Toxicology Flashcards

Question

Sodium fluoroacetate

Answer 1

Source(s): Sodium fluoroacetate (compound 1080; FCH2CO2Na) is an organofluorine chemical pesticide. It is tightly regulated in the USA so poisoning is rare. Only one company makes it in the US and it is shipped primarily to Mexico and Israel as a pesticide. Mechanism of action: It is rapidly metabolized to fluorocitrate, a potent inhibitor of aconitase, a Kreb’s cycle enzyme Clinical signs: Signs develop within 30-90 minutes of exposure. The chemical primarily affects the CNS in dogs and cardiovascular system in cats. Respiratory failure and death frequently occur within 12 hours of onset of clinical signs. Dogs: tremors, running fits, generalized seizures, vocalization, vomiting, diarrhea, urination Cats: hyperesthesia, salivation, vocalization, muscle tremors, seizures Diagnosis: Typically via known exposure Treatment: There is no antidote. Decontamination, anticonvulsants, and supportive care are recommended.

Answer 2

Source(s): Strychnine is a naturally-occurring compound found in seeds from the Strychnos nux-vomica tree. It has also been chemically synthesized and used as a pesticide. Its use was severely restricted by the EPA in the US in 1978. It is now only registered for below-ground use to control pocket gophers. Mechanism of action: Strychnine is a competitive and reversible inhibitor of glycine receptors postsynaptic membranes in the spinal cord and medulla, leading to excessive excitation. Clinical signs: Clinical signs develop rapidly (10 min to 2 hours) and progress to death within 1-2 hours if left untreated. Common clinical signs include muscle tremors, seizures, hyperesthesia, tetany (“sawhorse stance”), risus sardonicus (“sardonic grin”), opisthtonus, and extensor rigidity. These signs are very similar to those of tetanus, but occur much more quickly. Diagnosis: Typically via known exposure. Some labs are able to measure strychnine levels via TLC or mass spectrometry. Treatment: There is no antidote. Decontamination, anticonvulsants, muscle relaxants, and supportive care are recommended. Recommended therapies include: Diazepam 0.2-0.5 mg/kg IV to control seizures Methocarbamol 15 mg/kg IV or PO q8h as a muscle relaxant Propranolol 0.5-1.0 mg/kg IV to control tachychardia IV diuresis +/- forced diuresis with mannitol or 0.9% NaCl +/- urinary acidification (ammonium chloride 132 mg/kg PO)

Answer 3

Source(s): The combination of toluene & dichlorphen was once common in over-the-counter anthelmintics effective against hookworms, ascarids, and some tapeworms. It appears to be unavailable at this time, but old product may still remain. Clinical signs: Clinical signs usually develop within 6 hours of ingestion with as little as 1.5 times the recommended dose (264 mg/kg of toluene and 220 mg/kg of dicholorophen). In a review of 83 cases, the clinical signs reported in 38 dogs included “ataxia [13/38], tremors [12/38], aberrant behavior [10/38], depression [9/38], vomiting [8/38], mydriasis [7/38], weakness/paresis [6/38], hypersalivation [5/38], seizures [5/38], hyperthermia [3/38], dyspnea/coughing [3/38], anorexia [2/38], diarrhea [2/38], odor of paint thinner on breath [2/38], renal dysfunction [2/38], dehydration [1/38], and tachycardia [1/38].” In the 45 cats, clinical signs included “ataxia [28/45], aberrant behavior [16/45], mydriasis [12/45], vomiting [10/45], depression [8/45], hypersalivation [8/45], tremors [5/45], anorexia [4/45], dehydration [4/45], hyperthermia [3/45], tachycardia [3/45], seizures [2/45], diarrhea [2/45], weakness/paresis [1/45], dyspnea/coughing [1/45], and the odor of paint thinner on breath [1/45].” Diagnosis: Typically via known recent exposure. Treatment: There is no antidote. The most common treatments utilized in the 83 cases described above included GI decontamination (induction of emesis, administration of activated charcoal, gastric lavage), demulcents (milk, kaolin-pectin) if GI irritation, correction of fluid and electrolyte imbalances, a quiet environment, and monitoring liver & kidney function.

Answer 4

Source(s): Rodenticides containing zinc phosphide (Zn3P2) Mechanism of action: It is unknown how this chemical affects the CNS, but it is known that hydrolysis by stomach acid liberates phosphine gas that causes pulmonary edema. Clinical signs: One large retrospective study found that GI signs are most common (66.7%; vomiting, diarrhea, anorexia, ptyalism, abdominal distension), followed by general malaise (17.8%), CNS signs (8.9%; altered mentation, unusual behavior, ataxia, tremors, and seizures), respiratory signs (3.3%; tachypnea, increased respi- ratory effort, coughing, sneezing, pulmonary edema) and cardiovascular signs (1.7%; tachycardia, arrhythmia, hypovolemic shock) Diagnosis: Stomach contents often have a distinct acetylene smell. Treatment: Decontamination (inducing emesis, gastric lavage, activated charcoal), supportive care, antiarrhythmics, anticonvulsants

