ACMT Board Review Course

J. Dave Barry Naval Medical Center Portsmouth Portsmouth, VA Disclosure

 Views expressed are solely those of the speaker and in no way reflect the official policy, position or doctrine of the US ARMY, US NAVY, DOD or the US Government.

 The contents of this presentation are not endorsed in any way by the US ARMY, US NAVY, DOD, or the US Government.

Pesticides

 Insecticides  Fungicides

 Rodenticides  Fumigants

 Herbicides  Others Insecticides

 Cholinesterase Inhibitors  Organophosphates  Carbamates  Organochlorines  Pyrethrins/Pyrethroids  Newer Insecticides Insecticides Cholinesterase Inhibitors

O  Carbamates R1  Ordeal (Calabar) Bean R-O C N (or S) R2 Carbamates

 Organophosphates O (or S)  Synthesized R2 P R1 X Organophosphates Insecticides Cholinesterase Inhibitors

Goldfrank’s Toxicologic Emergencies – 8th Ed (2006) sympathetic Autonomic Nervous System parasympathetic

N M M C

N T ne

N ne L

N M S N Sympathetic Parasympathetic (cholinergic)

agit N M Sz M C sec mio

N T sec rr ne

sec vasoconstr hr N hr ne L

mot N M S sec N Fasic paraly mict Insecticides Organophosphates Delayed Syndromes  Intermediate Syndrome  Weakness 1-4d after exposure  peripheral NMJ dysfunction  ineffective AChE reactivation

 OPIDN  Neuropathy target esterase (NTE)  Lysophospholipase (lysoPLA)  TOCP (tri-ortho cresyl phosphate)  Jamaican ginger paralysis (1930’s)  Cooking oils (1950’s) Insecticides Organophosphates Diagnosis  RBC Cholinesterase  Butyrylcholinesterase (pseudocholinesterase)  Better reflection of  Falls first synaptic inhibition  Recovers rapidly (few days)  Regenerates more  Wide daily variation slowly than neuronal  in other disorders AchE  Liver dysfunction  Wide variations  Malnutrition  in RBC disorders  Drugs  Pregnancy  Genetic deficiency Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Protect Providers  Glove  Bag  Skin  Triple wash – soap/water  Shave scalp?  GI  Gastric?  AC? Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Antimuscarinic Agents  Atropine  Infusion 0.02 – 0.08 mg/kg/hr  Bolus 2mg q 2-15 min / double dose  Glycopyrrolate  Scopolamine Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Antimuscarinic Agents  Benzodiazepine  Diazepam Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Antimuscarinic Agents  Benzodiazepine

(Organophosphates)  Oximes  Pralidoxime Bolus: 600mg q ?4hr Infusion: 1-2g load f/b  Obidoxime, HI-6 500mg/hr  ?carbaryl? Insecticides Organophosphates

 Aging & Oximes

R

“Aging”

Goldfrank’s Toxicologic Emergencies 8th Ed. Insecticides Organochlorines

 Large family of neuroexcitatory toxins  DDT and analogues

 Cyclodienes

 Hexachlorocyclohexane (lindane)

 Mirex and chlordecone Insecticides Organochlorines

 Large family of neuroexcitatory toxins  DDT and analogues  Most banned from industrialized countries  Na Ch Blockade  Neuroexcitation Insecticides Organochlorines

 Large family of neuroexcitatory toxins

 DDT and analogues  Cyclodienes  Most banned from industrialized countries  GABA Antagonists  neuroexcitation Goldfrank’s Toxicologic Emergencies 8th Ed. Insecticides Organochlorines

 Large family of neuroexcitatory toxins

 DDT and analogues

 Cyclodienes  Hexachlorocyclohexane (lindane)  Scabicide  GABA Antagonist  Seizures, neuroexcitation Goldfrank’s Toxicologic Emergencies 8th Ed. Insecticides Organochlorines

