Toxicology Final Review 2024 PDF

Toxicology Final Review By Emily Nunan DVM Fluoride Mineral (think mineral beds, soil, water) commonly livestock problem Overdosing Flouride results in TWO major problems 1. Bone Growth - sponge like bone (think severe lameness, joint spurs) 2. Enamel of Teeth in young (softens the...

Toxicology Final Review By Emily Nunan DVM Fluoride Mineral (think mineral beds, soil, water) commonly livestock problem Overdosing Flouride results in TWO major problems 1. Bone Growth - sponge like bone (think severe lameness, joint spurs) 2. Enamel of Teeth in young (softens the enamel when growing) Diagnosis: Mineral/Soil/water analysis or bone biopsy(coccygeal vertebra) OR in urine within 1-3 weeks of exposure or in kidney/liver Treatment: Transfer to Jesus (no cure) or can manage by adding Aluminum or Ca-Carbonate Anticholinesterases – Ag and household pesticides Organophosphates (oxygen-phosphate) Sarin gas-bioagent! STABLE in body – difficult to remove on own, aka animal will need treatment Carbamates (carbon-phosphate) Unstable – easily metabolized (to clear) BUT fast acting and lethal Put on some animals (cattle) for pesticide control Illegal aldicarb – present near southern border (can kill dogs almost instantly) Anticholinesterases Acute toxicity causes parasympathetic overdrive: SLUD signs, and neuromuscular signs SLUD signs and muscular contractions (twitching then leads to paralysis due to fatigue) Cumulative effect (clinical signs becomes worse and worse ) SPECIFIC to some organophosphates: Exposure led to Delayed Neuropathy by inhibiting neuropathy target esters, NTEs (distal end of Neurons) Persistent paresis/paralysis 10-14 days (sometimes more) after exposure Parasympathetic Overdrive Rapid progression of SLUD signs, salivation, lacrimation, urination, defecation, dyspnoea (with lung edema, respiratory rales) Muscle tremors, seizures, then later paralysis if survives Acute death due to loss of respiratory muscle control Long duration in ruminants (slow digestion) Dogs can develop pancreatitis (acute necrotic necrohaemorrhagic pancreatitis) Anticholinesterases Treatment: Quick! High Doses Activated Charcoal (once safe) Atropine! To effect 2-PAM (pralidoxime) to promote release of OP from AChE BEWARE, anti-AChE toxins are passed into milk Pyrethrins and Pyrethroids Different Kinds Pyrethrins - Naturally occurring; Extracted from Chrysanthemum spp. Pyrethroids – Synthetic (andROIDs = man-made) Cats are especially sensitive Lipidphilic and quickly metabolized (cleared by Liver P450) BUT skin and body fat provides a reservoir “Flip-flop” kinetics (fat release rate) Pyrethrins and Pyrethroids Excitatory neurotoxic effects Clinical Picture: (especially in cats) Salivation due to lack of swallowing Hyperesthesia Twitching! Ataxia and abnormal behavior Skin irritation Treatment No specific antidote Decontamination Clean skin with mild dishwashing detergent (Must use Soap!!) Activated charcoal Control neurological effects (seizure meds, Methocarbamol) May need Dextrose (glucose supply) Anticoagulants (Rat Bait) Becoming less common 1st Generation: warfarin, coumafuryl etc Less potent Effects last a few days 2nd Generation more common More potent Effects last a 12-30 days Eg. bromadialone, brodifacoum, diphacinone chlorophacinone etc.  Mechanism Clotting factors II, VII, IX and X activation requires Vit K1- dependend enzymes Anticoagulants interfere with Vit K1 recycling by inhibiting Vit K epoxide reductase Compromises the intrinsic, extrinsic and common coagulation pathways He stated to know this slide! Anticoagulants (Rat Bait) Clotting factors II, VII, IX and X activation requires Vit K1- dependent enzymes (2, 7, 9, 10) ALL coagulation pathways effected Poor liver health OR drugs affecting metabolism prolongs effects Drugs: cimetidine, sulfonamides, fluconazole, phenylbutazone Anticoagulants (Rat Bait) Clinical signs usually delayed for 12-24 hours Initial signs are non-specific Lethargy, depression, pallor Varied Sx of bleeding tendency Anemia Melena, bloody vomit/diarrhea, point/area