Answer 5

Bromethalin (N-methyl-2,4-dinitro-N-[2,4,6-tribromophenyl]-6-[trifluoro-methyl] benzeneamine) is a lipid-soluble chemical that is metabolized via N-demethylation to desmethylbromethalin, which is even more potent. Desmethylbromethalin easily crosses the blood-brain barrier where it uncouples oxidative phosporylation leading to reduced ATP synthesis. This subsequently decreases the activity of Na+/K+ ATPase channels, leading to an inability to maintain the osmotic gradient and normal cell membrane potential. Na+ enters the cells, leading to cellular swelling (cytotoxic edema) and dysfunction, as well as intramyelinic edema resulting in the splitting of myelin sheaths. These alterations lead to increased intracranial pressure and death. The LD50 is 4.7 mg/kg for dogs and 0.54-1.8 mg/kg for cats. Clinical signs: Acute toxicosis occurs with ingestion above the LD50, while chronic toxicosis can occur with ingestion of repeated doses below the LD50. Clinical signs of acute toxicosis usually develop within 8-12 hours of exposure, sometimes much earlier. Common clinical signs at higher dose exposure include muscle tremors, hyperthermia, seizures, forelimb extensor rigidity, and ataxia. Clinical signs of repeated sublethal exposure usually develop within 12-24 hours of ingestion but may take several days to appear. The patient may display ataxia, paraparesis to paraplegia, decreased spinal reflexes, muscle tremors, CNS depression, and vomiting. Antemortem definitive diagnosis can be very difficult. A presumptive diagnosis may be made based on compatible clinical signs in patients with potential exposure. The rodenticide is often blue or bright green in color, which may be detected in the stool of some patients. Note that anticoagulant rodenticides are similarly colored, so the active ingredient needs to be determined as they are treated very differently. Analysis of tissues (fat, liver), serum, and vomitus is available, but results are usually not available in time to help the patient. Therefore, early and aggressive treatment is necessary to improve the patient’s chances for survival. Abnormalities on MRI of the brain (fig. 2) can further support a diagnosis of bromethalin toxicity. There is usually marked hyperintensity of the white matter on T2-weighted and diffusion-weighted images and hypointensity on apparent diffusion coefficient (ADC) maps consistent with cytotoxic edema. Gross examination of the brain is usually normal, although compression of the caudal cerebellar vermis due to foramen magnum herniation may be present. Histologic examination usually reveals diffuse vacuolation of the white matter. Treatment Treatment is largely supportive, including the following: GI decontamination with induction of emesis or gastric lavage, followed by repeated activated charcoal due to enterohepatic recirculation Intravenous lipid emulsion has been shown to successfully manage some patients with bromethalin toxicity Control seizures with diazepam or barbiturates Diazepam 0.5-2.0 mg/kg IV Phenobarbital 2-4 mg/kg IV Control cerebral edema & CSF pressure Mannitol 0.5 gram/kg IV slowly over 15 minutes Corticosteroids Prognosis The prognosis is guarded to poor once neurologic signs develop and most animals die within a few days. Experimentally, dogs exposed to a sublethal dose may improve and even return to normal in 10 days.

Answer 6

Ethylene glycol (EG) is a very common source of poisoning in companion animals. EG tastes sweet, so dogs and cats frequently consume a large amount. The most common source is environmental contamination from antifreeze leaking from automobiles (fig. 1). EG readily crosses the blood-brain barrier (BBB) and causes CNS depression. It is also metabolized in the liver by alcohol dehydrogenase into glycoaldehyde, which is then metabolized into glycolic acid. This compound is slowly converted to glyoxylic acid, which causes severe metabolic acidosis. Glyoxylic acid can be metabolized into several compounds, such as glycine or formic acid, or can form oxalic acid that combines with calcium to form calcium oxalate crystals (fig. 2), which can cause renal tubular damage and hypocalcemia, leading to seizures by lowering the seizure threshold. Signs of intoxication Stage 1: occurs 30 minutes to 12 hours after ingestion; severe PU/PD, depression, ataxia, paresis, seizures, coma Stage 2: occurs 12-24 hours after ingestion; severe metabolic acidosis causing tachypnea, tachycardia, and pulmonary edema or congestion Stage 3: occurs 24-72 hours after ingestion; depression, anorexia, vomiting, oliguric renal failure; azotemia, low urine specific gravity (s.g.), anuria, oral ulcers, seizures and uremic encephalopathy Diagnosis A presumptive diagnosis can be made based on clinical signs with known exposure. Routine blood tests (CBC, biochemical profile, electrolytes) and urinalysis should be performed. Blood tests may reveal increased serum osmolality within 1 hour of ingestion. Serum osmolality is calculated using the following equation: 2(Na+) + [glucose/18] + [BUN/2.8] Other biochemical changes include hypocalcemia, hyerglycemia, hyperphosphatemia, hyperkalemia, and increased blood urea nitrogen (BUN) and creatinine. Fig. 2: Calcium oxalate crystalluria. Calcium oxalate crystalluria may be present soon after ingestion (dogs: 5 hours, cats: 3 hours), along with renal tubular casts. Isosthenuria (urine s.g. 1.008-1.012) is usually present by 3 hours after ingestion. Some commercial antifreeze products contain sodium fluorescein dye to help detect coolant leaks in automobiles, so detecting fluoresence of urine, vomitus or the oral cavity with a Wood’s lamp helps support the diagnosis. However, not all antifreeze products contain the dye, so false negative results are common. False positives are also common and have been reported due to a large number of other reasons in human medicine. Definitive diagnosis is made by detection of EG using a rapid, benchtop Ethylene Glycol Test Kit. It can detect EG in the blood as early as 30 minutes and for up to 12 hours after ingestion. The test is more reliable in dogs than cats. The toxic level for cats is lower than dogs and may fall below the detection limit for the test kit. The blood sample for the test should be collected prior to administration of any IV medications that contain propylene glycol (e.g., diazepam) or administration of activated charcoal. Treatment Specific treatment Decontamination: induction of vomiting, gastric lavage, and/or administration of oral activated charcoal Administration of 4-methylpyrazole (4-MP; fomepizole) or ethanol. These must be administered within 8 hours of EG ingestion. a. Ethanol is the treatment of choice for cats, but can also be used in dogs if 4-MP is unavailable. Ethanol displaces EG from the receptors. It is very effective, but has significant side effects, including CNS depression, metabolic acidosis and hyperosmolality. Make a 7% ethanol solution (see box) and give 8.6 mL/kg IV slowly followed by a CRI of 1.43 mL/kg/hr for 36-48 hours. To make a 7% ethanol solution, using the following calculation: 7 / (Proof number/2) * 1000mL = number of mL to put into 1 L of 5% dextrose or 0.9% NaCl For example, if using 80 proof vodka, the calculation would be: 7 / (80/2) * 1000 = 7 / 40 * 1000 = 0.175 * 1000 = 175 mL b. 4-MP (fomepizole, Antizol-Vet) is a synthetic alcohol dehydrogenase inhibitor, which prevents EG from being metabolized into more toxic byproducts as described above. EG, which in its native form is not very toxic, is then excreted unchanged into the urine. Dosing (dogs): Load with 20 mg/kg IV slowly At 12 hours, give 15 mg/kg IV At 24 hours, give 15 mg/kg IV At 36 hours, give 5 mg/kg IV. This can be repeated as necessary if the patient hasn’t recovered or if a continued positive ethylene glycol test. Dosing in cats is listed below. 4-MP must be given within 3 hours of ingestion. By 4 hours post-ingestion, there is 100% mortality in cats. 4-MP must be given at a much higher dose than in dogs and is more likely to cause worsened neurological signs. Load with 125 mg/kg IV slowly At 12, 24, and 36 hours, give 31.25 mg/kg IV NOTE: BOTH ethanol and 4-MP will be ineffective if azotemia or oliguria/anuria are present, so dialysis would be required. Supportive measures Intravenous fluids to diurese the patient Treat metabolic acidosis Bicarbonate dose = bicarbonate deficit x body weight (kg) x 0.3 Give 1/4 to 1/3 of the dose IV slowly over 5-10 minutes and reassess Treat seizures as with any other seizure disorder General nursing care Monitor ins and outs

