammonia, CNS depression, hepatitis deserve consideration • Anticonvulsant Hypersensitivity Syndrome o Insufficient detoxification of epoxide hydrolase o Aromatic stuctures . Carbamazepine (HLA link?) . Phenytoin . Phenobarbital/Primidone o Onset 4 weeks to 3 months o Clinical picture . Mucocutaneous erruptions (may progress to TEN) . Fever . Hepatitis (ominous finding) . BM suppression . Pneumonitis o Diagnosis: lymphocyte killing assay with mouse microsomes • New Anticonvulsants o Felbamate (Felbatol) o Oxcarbazepine (Trileptal) o Fosphenytoin (Cerebyx) o Tiagabine (Gabitril) o Gabapentin (Neurontin) o Topiramate (Topamax) o Lamotragine (Lamictal) o Vigabatrin (Sabril) o Levetiracetam (Keppra) o Zonisamide (Zonegran) 4

• New Anticonvulsant Pearls o Felbamate (Felbatol) . Mild CNS depression . Aplastic anemia o Gabapentin (Neurontin) . Decreased bioavailability in OD . Not metabolized - no interactions o Lamotragine (Lamictal) . Coma, seizures, QRS prolongation . Hypersensitivity Syndrome o Oxcarbazepine (Trileptal) . Inhibits CYP2C19 . Hyponatremia (SIADH), seizures o Tiagabine (Gabitril) . Coma, seizures o Topiramate (Topamax) . Removed by hemodialysis . Renal nephrolithiasis-calcium phosphate . Acute angle closure glaucoma . Hyperammonemia - carbonic anhydrase inhibition slows ammonia urinary excretion o Vigabatrin (Sabril) . Agitation and psychosis o Zonisamide (Zonegran) . Carbonic anhydrase Inhibitor . Nephrolithiasis QUESTIONS 1. A 37-year-old male is transported to the emergency department via ambulance because of decreased mentation. His vital signs are normal and his physical exam is unremarkable except for a decreased level of consciousness and asterixis. His ammonia level is 145 ug/dL (normal < 20 ug/dL). His friend tells you that he is on a medication for seizures. Which anticonvulsant is he most likely taking? A. Carbamazepine (Tegretol) B. Lamotrigine (Lamictal) D. Phenytoin (Dilantin) C. Phenobarbital (Luminal) E. Valproic acid (Depakote)

The patient’s presentation is consistent with valproic acid toxicity. The most distinctive feature is the elevated ammonia level. None of the other medications would produce this in acute toxicity.

2. What is the diluent found in intravenous phenytoin that is responsible for cardiotoxicity with rapid infusions and production of lactic acid with prolonged infusions? 5

A. Ethylene glycol B. Propylene glycol C. Polyethylene glycol D. Diethylene glycol E. Ethylene glycol monobutyl ether

The diluent in intravenous phenytoin is propylene glycol. Ethylene glycol would not be used as a pharmaceutical diluent. Diethylene glycol has been used as a diluent with disastrous results. Diethylene glycol poisoning causes severe renal failure and acidosis following exposure.

3. Which of the following anticonvulsant drugs is most likely to require cardiac monitoring in acute oral overdose? A. Carbamazepine B. Gabapentin C. Levetiracetam D. Phenytoin E. Valproic acid

Carbamazepine is the most cardiac active of the medications listed with its cyclic antidepressant structure. Valproic acid can cause prolonged QT intervals but is not expected to be as problematic as carbamazepine. Gabapentin and levetiracetam are not known to cause cardiac toxicity. Oral exposures to phenytoin do not result in cardiac toxicity as apposed to rapid intravenous administration of phenytoin (due to propylene glycol).

4. A patient presents to you from an outside clinic where she was receiving follow-up for post-traumatic seizures. She was taking phenytoin (Dilantin) 300 mg TID but developed break-through seizures prompting the family physician to increase her dose to 400 mg TID. She is now ataxic, with slurred speech, notable incoordination, and horizontal nystagmus. Her phenytoin level is 48 mg/L. What is the likely cause of this patient’s phenytoin toxicity? A. Auto-inhibition of phenytoin on P450 due to the increase in dose resulting in elevated levels B. Her symptoms are likely due to the diluent propylene glycol C. Poor outpatient compliance with her medication D. She has been consuming alcohol with her medication E. She is demonstrating Michaelis-Menton kinetics with the increase dose of phenytoin

Phenytoin demonstrates Michaelis-Menton kinetics at serum levels greater that approximately 20 mg/L. Serum levels will decrease at a much slower rate than levels in the therapeutic range.

1E 2B 3A 4E