bleeding on mucous membranes, epistaxis, hematomas etc. Bleeding into joints/sc bleeding in feet can cause lameness Labs: Regenerative/non-regenarative normocytic, normochromic anemia Prothrombin time (PT) Most sensitive; responds earliest Partial thromboplastin time (PTT) Treatment Decontamination depends on timing (Activated Charcoal) Vitamin K1 2-5 mg/kg IM/SC/per os (once a day) Treat 1 week for 1st generation; up to 6 weeks for 2nd generation Or: treat for 7-10 days, withdraw 2 days and check coagulation; repeat treatment if needed Blood transfusions Increases blood oxygen carrying capacity and supplies clotting factors Fresh frozen plasma should be used in non-anemic patients Prognosis Good with early treatment and low to moderate dose Guarded to poor if treatment is delayed or dose is very high Cholecalciferol (Vitamin D3) Leads to hypercalcemia and hyperphosphatemia Results from hypercalcemia Depression, weakness, ataxia Vomiting, hematemesis (due to gastric ulceration), constipation, melena PU/PD (due to interference with vasopressin function), dehydration Bradycardia and other cardiac arrhythmias Tissue mineralization leads to various signs, depending on tissue/severity Labs: Parathyroid hormone levels become depressed Hypercalcemia and calciuria Treatment Decontamination Emesis and AC Restrict dietary calcium and phosphorus Monitor blood Ca every 24 hours for 6 days Prednisolone (inhibits Vitamin D conversion to active form), furosemide and IV fluids Pamidronate disodium 1.3-2 mg/kg IV in 0.9% NaCl over 2-4 hours Repeat after 4 days Metoclopramide, antacids and GI protectants Prognosis Good if hypercalcemia is avoided Poor if hypercalcemia is severe/prolonged Strychnine (think Coyote bait) very potent, Poisoning relatively common in dogs Blocks the effect of glycine on inhibitory GABA receptors and Suppresses chloride conductance Exaggerated reflexes, muscle spasms, convulsions Early signs include apprehension, anxiety and salivation Then muscle spasms, severe extensor rigidity and tonic convulsions Hyper GIFs | Tenor Treatment Decontamination Emesis; gastric lavage; activated charcoal; cathartics Control muscle spasms Diazepam; methocarbamol; barbiturates Supportive IV fluids Control hyperthermia; acidosis; hypoxia Prognosis is guarded Depends on early intervention; severity of Sx Diagnosis: CS and test stomach contents (for legal cases) Zinc phosphide Rodenticide (think Moles!!!) Mostly used against moles, gophers and rats Mechanism: Zn-phosphide reacts with stomach acid to release phosphine gas; Al-phosphide and Ca- phosphide only requires moisture Heart, brain, liver, kidney and lung tissues are most vulnerable Clinical picture Rapid onset (< 1 hour) Severe GIT upset and hemorrhage Vomiting (often with blood), salivation Followed by tremors/fasciculations, respiratory distress, convulsions, shock Death typically occurs within hours Animals may exhale phosphine gas (“garlicky” odor) Handlers may be affected. Ensure good ventilation!!!!! Human health risk Confirming the Diagnosis and Treatment Phosphine gas dissipates rapidly Samples for phosphine gas (stomach contents, liver kidney) must be collected in airtight containers and frozen Zn may be elevated in stomach contents, liver and kidney Treatment: Decontamination Induce vomiting??? Direct acting antacids to reduce phosphine release Consider gastric lavage Control muscle contractions Bromethalin Rodenticide, becoming more Prevalent Formulated into baits Blocks mitochondrial energy production Major toxic effect is cerebral edema (neuro signs!!) LD50: 0.3 mg/kg (cats); 2.5 mg/kg (dogs) Dose dependent clinical effects: At HIGHER doses (>0.5 mg/kg) Signs develop 4-24 hours after ingestion Muscle tremors, hyperthermia, hyperaesthesia, excitability, seizures At LOWER doses Signs develop within 2-7 days Progressive CNS depression with ataxia, paresis, hind limb paralysis, coma Bromethalin Diagnosis and Treatment Chemical identification in fat, brain (white mater), liver, kidney Decontamination Induce vomiting Activated charcoal (repeated) Control CNS edema and seizures Mannitol diuresis; corticosteroids; furosemide Diazepam, barbiturates (if high-dose syndrome) Prognosis Grave if animal is comatose or paralyzed Fair if Sx are mild; subtle neurological signs may persist Metaldehyde Moluscicide (slugs and snails) Formulated into baits Often combined with methiocarb (carbamate) Dogs generally find the baits attractive; cats are less vulnerable Some recently developed baits are formulated to be less attractive to dogs Toxic dose: 200-600 mg/kg (dog) Suppresses GABA production = Excitability Causes lack of inhibition of CNS neuronal activity Metaldehyde Initially depression, salivation, vomiting diarrhea Followed by hyperaesthesia, muscle tremors, hyperthermia, ataxia, convulsions Death from respiratory paralysis, usually after deepening depression and narcosis Liver failure may set in after 2-3 days if the animal survives the acute phase Can smell like formaldehyde-like Diagnosis: sample contents (frozen) No antidote; Decontamination, control: convulsions and hyperthermia Supportive treatment If develops liver failure: Transfer to Jesus Similar to Strychnine… Metaldehyde vs Strychnine General muscle tremors/seizures vs Rigid plank-like (extensor seizures) Sodium monofluoroacetate (Compound 1080) Used for predator control Restricted to licensed applicators Only registered for use in poison collars on sheep and goats Potent and fast-acting Found in plants in Africa, Australia, India and South America: livestock losses Inhibits the enzyme aconitase Blocks the krebs cycle (oxidative energy production) Most severe effects in the CNS and heart Tissues most dependent on oxidative energy Mixed effects, but emphasis on heart or CNS depends on species Livestock – mostly heart Carnivores – mostly CNS Compound 1080 (Bromethalin on Roids) In carnivores (coyotes; dogs; cats) Latent period 30 min-2 hours Vomiting, salivation, urination, defecation, tenesmus, vocalization, hyperaesthesia and frenzied behavior, hyperthermia, convulsions, coma, respiratory failure Death typically within 12 hours Livestock: heart failure Diagnosis: Stomach contents (vomitus) is the best sample for chemical analysis Rapid and firm rigor mortis is typical No antidote; decontamination, Supportive treatment control: convulsions Chlorinated hydrocarbons - DDT Insecticides Highly lipid soluble and resistant to breakdown in the environment Egg shell breaking (especially effected wild birds), now illegal Lowers action potential thresholds – especially in CNS Affects GABA receptors; similar to strychnine Excitatory CNS signs Clinical Signs and Treatment intermittent seizures (with paddling and jaw clamping), periods between seizures may be almost normal with the animal being depressed Death due to respiratory failure If topical exposure, wash with soap If oral exposure, decontamination by emesis and activated charcoal (repeat AC to interrupt enterohepatic cycling) Control seizures (diazepam, barbiturates, methocarbamol), hyperthermia and acidosis Household Chemicals DEET (Insecticide!) Excessive contact to high concentrations/ingestion causes progressive peripheral and central nervous dysfunction Excitability, tremors Ant and Roach Baits…. Not really a concern (too low of dose) Foreign Body concern due to plastic Birth Control Pills, only really care about Iron placebo pills (still need a fair amount), but honestly the plastic FB is more of concern Silica Gel Desiccants mild GI signs, possible FB Glow Toys, Dibutyl-phthalate causes salivating, wipe off that Glow juice Soaps, Mild detergents, mild GI signs Toilet water detergent, mild GI signs unless tablets are ingested  Cyanoacrylate (super glue) Polymerizes instantly on skin/mucous membranes and become inert aka NOT POISONOUS Heat and irritant vapors produced during activation = Irritant Risk to eyes Individuals may become sensitized Treatment: Wash Don’t pull stuck eye lids or skin apart; Flush Eyes Eyelids will separate in 1-4 days Skin contact: mineral oil/vegetable oil Mouth: let it wear away on its own Topical medications minor