Answer 7

Ivermectin is a naturally occurring chemical combination of 22,23-dihydro avermetic β1a and β1b. Synthetic ivermectin is used primarily as an anthelmintic in large animals and as a preventive for canine heartworm disease (6 µg/kg PO monthly). It is also used off-label in dogs at higher doses (50-300 µg/kg PO or SQ) for ectoparasites (e.g., demodicosis). Intoxication occurs most commonly after well-meaning owners administer the equine product to their dog. It also occurs frequently in herding breed dogs with a mutation in the multidrug resistance (MDR) gene (see table). Doses as low as 100 µg/kg will cause mild clinical signs in 30-40% of dogs. The higher the dose, the higher the percentage of dogs affected and the more severe the clinical signs. Ivermectin potentiates glutamate- and/or GABA-gated chloride channels in invertebrates. In mammals, GABA receptors are restricted to the CNS. The blood-brain barrier (BBB) normally prevents ivermectin from entering the CNS, protecting mammals from neurotoxicity. However, in dogs with the MDR-1 gene mutation, there is a lack of a large transmembrane protein (P-glycoprotein; P-gp) that acts as a drug-transport pump that transports drugs from the brain back into the blood. Dogs that are homozygous for the mutation are at high risk of ivermectin toxicosis, but heterozygous dogs (i.e., 1 normal allele, 1 mutant allele) may also show signs of toxicity, especially at higher doses. Dogs that are homozygous normal are not at risk of toxicity. Intoxication can occur in the following situations: MDR-1 homozygous mutant patients. The heartworm prevention dose can be given safely to susceptible patients, but signs of intoxication can occur at doses as low at 100 µg/kg. Accidental overdose. It usually takes at least 2 mg/kg before dogs develop signs of intoxication. Cumulative toxicity. Intoxication from cumulative doses may occur at higher daily doses. Altered BBB. Care must be taken in using ivermectin in dogs with head trauma, encephalitis, brain tumors, etc. Clinical signs Neurological signs include ataxia, tremors, disorientation, weakness, seizures, stupor, and coma. Some dogs have mydriasis, absent menace, and blindness. Non-neurological signs include ptyalism, vomiting, diarrhea, bradycardia, and hyperthermia. Diagnosis Ivermectin toxicosis is typically diagnosed following possible exposure with compatible clinical signs. Treatment Immediate treatment after overdose Inducing emesis is recommended if ingestion has occurred in the previous 1-2 hours. Emesis should not be induced if the patient has any respiratory compromise or is in a stuporous or comatose state. Apomorphine: 0.04 mg/kg IV or 0.08 mg/kg IM, SQ, or crush 1 tablet and place in conjunctival sac (eye should be flushed out immediately after emesis occurs) Hydrogen peroxide: 5-10mL PO, may be repeated one time Gastric lavage Activated charcoal: Mix 1 gram/5mL water and give 10mL slurry/kg PO q6-8 hours, either via a stomach tube or mixing into food. Ivermectin undergoes enterohepatic recirculation so repeat doses are necessary. Intravenous lipid therapy Supportive care after signs have developed IV fluids Activated charcoal Intravenous lipid emulsion – doses vary; see reading list below Monitor airway and ventilate if necessary Anticonvulsants (phenobarbital); diazepam is not recommended because it stimulates GABA receptors similar to ivermectin. General nursing and bladder care Prognosis The prognosis for recovery is fair to good, especially if diagnosed and treated early and aggressively.

