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Clinically Relevant Toxicology

Clinically Relevant Toxicology. Tina Wismer DVM, DABVT, DABT ASPCA Animal Poison Control Center Urbana, IL. Silica Gel Dessicants. Silica is considered chemically and biologically inert Mild GI signs possible. Ant and Roach Baits.

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Clinically Relevant Toxicology

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  1. Clinically Relevant Toxicology Tina Wismer DVM, DABVT, DABT ASPCA Animal Poison Control Center Urbana, IL

  2. Silica Gel Dessicants • Silica is considered chemically and biologically inert • Mild GI signs possible

  3. Ant and Roach Baits • Active ingredients: sulfluramid, fipronil, propoxur, boric acid, and hydramethylnon • Avermectin, chlorpyrifos, and arsenic • Inert ingredients: peanut butter, breadcrumbs, sugar, animal fats • Plastic/metal may pose FB hazard

  4. Commonly encountered Accurate identification required Each class unique Color and formulation not unique Baits come in blocks, pellets and granules Blue, green, red or tan Rodenticides

  5. Rodenticides • Anticoagulants • Bromethalin • Cholecalciferol • Corn-based “Safe” rodenticide • Zinc phosphide

  6. Anticoagulants - Mechanism of Action • Stops production of clotting factors • Inhibit vitamin K 1,2,3-epoxide reductase • Prevents vitamin K recycling • Affected factors • II, VII, IX, and X • extrinsic, intrinsic and common coagulation pathways

  7. Anticoagulant Rodenticides • Short-acting • Warfarin • Pindone • Long-acting (second generation) • Brodifacoum • Bromadiolone • Diphacinone • Difethialone • Chlorophacinone

  8. Kinetics • Generally 3-7 days before clinical signs are seen • Factor VII has shortest half-life (6.2 hours) • Duration of clinical signs: • warfarin - 14 days • bromadiolone - 21 days • brodifacoum - 30 days (stored in the liver)

  9. Clinical Signs • Coagulopathies develop as vitamin K dependent clotting factors are depleted • Initially, signs are vague: • lethargy • exercise intolerance • +/- anorexia

  10. Clinical Signs • As signs progress: • weakness • frank hemorrhage • dyspnea • bruising • lameness • seizures • death

  11. Decontaminate • Warfarin • Decontaminate at 0.5 mg/kg • Second generation • Decontaminate at 0.02 mg/kg • Emesis • if less than 4 hours following ingestion • grain-baits stay in stomach longer • Activated charcoal • benefit of repeat doses not proven

  12. K1 or not K1, that is the question • Witnessed or just some evidence • Chewed package • Green stools • Age of animal - young are more sensitive • Previous health state • Concurrent medications • PT at baseline, 48 hours, 72 hour

  13. Treatment • Vitamin K1 • 2.5-5 mg/kg/day divided BID-TID PO, IM, SQ (difference in absorption is only minutes) • 6-12 hours for new clotting factors to be synthesized • give with fatty meal to increase absorption • injectable product may be given orally

  14. Treatment • Emergency needs for clotting factors (whole blood transfusion, fresh plasma, fresh frozen plasma) • Oxygen • Restrict exercise/cage rest • Recheck PT 48 hours after last dose of vitamin K1

  15. Primary and Secondary Toxicity • Primary toxicity to all mammals is high • Poisoned rodents have killed avian and mammalian secondary consumers © 2008. ASPCA®

  16. Prognosis • Excellent prognosis if treatment started before clinical signs are evident • If clinical signs are present, prognosis depends on the type of signs (chest bleed vs lameness) and severity

  17. Bromethalin • Vengence®, Assault®, Trounce®, Real Kill®, Sudden Death® • Neurotoxin - NOT an anticoagulant! • Increasing in popularity and usage • Concentration is 0.01%

  18. Mechanism of Action Oxidative phosphorylation uncoupled ATP production Edema of Myelin Sheaths Loss of Fluid Pumps

  19. Toxicity • Minimum toxic dose • literature 1.67 mg/kg • APCC 0.9 mg/kg • Converted to desmethylbromethalin • Several times more toxic than bromethalin • Half life (dog) = 5.6 days