concern: Zinc oxide ointments IF the patient vomits Steroid ointments Antibiotic ointments Dilute tea tree oil (melaleuca) MODERATE Concern Pyrethrin/permethrin – (Remember the twitching Cat signalment) Concentrated tea tree oil (melaleuca) Tea tree oil (melaleuca) A complex mixture of bioactive phytochemicals Signs Onset 2-8 hours CNS signs: weakness, depression, ataxia, tremors, hypothermia, liver failure in rare cases Resolves in 1-2 days regardless of what you do Treatment Wash with soap AC (even with dermal exposure) Intravenous lipids? – since this is lipophilic Citrus oil : D-limonene Found in soap/perfume fragrances or shampoo/sprays for flea control Clinical effects Eye/skin irritation, salivation, muscle weakness, tremors, shivering, ataxia, hypothermia if in a cool environment Mechanism unknown Treatment: Similar to Tea Tree Oil, but no Liver failure risk Wash repeatedly with warm water/soap Monitor body temperature, keep warm IV fluids, if needed Topical medications of major concern (has high concentration), must know 5-Fluorouracil (5-FU) For superficial skin cancers/keratosis Efudex®, Carac®, Adrucil®, Fluoroplex® Salicylic acid Topical NSAID Heet®, Bengay® Calcipotriene Vitamin D analogue for psoriasis treatment Dovonex® Dibucaine/benzocaine (local anesthetics) 5-Fluorouracil (5-FU) Inhibits DNA and RNA synthesis, Rapidly absorbed from GIT Toxic dose Cats are EXTREMELY sensitive (no NOAEL) Dogs (oral) Signs (onset in 1-5 hours) Vomiting, GIT membrane sloughing, multiple organ failure, seizures, pancytopenia, death in 10 mg/kg (cat) more sensitive > 100 mg/kg (dog) Cats typically develop MetHb, then liver failure Cats often develop facial and paw edema Dogs typically develop liver failure, then MetHb (if dose is >200 mg/kg) Treatment Absorbed too rapidly for emesis to be effective Activated charcoal Symptomatic/general support: O2; IV fluids; blood transfusion; anti-emetics; Liver support: SAMe or silymarin for 2-4 weeks; NAC(N-acetylcysteine) for 48 hours Methylene blue if MetHb is severe Vitamin A Cats fed high raw liver diets Especially fish liver Single high dose can cause vomiting, diarrhea, abdominal pain Problems more common if exposure is chronic Lethargy, anorexia, weight loss Cervical neck pain, skin/reproductive problems Neck and limb rigidity – exostosis Tense musculature Treatment – remove source, change diet aka nothing really Place on fluids; activated charcoal if acute exposure  Vitamin D3, think of Cholecalciferol rat bait Usually only a problem with high concentration supplements 40,000 IU = 1 mg >0.1 mg/kg (dog): possible signs of anorexia; lethargy; PU/PD >0.5 mg/kg (dog): hypercalcemia and hyperphosphatemia (P increases before Ca) Soft tissue mineralization 1/10 of dog dose is toxic to cats = cats more sensitive Aggressive decontamination; repeated AC (2-3 times within 24 hours) IV fluid (0.9 % NaCl; 3-4 x maintenance) Diuresis with furosemide Prednisone Monitor Ca and P every 24 hours; if necessary use: Pamidronate inhibits osteoclasts; Ca decreases in 24-48 hours Salmon calcitonin Suppresses parathyroid hormone If Ca is normal after 96 hours, no further treatment  Naphthalene vs Paradichlorobenzene mothballs Mechanism Also used in deodorizers for Irritant, Generates free radicals, hemoglobin to garbage cans, diaper pails, metHb bathrooms Methemoglobinemia Depletes glutathione Irritant Liver and kidney failure possible in severe cases Vomiting, diarrhea Clinical effects Neurological effects Vomiting Tremors, seizures Heinz body anemia with hemolysis, Treatment Treatment Decontaminate Diazepam Control vomiting IV fluids Methylene blue, N-acetylcysteine Paradichlorobenzene mothballs causes neuro-signs Darn Salty Paintballs Contain mixtures of glycerin, polyethylene glycol, gelatin, dipropylene glycol, sorbitol, mineral oil, ground pig skin, dyes and water Act as osmotic cathartics on ingestion – high Na causes hypovolemic shock Acute onset – 1-2 hrs after ingestion Vomiting, diarrhea, ataxia, tremors Cardiac irregularities, hyperactivity, hyperthermia, seizures, blindness