Answer 8

Lead poisoning was once one of the most common toxicoses in veterinary medicine, although the incidence has been declining over the past 20-30 years after regulations in the late 1970s prohibited its use in many common products (e.g., gasoline, house paint). Old paint remains the most common source of lead intoxication in dogs and cats. Exposure occurs most often following sanding or scraping of old lead-based paint, but can also occur with flaking paint and animals chewing on windowsills, doorjambs, and other locations in their environment. Lead can be found in numerous products, including building materials (roofing material, carpet padding, plumbers solder, caulk, linoleum), sporting goods (golf balls, ammunition, lead dust at shooting galleries fishing weights), automotive products (used motor oil and emissions, wheel weights) and other miscellaneous sources (pottery glaze, leaded glass and curtain weights, newspaper and magazine ink). Lead intoxication also occurs following ingestion of contaminated water such as inappropriately treated water sources (see Flint, MI) and old lead pipes. Lead is absorbed from the GI tract more readily in young patients (40-50%) than adults (5-10%). Lead causes increased erythrocyte membrane fragility and shorts the lifespan of erythrocytes, thereby reducing oxygen-carrying capacity. After absorption, lead is distributed to the liver, kidney cortex, and bone (90-98% of absorbed lead). It also readily crosses the placenta and blood-brain barrier (BBB). Lead causes neuronal damage, cerebral edema, and demyelination with reduced nerve conduction velocity. Signalment Lead intoxication is more common in dogs than cats and can occur in any age/breed. Clinical signs Clinical signs of lead poisoning are referable to the gastrointestinal (GI) tract and nervous system. Nervous system signs predominate with acute or high exposure level, while GI and bone signs are more frequently observed with chronic and lower exposure level. Clinical signs include vomiting, seizures, anorexia, abnormal behavior (e.g., barking/crying constantly, biting, running fits, and other bizarre behaviors), weight loss and megaesophagus with regurgitation. Lead intoxication should be a differential diagnosis for any seizure patient, especially if the owner’s house was built before 1978 or there is another potential exposure. Diagnosis A presumptive diagnosis can be made based on exposure risk, compatible clinical signs and the presence of basophilic stippling on erythrocytes or nucleated (and other immature) erythrocytes. Finding radiopaque material (e.g., lead paint chips or other lead-based objects) on survey abdominal radiographs further supports a presumptive diagnosis, but lack of radiopaque material does not completely rule out lead intoxication. Diagnosis of lead intoxication is usually straightforward via blood lead level measurement. Whole blood in an EDTA (purple top) or heparinized (green top) tube should be submitted for analysis. Serum should not be used because 90% of lead is bound to circulating erythrocytes. There is some variability in normal blood lead level. At the Idexx reference laboratory, levels greater than 60 µg/dL are diagnostic for lead poisoning, while 30-60 µg/dL is highly suspicious, especially in patients with compatible clinical or hematologic abnormalities. The severity of clinical signs does not correlate with blood lead level. Treatment Specific care Chelation therapy is the mainstay of treatment for lead poisoning. Removal of lead (e.g., surgical or endoscopic removal) and decontamination procedures are recommended before chelation therapy, as some medications increase GI absorption. Chelation therapy (see below) should be continued until the blood lead level is below the toxic level. Rebound increased blood level can occur after chelation therapy has finished due to redistribution out of bone and other tissues. Ensure that the patient is not being re-exposed to lead. If the level is elevated mildly to moderately elevated after chelation therapy, but the dog is asymptomatic, consider allowing the patient to eliminate the lead naturally. Chelation therapy can be restarted if the patient becomes symptomatic again. Succimer (meso-2,3-dimercaptosuccinic acid; DMSA) is the treatment of choice because it is a fairly selective chelating agent that can be given orally and is water soluble, unlike some of the others listed below. Succimer can be administered to both dogs and cats (10 mg/kg PO q8h for 5 days, then 10 mg/kg PO q12h for 2 weeks). Chelated lead is excreted by the kidneys into the urine. Succimer can be repeated in two weeks if the lead level remains high. Ensure that the patient is not being re-exposed to the lead source. Calcium disodium EDTA (CaEDTA; “calcium EDTA”) has historically been the most commonly used chelating agent used to treat lead toxicosis and can be used if succimer is not available. The calcium is displaced by divalent or trivalent metals. Its use has largely been supplanted by the succimer because CaEDTA also non-selectively binds other metals, including zinc, cadmium, copper, iron, and manganese. It should be used for a maximum of five days since it has effects on the health of the intestinal epithelium and enhances zinc elimination. Calcium EDTA can cause nephrotoxicity so it should not be given to patients with anuria or kidney disease. CaEDTA dose for dogs & cats: 25 mg/kg subcutaneously q6hr for 5 days (diluted in dextrose 5% to concentration of 10 mg/mL). Some sources recommend not exceeding 2 grams per patient per day. Rehceck lead level in 1-2 weeks and repeat if needed. D-penicillamine (110 mg/kg divided PO q6-8hr for 7-14 days; some recommend 33-55 mg/kg/day divided) is another non-selective chelating agent that is used primarily for copper toxicosis but can also be used for lead intoxication if necessary. All lead should be removed from the GI tract before administration because d-penicillamine increases lead absorption. It should be given on an empty stomach because it binds essential metals found in the diet. Side effects include vomiting, hematuria, and reversible proteinuria. Administration of antiemetics 30-60 minutes before dosing may reduce vomiting. General supportive care Seizures should be managed like any other seizure disorder. Stop seizures in the emergent setting Diazepam: 0.5-1.0 mg/kg IV Phenobarbital 4 mg/kg IV or levetiracetam (Keppra) 20-40 mg/kg IV if seizure doesn’t stop quickly Prevent ongoing seizures with one of the following: Phenobarbital 4 mg/kg IV q4-6hr until 16-20 mg/kg total dose given, then start maintenance dose 2 mg/kg IV or PO q12hr Levetiracetam 20 mg/kg IV or PO q8hr Zonisamide 5-10 mg/kg PO q12hr Treat cerebral edema with one of the following. Mannitol: 1.0 gram/kg IV slowly over 15 minutes Hypertonic saline: 4 mL/kg of 7.5% NaCl over 2-5 minutes (alternatively 5.3 mL/kg of 3% NaCl). Maintain hydration with IV fluids. It is important that the patient is euvolemic before giving mannitol or hypertonic saline. IV fluids should be continued after administration of mannitol/hypertonic saline to prevent dehydration. Prognosis The prognosis is usually very good to excellent if diagnosed early and treated appropriately. The neurological signs typically resolve. Public health concern Owners should be informed that other pets and people (especially children) in the same environment may be exposed to the same lead source and should be tested.

