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POISONS

POISONS. Cyanide Carbon monoxide Arsenic and other metals Organophosphates & Nerve Agents Inhalants (Toluene). POISONS Definitions. Therapeutic Index: The absolute difference between a tolerable (or therapeutic) concentration and a toxic concentration

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POISONS

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  1. POISONS • Cyanide • Carbon monoxide • Arsenic and other metals • Organophosphates & Nerve Agents • Inhalants (Toluene)

  2. POISONSDefinitions Therapeutic Index: The absolute difference between a tolerable (or therapeutic) concentration and a toxic concentration Poisons: Substances with little or no therapeutic index; we’ll use…‘Toxic’ Index Poisons in our environment • Plant Alkaloids, e.g. Strychnine • Venoms (Insect/Scorpion/Reptilian/Snake) • Mushrooms • amatoxin • Microbial (Botulinus toxin) • Chemical compounds (Cyanide CN) • Metals

  3. Cyanide CNPoison in the environment-background levels (sources/natural&industrial) • Many natural sources of CN or CN producing substances (cyanogenic) • Peach pits, Cassava fruit, apple seeds • Vitamin B12 (cyanocobalamin); many metabolic processes produce CN of cyanogenic chemicals; liver possesses enzymatic pathways to detoxify CN

  4. Cyanide CNPoison in the environment-background levels • Salts NaCN & KCN used widely (electroplating, gold production and recovery) • Many industrial uses • Rodenticides/Pesticides - fumigants • Nitroprusside used as an antihypertensive (action through effect of NO on relaxing vascular muscle) • CN (HCN) produced by burning synthetic materials

  5. Cyanide CNMechanism of poison’s action • Reversibly binds to a critical component of the respiratory chain (cytochrome c oxidase) causing a reversible stop in oxidative energy production • Other enzyme systems are affected; oxidate energy production is the most important

  6. Cyanide CNMechanism of poison’s action • Without oxidative energy production, glucose and other sugar energy pathways are the only source of energy • Two tissues in particular are obligate oxygen users: Brain and Heart

  7. Cyanide CNOnset of action • Toxic effects depend upon “route of administration” and concentration • HCN gas when breathed is the fastest; death can occur within minutes; individuals can be incapacitated in HCN vapour within seconds • Swallowed CN salts or cyanogenic substances take longer (absoprtion/ first pass effect)

  8. Cyanide CNCourse of toxic effect • CNS stimulation (counter effect) excitation • headache and stiff neck • giddiness • change in breathing pattern (dyspnea); can be confused for hyperventilation • nausea and vomiting

  9. Cyanide CNCourse of toxic effect *** asphyxia without cyanosis*** • the oxygen remains in the blood and individuals color looks good • convulsions and muscular contortion • breathing: short inhalation-long exhalation • heart races (tachycardia) then slows (bradycardia)

  10. Cyanide CNCourse of toxic effect • Death due to asphyxia, cardiac and respiratory arrest, with severe brain damage (depending on time to death

  11. Cyanide CNDisease states with similar (masking) symptoms • Heart attack • Acute asthma

  12. Cyanide CN‘Toxic’ Index • Relatively small • 50 mg HCN 200-300 mg of NaCN or KCN ResponsePPM • Immediately fatal 270 • Fatal in 10 min 181 • in 30 min 135 • 1 hr or dangerous to life 110-135 • slight symptoms (e.g. headache) 18-36

  13. Cyanide CN Routes of Absorption • Primarily by breathing vapor or oral administration • Dermal and Occular

  14. Cyanide CNPharmacokinetics – dynamics • Bioavailability: up to 77% by inhalation/ 50% orally/ also dermal (slow) and occular absorption • Vd 0.4 L/kg • t ½ - approximately 1- 2 hr / converted to thiocyante by rhodanase enzyme

  15. Cyanide CNPharmacokinetics – dynamics Blood concentrations mg/100 mL • No symptoms 0.01-0.05 • Flushing/tachycardia 0.05-0.1 • Toxicity-death 0.1-0.25 • Coma-Death > 0.25

  16. Cyanide CNPharmacokinetics – dynamics Overdose Treatment/Antidote • Lilly antidote kit (sodium bicarbonate, amyl nitrate and sodium thiosulfate) with 100% oxygen

  17. Carbon Monoxide COPoison in the environment-background levels (sources/natural;industrial) • Primary source is incomplete combustion

  18. Carbon Monoxide CO Mechanism of poison’s action • Binds reversibly to hemoglobin - affinity of hemoglobin for CO > O2

  19. Carbon Monoxide CO‘Toxic’ Index • Based on saturation of whole blood • Endogenous < 1 % • Up to 12% environmental (smokers living in high pollution areas) with no sequelae • Toxicity 12-35% • Fatal > 35% if acute/ >50% if gradual (i.e. accumulation over time.)