Acidosis, hypernatremia, electrolyte imbalances from salts Treatment Emesis IV fluids – 2-3 x maintenance – Correct electrolyte imbalances/acidosis Monitor 24 hours Xylitol, think Hypoglycemia and Liver Failure Sweetener in sugar-free candy, gum, baked goods, medications etc. Stimulates insulin release from pancreas in dogs, goats, cows, rabbits and baboons Dog toxic dose 0.1 g/kg: hypoglycemia; 0.5 g/kg: liver failure Signs Vomiting, weakness, ataxia, collapse in 30-60 min Tremors, seizures Hypokalaemia Liver necrosis at high doses (occasionally at lower doses) Liver enzymes typically increase in 12 hours; may be acute Possible coagulopathy related to liver failure Treatment IV infusion of 50% dextrose produces rapid clinical response AC; IV fluids; SAMe or silymarin Monitor blood glucose for 24-48 hours Household batteries Emesis not really awarding If left small size and intact, then OKAY to leave in and take retake rads Tract passage through GI , If still in after 36 hours, go in surgically IF risk of puncture or a lithium battery, go in surgically  Ethylene glycol Ethylene glycol (EG) antifreeze: – Typically 95% EG; often contains fluorescent dye – Sweet taste makes it attractive to dogs and cats Primary –First 8-12 hrs : Test for EG in serum/urine, Urine analysis : Ca oxalate crystals Poisoning has 3 phases: 1st: CNS depression; similar to ethanol Within minutes Other clues 2nd: Acidosis –Hypocalcaemia and acidosis Metabolized to glycolic/glyoxylic/oxalic acids –Serum osmolality >20 mOsm/kg Typically peaks at about 5-6 hours –Anion gap >25 mEq/L –Increased BUN and creatinine 3rd: Renal failure –Fluorescent urine Oxalic acid converted to insoluble calcium oxalate Signs of renal failure usually in 18-72 hours Necropsy –Renal tubular necrosis and crystals –Often obvious crystals in renal cortex Treatment Decontamination Emesis Activated charcoal?? (adsorption is limited) Inhibit alcohol dehydrogenase 4-Methyl-1H-pyrazole (fomepizole) IV Less side-effects compared to ethanol Dog: 20 mg/kg, then 15 mg/kg at 12 and 24 hours, then 5 mg/kg at 36 hours Cat: 125 mg/kg, then 30 mg/kg at 12, 24 and 36 hours 20 % Ethanol IV Dog: 5.5 ml/kg q 4 hours (x5) then q 6 hours (x4) Cat: 5.0 ml/kg q 6 hours (x5) then q 8 hours (x4) Aggressive fluid therapy Correct acidosis Sodium bicarbonate IV to effect according to base deficit (monitor every 4-6 hours) Prognosis: truly depented on renal damage Cats; BAD Dogs: decent if caught soon enough  Antifreezes -- others Methanol – wood alcohol, think CNS signs Windshield wiper fluid and Moonshine!!!! Dogs ingest more than cats Vomit, CNS depression, ataxia, disoriented Differences in methanol metabolism make neuronal necrosis and blindness not a concern in non-primates Serum levels can be requested from human hospitals De-icing agents – Mg-, Na-, Ca-, K-chloride, urea (airlines use ethylene and propylene glycol) Pet consumption of runoff may induce salt poisoning Free access to fresh water reduces the risk May cause skin irritation; particularly on the paws Chocolate (cacao) Ingestion of cacao products and byproducts containing methylxanthines theobromine, caffeine, theophylline Risk factors include small body size, pre-existing heart conditions, epilepsy Theobromine toxic dose (rough guide) 1. Agitation, GI: Vomiting, diarrhea, restless 2. Cardiotoxic: BP/HR increase, PU/PD, excitability, hyperthermia, cardiac arrhythmias, 3. Neurotoxic: ataxia, tremors, seizures Fatalities due to arrhythmias, respiratory failure or DIC Think chocolate goes first to my stomach, then warms my heart until my head hurts. Ascending order of organs if that helps. Remember, baking chocolate (and raw cacao beans) are the WORSE, while white chocolate is not even real chocolate (at least in terms of how scary it is) Chocolate Treatment Decontaminate Activated charcoal Emesis only if not symptomatic Control emesis CNS Diazapam; barbiturates; methocarbamol Cardiac Acepromazine If tachycardia stays >180 bpm, use a beta blocker (eg. esmolol/propranolol) Maintain urine output Fluids; diuretics Hyperthermia