Answer 9

Macadamia nut intoxication appears to be a phenomenon limited to dogs. The exact cause is unknown but may be due to the nuts themselves, processing contaminants, mycotoxins or other causes. Clinical signs have been reported after dogs ingested as little as 0.7-4.9 g/kg BW, or approximately 1 nut per kilogram body weight. Clinical signs Clinical signs typically start within 3-24 hours of ingestion. From most common to least common, clinical signs include weakness, CNS depression, vomiting, ataxia, tremor, hyperthermia, abdominal pain, lameness, stiffness, recumbency, and pale mucous membranes. Diagnosis Diagnosis is usually based on possible exposure and compatible clinical signs. Serum biochemical analyses from 4 dogs that were experimentally given 20 g/kg body weight of macadamia nuts showed mild elevations in serum triglycerides and alkaline phosphatase, as well as a spike in lipase values at 24 hours before returning to baseline by 48 hours. Treatment GI decontamination is recommended (induction of emesis, activated charcoal). Apomorphine: 0.02-0.04 mg/kg IV, SC, IM; may cause CNS depression so use with caution if mental dullness Hydrogen peroxide 3%: 2 mL/kg PO with a maximum dose of 45 mL IV fluids and antiemetics may be needed if the patient has more than mild vomiting. Prognosis All clinical and experimental dogs that have been described in the literature recovered within 1-2 days, regardless of whether they were treated by a veterinarian or not.

Answer 10

Marijuana (Cannabis sativa) is a commonly-used recreational drug because of its psychoactive properties, but more recently it is increasingly used for its potential medicinal properties. C. sativa (fig. 1) produces more than 60 different cannabinoids. The primary psychoactive ingredient is 9-tetrahydrocannabinol (THC) with concentrations ranging from 0.4% to 20%. THC binds to cannabinoid receptors in the CNS leading to the clinical signs of intoxication listed below. Although secondhand smoke can be a cause of marijuana intoxication in companion animals, toxicity in dogs and cats usually occurs following accidental ingestion of the owner’s “stash” or exposure to THC butter in baked goods. Only two other cannabinoids (cannabinol and cannabidiol) have been shown to have psychoactive effects, but with less than 1/10th the potency of THC. The toxic dose is difficult to determine because the concentration varies greatly between potential exposure sources. THC is very lipid soluble and easily distributes into the brain, fat, liver, and kidneys. THC is metabolized by the liver to its primary metabolite, 11-hydroxy-∆-9-THC and excreted into the urine (15%) and feces (85%) via biliary excretion with extensive enterohepatic recirculation. THC binds to cannabinoid receptors. CB1 receptors are located in the central nervous system (CNS), especially in the basal ganglia, substantia nigra, globes pallidus, hippocampus, frontal lobe, and cerebellum. The CB1 receptors are located in the presynaptic nerve terminal, and their activation leads to inhibition of numerous neurotransmitters, including acetylcholine, dopamine, gamma-aminobutyric acid (GABA), glutamate, noradrenaline, and serotonin. In humans, this leads to impaired cognition and memory, diminished motor activity, and reduced nausea, vomiting, and nociception (pain). CB2 receptors are located outside the CNS and appear to regulate inflammation and immune system responses. Signalment Any age and breed of dog and cat can be affected, but dogs are affected much more often than cats. Clinical signs & neurologic exam Clinical signs typically develop within 1-3 hours of ingestion and can last for 1-3 days (average duration 24 hours). Common clinical signs include CNS depression, agitation, vocalizing, ataxia, mydriasis, tachycardia, vomiting, diarrhea, urinary incontinence, and ptyalism. One study reported that almost 50% of the dogs displayed urinary incontinence. Higher doses can cause stupor/coma, agitation, vocalization, hyperexcitability, seizures, tachypnea, bradycardia, and hypotension. In one study of 125 dogs (Meola et al., 2012), 48% of affected dogs had mydriasis. Diagnosis Presumptive diagnosis is typically based on clinical signs with potential exposure. The diagnosis can be confirmed by demonstration of cannabinoids in stomach contents, vomitus, blood, and urine. Human urine drug-screening tests are sometimes used, but their use is controversial because there appears to be a high false-negative rate, which may be due to testing too early before metabolites appear in the urine, different metabolites in dog urine compared to humans, and artificially lowered THC due to binding to rubber stoppers and glass. A positive urine drug test is strongly supportive of the diagnosis, but a negative result does not exclude the possibility of marijuana intoxication. Treatment Treatment is largely supportive by decreasing intestinal absorption (inducing emesis, gastric lavage, or administration of activated charcoal) if the patient is presented to the hospital in an appropriate amount of time. More often, treatment consists of palliative control of clinical signs. Dehydration should be corrected with IV fluids. Hypothermic animals may require active warming. Antiemetics (e.g., maropitant 1 mg/kg SQ q24hr or ondansetron 0.1-0.2 mg/kg IV q8-12hr) should be considered for vomiting patients. Diazepam, quiet and darkened environment, and adequate protection are recommended for agitated patients. Recently, intravenous intralipid therapy has become increasingly common for the treatment of toxicosis from lipophilic toxins. Prognosis The prognosis for recovery is usually very good, barring any secondary complications (e.g., aspiration pneumonia). Clinical signs typically resolve in 2-3 days but may take up to 5 days. Most dogs recover fully without any residual signs.