  20. Clinical Signs • Acute syndrome (doses at or above LD50) • Signs appear about 10 hours post ingestion • Mortality rate ~100% • Agitation, depression, hind limb paresis, tremors, seizures, death • Chronic syndrome • Signs may occur 24-86 hours post exposure • Signs may last up to 12 days • may fully recover or may have permanent impairment • Tremors, depression, ataxia, rear limb paresis, vomiting, recumbency

  21. Treatment • DECONTAMINATION • DECONTAMINATION • DECONTAMINATION • Emesis, activated charcoal (repeated) • If clinical signs are present, try to decrease cerebral edema • dexamethasone • mannitol • furosemide

  22. Prognosis • Prognosis varies with severity of presenting signs • Asymptomatic or mild depression, ataxia = good prognosis, recovery in 1-2 weeks • Severe neurologic signs (coma, paralysis) = poor prognosis

  23. Cholecalciferol (Vitamin D) Rodenticides • Mouse-B-Gon®, Rat-B-Gon®, Quintox®, Rampage®, True Grit® • Marked increase in serum calcium and phosphorus • Soft tissue mineralization • Renal failure

  24. Mechanism of Action • Cholecalciferol  liver  calcifediol  kidney  calcitriol (active metabolite) • increases intestinal absorption of calcium • stimulates bone resorption of calcium • increases renal tubular reabsorption of calcium

  25. Toxicity • LD50 in dogs (technical product) • 88 mg/kg in the dog • Minimum toxic dose in dogs (bait) • 0.5 mg/kg • Decontaminate at 0.1mg/kg • Juvenile animals and animals with renal disease may be more sensitive

  26. Cholecalciferol - clinical signs • Early (12-36 h) • Weakness, lethargy, anorexia • Polyuria and polydipsia • Vomiting, often with blood • Increased P (12 h), Ca and azotemia (24 h) • Later signs • Oliguria and anuria • Calcification of renal tubules and other highly vascular tissues and vessel walls

  27. Decontamination • Emesis if ingestion was < 4 hours ago • decontaminate doses over 0.1mg/kg • Activated charcoal with cathartic • repeated doses • Baseline (< 8 hours post-exposure) Ca, P, BUN, creatinine • Repeat q 12-24 hours, for 4 days • Goal is Ca x P < 60

  28. Treatment • If Ca (mg/dl) x P (mg/dl) > 60 • soft tissue mineralization may occur • Diurese with 0.9% NaCl • avoid calcium containing fluids • Furosemide • Prednisolone • Phosphate binder • Low Ca diet • k/d, u/d, s/d, pasta and lean ground beef

  29. If Ca x P still rising… • Salmon calcitonin • SQ q 2-3 hours • Some animals may become refractory • Pamidronate (Aredia®) • Bisphosphonate, treats hypercalcemia in people • Advantages - rapid response, single IV treatment • Disadvantages - $$ (now generic), finding it

  30. Treatment - When are you done? • Normal renal values • Ca X Phos < 60 without ongoing treatment • Signs may last for 2-4 weeks as calcifediol has a half life of 16-30 days

  31. Prognosis • Good if caught early • Decreases with prolonged elevations of Ca and P • Depends upon the degree of soft tissue calcification (renal, cardiac, GI) • Lesions from soft tissue mineralization are poorly reversible and may result in long term sequelae or sudden death • rupture of great vessel several months later, at site of calcification

  32. Zinc Phosphide • Arrex®, Commando®, Kilrat®, Gopha-Rid®, Phosvin®, Ridall®, Ratol®, Zinc-Tox®, ZP® • Older rodenticide • Used to kill rats, mice, moles and gophers • Dark gray, often at 2%-5% • Paste, tracking powder, grain-based bait, pellets

  33. Mechanism of Action • Zinc phosphide + water  zinc hydroxide, phosphine gas • Unstable in acid environment • Non-cardiogenic pulmonary edema • If no food in the stomach and phosphine is not released, intact zinc phosphide can be absorbed • damage to liver and kidneys