 Large family of neuroexcitatory toxins

 DDT and analogues

 Cyclodienes

 Hexachlorocyclohexane (lindane)  Mirex and chlordecone  Hopewell Epidemic (1974)  “Kepone Shakes”

Goldfrank’s Toxicologic Emergencies 8th Ed. Insecticides Pyrethrins/Pyrethroids

 Pyrethrins  Naturally occuring  NaCh openers  Rapidly decompose

 Pyrethroids  Synthetic derivatives  More persistent, potent  Piperonyl butoxide  P450 inhibitor Insecticides Pyrethrins/Pyrethroids

 Toxicity  Pyrethrins  Allergic

 Pyrethroids  Type 1  Type II  Non-CN  -CN  “T” Syndrome  More potent  Tremor  “CS” Syndrome  Low tox in humans  Choreoathetosis, salivation  GI (saliv, n/v/d), pulmonary neuroexcitation Insecticides Pyrethrins/Pyrethroids

 Treatment  Supportive  Decontamination  Skin  GI - AC Insecticides Others

 Boric Acid  Ant/cockroach killer  Mechanism unclear  Symptoms  GI (blue-green emesis/diarrhea)  Kidney  CNS/Neuro  Derm (boiled lobster rash) Insecticides Others

 Amitraz  2-agonism  Treatment  Fipronil  supportive  GABA antagonist  Insect:Human 1000:1  Imidacloprid  Nicotinic  Avermectins (abamectin, ivermectin)  Fermentation of Streptomyces avermitilis Rodenticides Rodenticides Compound 1080/1081

 Sodium Monofluoroacetate (SMFA)  Compound 1080  Flouroacetamide  Compound 1081

 Inhibit aconitase in Krebs cycle  “lethal synthesis” Compound 1080/1081 Rodenticides Compound 1080/1081

 Symptoms  apprehension  dysrhythmias, seizures, coma, ↓ Ca  Not flouride toxicity

 Treatment  Unknown  Ethanol, Glycerol monoacetate, Rodenticides PNU (Vacor)

 n-3-pyridylmethyl-N-p-nitrophenyl urea  Interferes with nicotinamide activity in pancreas, brain, liver

 Rapid development of  Diabetes mellitus (DKA)  Orthostatic hypotension  CNS toxicity  GI perforation Rodenticides PNU (Vacor)

 Treatment  Aggressive Decontamination

 Nicotinamide

 Niacin Rodenticides Phosphine

 Rodenticide (Zinc Phosphide)  Fumigant (Aluminum Phosphide)

 Phosphine gas  Cellular poison  Inhibits cytochrome oxidase and ETC  Rotten fish / garlic-like odor Rodenticides Phosphene

 Symptoms

 Low level exposure  Pulmonary edema (delayed)

 High level exposure  Multisystem failure  N/V, coma, seizures, hypertension, pulmonary edema Rodenticides Phosphene

 Treatment  Inhalation – supportive

 Ingestion  Intubation  lavage/suction  diluted HCO3 solution, milk  Supportive  NAC, Mg Rodenticides Strychnine

 Strychnos nux vomica  Glycine inhibition  Involuntary generalized muscular contractions  Opisthotonos, trismus, risus sardonicus  Treatment  Benzodiazepines  NM Blockade Rodenticides ATNU

 α-naphthyl-thiourea

 Acute pulmonary edema

 Mechanism unknown  History

 ‘superwarfarins’  Longer T1/2  100X more potent  Same mechanism Warfarins Exogenous Vitamin K Vit K (phytonadione) Quinone

Vit Ki (inactive) Vit Ka (active) Vit K 2,3 epoxide hydroquinone FFP

Factors II,VII,IX,X Factors Iia,VIIa,Ixa,Xa (active)  Diagnosis & Treatment  Child/unintentional  none

 Suicidal/other  Labs

 Vit K1 (phytonadione) IV, PO, IM  FFP  Bromethalin  Uncouples oxidative phosphorylation  AMS, myoclonus, seizures, coma