Answer 11

Metaldehyde intoxication usually occurs following ingestion of molluscicides (e.g., snail & slug bait) containing metaldehyde (fig. 1). The reported lethal dose ranges from 100-360 mg/kg. The mechanism of action is unknown, but it appears to decrease serotonin, GABA, and noradrenaline in the brain. Clinical signs Clinical signs typically develop within three hours of ingestion. Common clinical signs include seizures, tachycardia, ptyalism, tremors, hyperesthesia, CNS depression, hyperthermia, vomiting, and diarrhea. Death may occur soon after ingestion (< 1 day) secondary to metabolic acidosis and respiratory system failure or be delayed (3-4 days) secondary to liver failure. Diagnosis A presumptive diagnosis is typically made following known or suspected exposure and compatible clinical signs. Definitive diagnosis can be made at some diagnostic laboratories by chemical analysis of frozen stomach contents, liver, and urine. Treatment Treatment is largely supportive with GI decontamination (induction of emesis, administration of activated charcoal, gastric lavage), anticonvulsants, methocarbamol (55-220 mg/kg IV; not to exceed 330 mg/kg/day) to control muscle tremors, and IV fluids to control acidosis.

Answer 12

Pyrethrin and pyrethroid poisoning remains a common occurrence in companion animals, especially cats. There is a very wide safety margin for dogs so intoxication is uncommon if used at labeled doses. Most cases occur in cats by well-meaning owners who apply a topical canine flea and tick product to their cat. Pyrethrins are naturally-occurring insecticides that penetrate the nervous system of insects, leading to inability to move or fly away. Pyrethroids are synthetic insecticides (e.g., permethrin) that are more stable and effective at killing insects. These insecticides interfere with sodium ion channels, prolonging sodium conductance, and block postsynaptic GAPA receptor-chloride ionophore complex. Other ingredients are often added to delay metabolism of pyrethroids to prolong the toxic activity and ensure insect killing. Clinical signs include depression, ptyalism, muscle tremors, ataxia, vomiting, diarrhea, and anorexia. Other clinical signs occasionally noted are seizures, hyper- or hypothermia, dyspnea, and contact dermatitis. The video at right shows 3 different patients with varying degree of pyrethrin/permethrin intoxication. Diagnosis A presumptive diagnosis is based on possible exposure with compatible clinical signs. Care must be taken to distinguish this from organophosphate and carbamate intoxication as the clinical signs are similar, but they are treated differently. Treatment There is no antidote for this toxicity. Following dermal exposure, the patient should be bathed in warm water with a mild dish soap (e.g., Dawn) to remove any residue and to prevent additional absorption. For recent oral exposure (less than a few hours), decontamination with activated charcoal is recommended. Intravenous lipid emulsion therapy has been reported to successfully treat patients with permethrin exposure. Muscle tremors should be treated with methocarbamol at 55-220 mg/kg IV (not to exceed 330 mg/kg/day). Seizures can be treated with diazepam CRI at 0.5-2 mg/kg/hr in 0.9% NaCL or 5% dextrose. Prognosis The prognosis for recovery is very good if treated early and aggressively.

Answer 13

A variety of toxins have been reported to cause tremors in dogs and cats (see table), but the mycotoxins Penitrem A and roquefortine, which cause generalized tremors, have been best described. They are produced by Penicillium crustosum and Penicillium roquefortii, respectively, although P. crustosum can produce both toxins concurrently. Common sources include garbage, compost, moldy foods (especially cheese-containing and dairy food products), moldy bread, moldy nuts (e.g., walnuts, peanuts), and contaminated feeds/grains.The mechanism of action is unclear, especially for roquefortine. Penitrem A has several actions, including increased excitatory activity via alteration of resting membrane potentials, end plate potentials, and duration of neuronal depolarization, as well as inhibition of glycine, an inhibitory neurotransmitter. Clinical signs Clinical signs include generalized tremors, seizures, and muscle tremors. Polyuria also has been reported. Neurologic exam Generalized tremors tend to be small amplitude / high frequency in nature (i.e., small, fast tremors) and occur when the patient is moving, but tend to resolve at rest (see video). Affected dogs may display signs of vestibular dysfunction, such as nystagmus, vestibular ataxia, head tilt, absent menace, weakness, and potentially seizures. The tremors are indistinguishable from the tremors seen with Steroid-Responsive Tremor Syndrome. Diagnosis Diagnosis is typically based on compatible clinical clinical signs and exposure risk. Confirmation can be obtained via measurement of penitrem A or roquefortine in biological samples, but testing is generally not necessary as the tremors tend to resolve very quickly (within a few days). Treatment Treatment is largely supportive with GI decontamination, IV fluids, oxygen and ventilatory support, methocarbamol and anticonvulsants. Commonly used medications Induction of emesis Ampomorphoine: 0.03-0.04 mg/kg IV; 0.25 mg/kg into conjunctival sac Hydrogen peroxide: 1 tsp/2.5 kg of 3% hydrogen peroxide GI decontamination Activated charcoal: 1-4 g/kg PO Sorbitol: 1-3 mL/kg 70% Muscle relaxants Methocarbamol: 40-50 mg/kg IV over 3-5 minutes; repeat as necessary or use CRI at 10 mg/kg/hr; maximum daily dose = 330 mg/kg Anticonvulsant options if seizures Diazepam: 0.5-1.0 mg/kg IV bolus; 0.5 mg/kg/hr CRI Phenobarbital: 2-4 mg/kg IV bolus; can load up to 20 mg/kg IV total dose Levetiracetam: 30-60 mg/kg IV loading, then 20 mg/kg IV or PO q8hr Prognosis The prognosis for full recovery is excellent, especially when treated early and aggressively. Clinical signs often resolve within 1-4 days, although long-term signs (e.g., 2-3 months) have been reported.