  20. Carbon Monoxide COOnset of action • Depends strictly with saturation levels • e.g. Response PPM Headache (20%) 60 min @ 200 20 min @ 500 Death (50%) 80 min @ 500 20 min @ 1500 In an area of high concentration - minutes to incapacitation and death

  21. Carbon Monoxide COCourse of toxic effect • Headache, drowsiness, dizziness, NV, blurred vision, confusion, disorientation, dementia, bradycardia-tachycardia, hyperglycemia, seizures, coma, death • Depends on concentration

  22. Carbon Monoxide CODisease states with similar (masking) symptoms • Severe headache often not recognized as a symptom by victims

  23. Carbon Monoxide COPharmacokinetics – dynamics • Inhalation • Half-life 5-6 hrs. • Binds to hemoglobin carboxyhemoglobin

  24. Carbon Monoxide COOverdose Treatment/Antidote • Oxygen and Hyberbaric pressure chamber • Half-life 5-6 hrs in std atmosphere • 30-90 minutes with 100% oxygen • 30 minutes in hyperbaric chamber

  25. METALS Poison in the environment-background levels (sources/natural;industrial) • Most are relatively abundant in the environment or vital ligands for enzymes/co-enzymes and other macromolecules • Metals vital to Health Iron, Copper, Selenium, Zinc • Some Common Toxic Metals Arsenic, Lead, Mercury, Thallium, Nickel, Cadmium, Iron

  26. METALS Mechanism of poison’s action • As- Multisystem disease due to inhibition of oxidative energy pathway attacks SH groups • Pb - Same as As (SH groups) • Tl - SH groups + subtitutes for K in ATPase (energy) pump.

  27. METALS Mechanism of poison’s action • Fe - Corrosive for GI tract -blood coagulation & cardiovascular collapse • Hg - Binds to thiol and sulfhydryl groups

  28. METALS ‘Toxic’ Index

  29. METALS Onset of action • As - 30 min - 2 hr; 200 mg Fatal 24 hr - 4 days • Fe - 30 min - 6 hr; Fatal within 6 hrs or longer • Hg - usually long, slow build up • Pb - usually long, slow build up • Tl - GI symptoms within 12-24 hrs.

  30. METALS Course of toxic effect Arsenic • Nausea &Vomiting, • bloody diarrhea, • abdominal pain, • burning on soles of feet, • sensory loss in extremities (lines in nail bed 4-6 weeks; Aldrich-Mees lines) • death due to circulatory collapse

  31. METALS Course of toxic effect Fe (Iron) • Primarily GI- affects lining; NV, GI pain, cardiovascular collapse Hg (Mercury) • CNS - tremor and loss of memory Pb (Lead) • CNS - difficulty concentrating, lead (blue-black) line on gums

  32. METALS Course of toxic effect Tl (Thallium) • Abdominal pain, • Nausea, Vomiting & Diarrhea, • peripheral neuropathy, • Aldrich-Mees lines, • *hair loss (2-4 weeks), • depressed respiration, delirium, seizure, coma, and death

  33. METALS Disease states with similar (masking) symptoms • As -gastroenteritis, neurological disease • Fe - gastroenteritis, but easily detected • Hg - classic symptoms • Pb - classic symptoms • Tl - Viral disease; Guillain - Barre syndrome (often misdiagnosed)

  34. METALS Routes of Absorption • Mostly through industrial exposure or surreptitious consumption (poisoning) or suicide.