  34. Zinc Phosphide Toxicosis - Signs • Vomiting (if capable of vomiting) • often with blood • Abdominal pain, ataxia, weakness, leading to recumbency • Tremors, salivation • Hyperesthesia and seizures • Dyspnea

  35. Chronology and Toxicity • Onset of clinical signs: 15 min. - 4 hours • Lethal dose = 20-50 mg/kg • cattle, sheep, pigs, dogs, and cats • Species that are able to vomit may partially self-decontaminate

  36. Decontamination • Emesis - use apomorphine • NO HYDROGEN PEROXIDE • Want to keep gastric pH high, don’t feed first • Lavage • NO WATER • Aluminum or magnesium hydroxide antacid • Activated charcoal?

  37. Treatment • Seizure control (valium, barbiturates) • Supportive therapy • IV fluids +/- bicarb (metabolic acidosis) • n-acetylcysteine via nebulizer • liver “protectants” (B vitamins, dextrose, Vitamin C, Vitamin E) • magnesium (decreases cardiac injury) • gastroprotectants

  38. Zinc Phosphide - Prognosis • If symptomatic, prognosis is guarded for 24-48 hours • Can see death in 3-5 hours • Monitor liver and kidney for 48 hours

  39. Caution • Phosphine smells like rotten fish or garlic • If you can smell it, you are being exposed to a harmful amount • Always have adequate ventilation and gown, glove and mask when decontaminating/treating • Do not wash vomitus down the drain

  40. Unknown Rodenticide • Calculate worst case scenario for each type of rodenticide • Emesis • Charcoal • Multiple dose? • PT vs Vitamin K1 • Ca, BUN, creat • Baseline, 24 hours

  41. Unknown Rodenticide Example Case • Dog 65# ate 0.75 oz of unknown green bait • If bromethalin: 0.07 mg/kg • No tx necessary • If anticoagulant: 0.03 mg/kg • Potential problem – emesis, base charcoal and Vitamin K1 on amount recovered • If cholecalciferol: 0.57 mg/kg • Serious problem – emesis, charcoal, monitor bloodwork

  42. Acetaminophen • Analgesic, antipyretic, mild antiinflammatory • Forms: • Tablets: 80-650 mg • Liquid: 32-100 mg/ml • Rapidly absorbed from the GI tract • Peak plasma levels • 10-60 m for regular products • 60-120 m for extended release

  43. Acetaminophen • Formation of reactive metabolites responsible for toxicity • Metabolites are detoxified by glucuronidation or sulfation • Overdose situations saturate pathways • Cats are deficient in glucuronyl sulfatase • Decreased ability to metabolize APAP

  44. Glucuronide Conjugate (non-toxic) APAP Sulfation Conjugate (non-toxic) Cytochrome P450 PAP Hepato- toxicosis Methemo- globinemia NAPQI Nephrotoxicosis

  45. Acetaminophen- Dogs • Therapeutic dose • 10 mg/kg q 12 h • Toxic Doses • 100 mg/kg - hepatotoxicity • 200 mg/kg - methemoglobinemia • any dose - KCS (48-72 hr post ingestion)

  46. Acetaminophen - Cats • There is no safe acetaminophen dose for cats • 10 mg/kg has produced signs of toxicity • Ferrets are as sensitive as cats

  47. Liver necrosis • Depletion of glutathione → hepatotoxicity • NAPQI binds to sulfhydryl groups on cell membranes • Central lobular necrosis (cytochrome P-450) • Liver necrosis is less common in cats than dogs

  48. Methemoglobinemia • Mucous membranes appear muddy or brown in color • accompanied by tachycardia, tachypnea, weakness, and lethargy

  49. Depression Facial or paw edema More common in cats Hypothermia Vomiting Death Acetaminophen – Other Clinical Signs Photos: Robert Russon, DVM

  50. Diagnosis • Exposure history • Clinical signs • Qualitative acetaminophen plasma levels can confirm exposure • Human hospital • 4 hours post exposure • Not sensitive enough for cats

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