Answer 14

Overview Metronidazole is commonly used to treat bacterial and protozoal infections in small animals. Mechanism of action The exact mechanism for metronidazole’s neurotoxic effects is unknown; proposed mechanisms include inhibition of neuronal protein synthesis by binding to RNA and thiamine antagonism. Studies in dogs with metronidazole toxicity revealed axonal swelling and degeneration in vestibular nuclei, as well as leucomalacia of the brainstem. The toxic dose is generally stated as >60 mg/kg/day; however, lower dosages have been reported to cause neurotoxicity even after just a few days of administration. Clinical presentation Ataxia and vestibular signs (mostly bilateral), tremors, peripheral neuropathies and seizures are common manifestations of metronidazole toxicity. Vomiting, anorexia, stomatitis and glossitis may also be noted. Diagnosis A history of administration of metronidazole with consistent clinical signs provides supportive evidence of toxicosis. Discontinuation of therapy followed by resolution of clinical signs is also supportive. Management Discontinuation of metronidazole and supportive care are generally all that is necessary for treatment. Diazepam has been reported in dogs to hasten the recovery response times. Treatment with an initial dose of 0.2–0.5 mg/kg IV followed by 0.3–0.5 mg/kg PO q8h for 3 days can be considered in severely affected animals in an effort to promote resolution of clinical signs. Treatment with diazepam is not recommended in cats. Prognosis Metronidazole intoxication generally has an excellent prognosis, with most animals recovering completely within 14 days. Animals with severe CNS signs may take months to recover; however, this is very rare.

Answer 15

Organophosphates and carbamates Overview These toxins are commonly used in agriculture and for domestic garden and household pest use. Additionally, they are used for external parasite control. Pets are generally exposed by ingestion or dermal contact. Mechanism of action OPs and carbamates inhibit the action of AChE, allowing ACh to accumulate at cholinergic synapses. Continued stimulation at cholinergic synapses results in excessive stimulation of the distal neuron, gland or muscle, causing (1) familiar cholinergic signs of muscarinic toxicity, which include salivation, lacrimation, urination and defecation, in addition to bronchospasm, (2) CNS toxicity (depression, decreased level of consciousness and seizuring), and (3) nicotinic toxicity (weakness and muscle tremors). OPs bind tightly to AChE and can become permanently bound, which is known as ‘ageing’ of the AChE. There are three syndromes associated with OP toxicity: * Acute toxicity. * Intermediate syndrome for which the underlying pathology has not been determined. * OP-induced delayed neuropathy (OPIDN), which is a toxin-induced degeneration of the long motor nerves. Carbamates do not become permanently bound and they bind to AChE for a significantly shorter period, generally <40 minutes. Clinical presentation Acute toxicity presents with a combination of muscarinic, nicotinic and CNS signs: * Muscarinic clinical signs include hypersalivation, lacrimation, urination, defecation, diarrhoea, vomiting, miosis, bradycardia, bronchospasm and bronchorrhoea. Respiratory compromise may result in cyanosis. Tachycardia and mydriasis may be present secondary to catecholamine release. * Nicotinic clinical signs include muscle fasciculations, muscle twitches and tremors. Weakness and paralysis can be a delayed NM sign. * Central nervous system signs include anxiety, ataxia, seizures, obtundation and coma. The intermediate syndrome develops 7–96 hours after an acute OP toxicity. Clinical signs of severe NM weakness are present, particularly affecting the cranial half of the body, with cervical ventroflexion, forelimb weakness and hypoventilation reported. Chronic toxicity or exposure can cause OPIDN. This generally occurs 1–4 weeks after exposure to the OP. Anorexia, lethargy, hindlimb paresis, hyperaesthesia and cervical ventroflexion have been reported in cats. Anorexia is an early sign. Diagnosis Known contact with the toxin and appropriate clinical signs are compatible with the diagnosis. Whole blood cholinesterase activity <25% of normal can be diagnostic. Values <50% of normal are suspicious in both acute toxicity and the intermediate syndrome. Reference levels, which are normally measured on heparinized whole blood, are specific to the laboratory. Sample handling and transport should be confirmed with the laboratory. Cholinesterase activity testing can be problematic in carbamate toxicity due to the short half-life of carbamate’s binding to cholinesterase; the cholinesterase activity may normalize during transport. Gastric contents can be tested for the specific toxin in acute ingestions. An atropine response test can be used in suspected cases of acute OP or carbamate toxicity: 0.02 mg/kg atropine is given intravenously; if muscarinic signs resolve and mydriasis and tachycardia develop, then acute OP or carbamate toxicity is not present and no further atropine should be administered. Management Acute toxicity If there is dermal exposure, decontamination is by washing. If the exposure is oral, decontamination is by emesis, lavage and activated charcoal. Atropine is the antidote for muscarinic signs; it has no effect on nicotinic and central signs. If severe or lifethreatening muscarinic signs (cyanosis, bradycardia, bronchial secretions) are present, the use of atropine is indicated. An initial dose of 0.02 mg/kg IV can be administered as an atropine response test if there is any uncertainty about the diagnosis. Rapid resolution of muscarinic signs at this dose of atropine indicates that OP or carbamate toxicity is unlikely. Atropine doses of up to 0.1–0.5 mg/kg can be administered slowly (1/4 slow IV; remainder IM if required) to effect in confirmed cases until cyanosis, dyspnoea, salivation and bradycardia are resolved. For carbamate toxicity lower doses are generally required because of the short half-life of carbamate toxicity and repeated doses of atropine are unlikely to be required. With OP toxicity, higher and repeated doses are frequently required. Atropine frequently causes gut stasis (delaying GI transit times) and this should be taken into account when treating orally ingested OPs and carbamates with minimal muscarinic signs. Pralidoxime (2-PAM) (10–20 mg/kg SC, IM or slow IV up to q8h) acts to reactivate phosphorylated cholinesterase and is indicated for severe nicotinic signs of OP toxicity. Atropine should be co-administered with 2-PAM. 2-PAM has anticholinesterase properties and can cause clinical signs of OP toxicity if used when OP toxicity is not present or when the OP has become permanently bound to AchE and can no longer be dislodged by the 2-PAM. In carbamate toxicity there is a risk that administration of 2-PAM may worsen clinical signs, which is definitely the case with carbaryl toxicity. Diazepam can be administered for seizures. Intermediate syndrome Supportive care, including ventilation when required, should be administered. 2-PAM may be useful if given before permanent ‘ageing’ of AChE occurs; however, there have been anecdotal reports of death of cats in association with use of this drug. Organophosphate-induced delayed neuropathy OPIDN treatment involves removal of the source of the OP and supportive care. Diazepam should not be used as an appetite stimulant in cats suffering from chronic toxicity as it has occasionally been associated with the development of muscle tremors and muscarinic signs. The mechanism for this is unknown. Prognosis The prognosis for acute toxicity is good if the patient survives the initial toxicity. Potential complications include aspiration pneumonia, intussusceptions and the side-effects of heat stroke if severe hyperthermia develops. The prognosis for the intermediate syndrome and OPIDN appears to be good if appropriate supportive care is provided, but weeks of support may be required for OPIDN and ventilation may be required for severe cases of intermediate syndrome.