  35. METALS Pharmacokinetics – dynamics

  36. METALS Overdose Treatment/Antidote Specific chemicals sequester metals • As - Dimercaprol, Penicillamine, Succimer • Fe -Deferoxamine, Polyethylene glycol • Hg - Dimercaprol, Succimer • Pb - Dimercaprol, Penicillamine, Succimer • Tl - Prussian blue (exchanges K for Tl) not FDA approved; acetylcysteine investigational

  37. Organophosphates & Chemical Warfare Nerve AgentsPoison in the environment-background levels (sources/natural;industrial) • Organophosphates were designed as pesticides against eukaryotic pests (e.g. they will also affect all pets and family members) • Most warfare nerve agents attack the same metabolic pathways, but take minutes to kill rather than hours - days. • Organochlorines (DDT; 2,4 D) are generally less toxic.

  38. Parathion treated Cotton

  39. Chemical Nerve Agents

  40. Organophosphates & Chemical Warfare Nerve AgentsPoison in the environment-background levels (sources/natural;industrial) • Organophosphates: e.g. Parathion, (phosphorothionic acid O,O-diethyl O-(4-nitrophenyl) ester), Diazinon & Malathion • Nerve agents: Sarin (isopropyl Methylphosphonofluoridate), Soman, Tabun, VX (Methylphosphothionic acid S-(2-bis(1-Methyl-Ethyl)Amino)Ethyl)O-Ethyl Ester)

  41. Organophosphates & Chemical Warfare Nerve AgentsMechanism of poison’s action • Acetylcholinesterase inhibitors • Three stage action • Stage 1&2: Reversible for a period of time • Stage 3 : Becomes irreversible • Acetylcholinesterase has 2 binding sites for these agents; the first can be reversed, the second can not. • Nerve agents may slao penetrate the brain & disrupt GABA transmissions

  42. Organophosphates & Chemical Warfare Nerve Agents‘Toxic’ Index • Small to virtually non-existent • Parathion • Nerve agents: Sarin 4000x more potent than parathion • Lethal inhaled doses of sarin, tabun & soman is 1mg • VX - oily liquid absorbed dermally - 6 mg is lethal

  43. Organophosphates & Chemical Warfare Nerve Agents‘Toxic’ Index • Maximum Control Limits (over 8 hrs) AgentPPM Sarin & Tabun 1 x 10-5 (0.00001) VX 1 x 10-4 (0.0001) CN 36 5 to 6 orders of magnitude (100,000 to 1 M) more potent than Cyanide.

  44. Organophosphates & Chemical Warfare Nerve AgentsOnset of action • Organophosphates: depends on amount consumed hours to days to weeks & months • Nerve agents: within 5 minutes • Aging of nerve agent-acetylcholinesterase complex (stage 3): Sarin 5 hours Soman 2 minutes

  45. Organophosphates & Chemical Warfare Nerve AgentsCourse of toxic effect • Insomnia fatigue, memory loss, seizures, ataxia, coma, salivation, sweating, tearing, diarrhea, bradycardia, meiosis (pinpoint pupils) muscle twitching, weakness or paralysis. • Death by respiratory arrest

  46. Organophosphates & Chemical Warfare Nerve AgentsDisease states with similar (masking) symptoms Cholinergic symptoms: • salivation, • sweating, tearing, • diarrhea, • bradycardia, • meiosis (pinpoint pupils) • and memory loss/confusion are classic symptoms for these agents

  47. Organophosphates & Chemical Warfare Nerve AgentsRoutes of Absorption • Readily absorpable by all routes • Inhalation of gas and/or dust • Dermal/Occular absorption (especially VX) • Oral possible

  48. Organophosphates & Chemical Warfare Nerve AgentsPharmacokinetics – dynamics • Bioavailability not 100% • hepatic conversion of organophosphates to weakly active compounds • onset of irreversible acetylcholinesterase binding and extent of GABA inhibition (pharmacodynamics) determine toxicity despite kinetics

  49. Organophosphates & Chemical Warfare Nerve AgentsPharmacokinetics – dynamics • Organophosphates are cumulative • Vd’s ? • t 1/2 Malathion ~ 3hr others ?

  50. Organophosphates & Chemical Warfare Nerve AgentsOverdose Treatment/Antidote • Anticholinergic - 1o Atropine • Specific competative inhibitor of stage 2 binding is Pralidoxone (PAM) • PAM binds phosphotase (or related) portion of the toxin and reactivates the ACH ase

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