 Norbormide (dicarboximide)  Norway rat selective smooth muscle constriction  Death from profound vasoconstriction  Other rats, rodents, humans don’t have the same receptor or transporter Herbicides

 Bipyridyl herbicides  Paraquat  Diquat  Chlorphenoxy herbicides  2,4-D, 2,4,5-T and Agent Orange  Glyphosate  Anilide derivatives  Paraquat/Diquat

 Redox cycling

 1 – depletion of NADPH  2 – superoxide formation  3 – lipid peroxidation cascade  4 – glutathione & NADPH depletion Goldfrank’s Toxicologic Emergencies 8th Ed.  Paraquat

 Active transport into Type I & II alveolar epithelial cells

 Surfactant depletion, destruction of alveoli Goldfrank’s Toxicologic Emergencies 8th Ed.  Symptoms

 Dependant on amount ingested  May be delayed, especially with dilute products

 Caustic (Skin, GI Mucosa)

 Renal Toxicity/Failure  ARDS

 Paraquat – pulmonary fibrosis  CNS (somnolence, coma, sz, etc)  Diquat – predilection for pontine hemorrhage?  Treatment  Skin Decon  Lavage (N/V usually occur though)  AC, Fuller’s earth, bentonite, garden clay  Hemodialysis, hemoperfusion, hemofiltration

 ?No O2 until PaO2 < 50mm Hg  chemical analogs of auxins (a plant growth hormone)  Uncontrolled and lethal growth  Corrosive, cell membrane damage  form Acetyl Co-A analogues, uncouple oxid phos?

 Symptoms  Treatment  GI  supportive  N/V, abdominal pain, diarrhea  CV  hypotension, nonspecific ECG abnormalities  CNS  coma, hypertonia, hyperreflexia,

Ukrainian opposition presidential candidate Viktor Yushchenko  Plant mechanism –  amino acid analogue  Human mechanism – unclear,  difficult to separate the toxicity of glyphosate from surfactants and other additives

 Symptoms  Treatment  GI/caustic  supportive  Pulmonary (?aspiration)  CV, renal, CNS toxicity acetochlor amide propanil

 Symptoms  Treatment  methemoglobinemia  Methylene blue Fungicides

 Metallic/organo-metallic  Ba, Cu, Cd, Sb, Hg  Substituted Aromatics  Chlorothalonil, pentachlorophenol, hexachlorobenzene  Thiabendazoles  Benomyl, terrazole, thiabendazole Fungicides Dithiocarbamates Fumigants

 Phosphene – see rodenticides

 Methyl bromide

 Sulfuryl flouride Fumigants Methyl Bromide

 Heavier than air  Chloropicrin additive  Phased out (oxone-depleting agent)

 Skin  Treatment  irritation, blistering  supportive  Pulmonary  dyspnea, NCPE  CNS  visual disturbances, tremor, sz, coma Fumigants Sulfuryl Fluoride (Vikane)

 Heavier than air  Chloropicrin  Suspected flouride poisoning mechanism

 Mucus membranes (skin, GI, resp)  irritation, blistering  Treatment  CNS  Supportive  paresthesias, tremor, sz, coma  monitor Ca  CV  Shock, cardiac dysrhythmias Pesticides Others

 Moth balls

 DEET

 Molluscicides Others Moth Balls

Salt H2O XR Sx Tx water Camphor float float luc CNS/Sz support

faint metHb meth Napthalene sink float op Hemolysis blue Paradichloro N/V, HA, sink sink op support -benzene CNS Others DEET

 N,N-diethyl-3-methylbenzamide  Wide safety margin

 Primarily CNS toxicity  Only after high doses Others Molluscicides

 quaternary ammonium compounds  carbamates  metals

 Metaldehyde  acetaldehyde?  GI – N/V/D, abdominal pain  CNS – seizures, coma, hyperthermia Pesticides

 Insecticides  Fungicides

 Rodenticides  Fumigants

 Herbicides  Others