Fluids, cold infusions Monitor for 24 hours  Corrosives Corrosive acids Caustics – Basic Generally less hazardous than Generally more hazardous than acids caustics Delayed and relatively poor initial Immediate pain and irritation pain/irritation Leads to larger ingestions upon contact limits ingestion Causes deep, liquefactive necrosis Causes coagulative necrosis Deep ulceration/perforation “Burned” tissue tends to form a Esophagus is highly susceptible protective layer DO NOT INDUCE VOMITING !!! Less chance for perforation Emesis will expose the esophagus again Dilute and protect Water/milk Think Battery ACID hurts when Egg white touched Provides an alternative “tissue” to react with Sucralfate Laundry detergent pods: C/S: esophageal, GI, and skin ulcerations, depression, acidosis due to propylene glycol Cationic detergents: Based on quaternary ammonium cations Found in disinfectants, some detergents High concentrations are corrosive Systemic Neuromuscular blocking (curare-like effect) Oxidative cytotoxicity Might need gastric lavage in large consumption; treat supportively THC Toxicity - Mechanism THC affects CB1 receptors in the brain and alters neuron activity Indirectly affects the heart and thermal management: bradycardia or tachycardia Hyperthermia or hypothermia Various components of the plant causes GIT irritation Usually based on history of exposure and clinical signs No good way to diagnosis On-site urine/blood tests are often in dogs Metabolites differ from humans False positives and false negatives are possible Best is GC/MS or LC/MS (mass spec) (a fancy machine and test), but not conventional Treatment – if they are High, let them Ride (not much you can do after intoxication) Detoxification Emesis not very rewarding AC plus cathartic Gastric lavage if large quantities Opposing effects No specific antidotes Antiemetics – maropitant or ondansetron Sedation if needed – diazepam or chlorpromazine Support Correct and maintain core temperature IV fluids Tilmicosin Cardiotoxic Depletion of cardiac intracellular calcium Negative inotropic effect Increased heart rate, arrhythmia and depressed contractility Worsened by epinephrine Dose- and route-dependent 20-30 mg/kg injected is toxic in pigs, but produces no toxic effects orally SEEK IMMEDIATE MEDICAL ATTENTION Chloramphenicol Reversible bone marrow suppression Described in humans and animals Dose-related (amount and duration) Suppression of mitochondrial protein synthesis in precursor cells Signs of toxicity reverse when treatment is discontinued Irreversible aplastic anemia Rare Described only in humans Dose-independent Bone marrow aplasia with profound and persistent pancytopenia Modification of the molecule has given us safer variants Drug that are potentially harmful to pregnant woman Prostaglandins and corticosteroids Abortion or early labor Absorption through the skin is possible !!! Also, don’t use Prostaglandins in asthmatics/respiratory diseased people  Potent sedatives and anesthetics Etorphine (M99) Extremely potent opioid 1,000 - 3,000 x more potent than morphine Used for the immobilization of wildlife Can be rapidly life-threatening in humans following an accidental needle stick or splash 120-250 lbs onto mucous membranes. Never use etorphine when you are alone Always have reversing agent available 9,000-14,000 lbs Naloxone (Narcan; 0.4 mg/ml) 1 ml IV (preferred) or IM Repeat at 2-3 minute intervals until Sx are reversed Do not use diprenorphine (will increase respiratory signs) Xylazine Veterinary dose 0.1 - 0.2 mg/kg for cattle sedation 0.5 mg/kg as euthanasia premed for cattle 2.2 mg/kg as euthanasia premed for horses Toxicosis Hypotension, sinus bradycardia, CNS depression and apnea Convulsions Can be absorbed across mucosae Minimum lethal dose (cattle and horses): 0.5-2.8 mg/kg Antidotes: atipamezole and yohimbine Detomidine Sedative doses for horses and cattle are similar 0.1 mg/kg Toxicosis Hypotension, sinus bradycardia, CNS depression and apnea Convulsions Can be absorbed across mucosae Antidotes: atipamezole and yohimbine