Answer 16

Overview Sources of excess sodium include table salt (especially when used as an emetic), home-made play dough, paintballs, seawater and iatrogenic sources such as hypertonic saline solutions and sodium phosphate enemas. Mechanism of action An increase in serum sodium creates an increase in plasma osmolality. Water shifts from the interstitium to the vasculature, as well as from the intracellular fluid (ICF) to the ECF to maintain equilibrium. The ECF expands to a state of hypervolaemia, and dehydration of the cells results. The lethal dose of sodium chloride is reported to be 4 g/kg PO, with clinical signs noted at dosages of approximately 1.9 g/kg PO. The level of resulting hypernatraemia seems to be a more accurate way of predicting clinical signs than the amount of sodium chloride ingested, with one study reporting seizures in all animals with serum sodium levels greater than 180 mmol/l (180 mEq/l). Clinical presentation Sodium chloride is a gastric irritant and ingestion of large amounts can lead to acute gastroenteritis and dehydration. Immediate clinical signs may include vomiting, polydipsia and polyuria. Ataxia, tremors, hyperthermia, seizures and death may be seen as a result of ICF shifts. Diagnosis A history of ingestion of sodium chloride-containing products and acute increases in serum sodium are strongly supportive. Management For recent exposure, induction of emesis is recommended. Activated charcoal is likely to be of little benefit and is not recommended. Decreases in serum sodium must be monitored frequently and should not exceed 0.5–1.0 mmol/l/hour (mEq/l/hour). Acute elevations in serum sodium (i.e. within 2–4 hours) may be reduced more quickly than in animals with chronically elevated sodium, as the neurons have not had time to adjust osmolality. In the absence of a known time of ingestion, all hypernatraemic animals should be assumed to have chronic hypernatraemia (see Chapters 2 and 27). Rapid reduction in serum sodium levels can result in cerebral oedema and exacerbation of neurological signs if toxicity is chronic. The deficit of free water is calculated as: Free water deficit (l) = 0.6 × body weight (kg) × (patient’s Na/normal Na –1). The deficit should be replaced over the number of hours calculated to maintain a safe and slow decrease in sodium plasma levels, not to exceed 8–12 mmol/l (mEq/l) in a 24-hour period. 5% Dextrose in water is the fluid of choice for replacement of free water. Intravenous administration of 5% dextrose at up to 3.7 ml/kg/hour, in addition to regular isotonic maintenance fluids, should decrease serum sodium by approximately 1 mmol/l/hour (mEq/l/hour). Serum sodium and other electrolytes should be monitored at least every 4 hours and adjustments to fluid therapy made as needed. Combination with other isotonic fluids (lactated Ringer’s solution, Normosol- R) is usually needed to prevent the sodium from dropping too quickly. If the neurological signs worsen, or sodium levels drop too quickly, free water supplementation should be temporarily discontinued and mannitol administered (0.5–1 g/kg IV) to treat cerebral oedema. Increasing serum sodium concentrations can indicate inadequate decontamination. Repeat gastric lavage, or even surgical removal in extreme cases, has been recommended to remove ongoing sources of sodium. A loop diuretic (furosemide, 1–2 mg/kg IV) can be used to promote sodium excretion; however, it is important not to decrease sodium levels too quickly if this therapy is instituted. Frequent access to small amounts of water may be sufficient to lower serum sodium levels in patients showing no clinical signs and only mild elevations in serum sodium concentration. Animals should not be allowed unlimited access to water at the risk of decreasing sodium too quickly. Symptomatic and supportive care should be given as indicated. Prognosis The prognosis depends on the underlying cause, as well as the degree of hypernatraemia and associated clinical signs. Most animals treated appropriately with slow decreases in serum sodium will fully recover.

Answer 17

North American coral snake venom contains several neurotoxins that cause postsynaptic blockade at the NM junction. Coral snake envenomation results in generalized LMN paralysis. The onset may be rapid or delayed up to 18 hours. The neurological signs are the same as for Australian snakes (see above). In dogs, haemolytic anaemia, haemoglobinuria and elevations in CK also occur.

Answer 18

OP irreversibly binds to AChE and requires denovo AChE synthesis (slow recovery) while carbamate binding is reversible and spontaneously dissociates after 30-40 min OP can produce a **cholinergic and somatic crisis** initially and delayed polyneuropathy, myopathy and CNS impairment (rare)

Answer 19

Pyrethroid binds and blocks sodium channels in open state --> repeated neuronal discharge

Answer 20

Uncouples oxidative phosphorylation in mitochondria 🡪 lack of ATP

Answer 21

Salt toxicity, rapid correct of hypernatremia

Toxicology Flashcards

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