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INTOXICATIONEMERGENCY
Presented by :
Dr. Kanwarpal Singh Dhillon
M.V.Sc (Medicine)
 Acetaminophen Toxicity
 Amitraz Toxi...
IVERMECTIN TOXICITY
DEFINITION/OVERVIEW
Ivermectin and other macrolides, such as selamectin,
dormectin, moxidectin, and milbemycin, are antip...
ETIOLOGY/PATHOPHYSIOLOGY
 Ivermectin and other similarly acting drugs act as GABA
agonists at the neuromuscular junction ...
SIGNALMENT/HISTORY
Genetic Basis :
oAnalysis of the history of the canine mutation shows that
dogs carrying the mutant all...
Signs :
 Toxicity is to the CNS with other systems affected
secondarily.
 Ataxia
 Tremors
 Seizures
 Coma
 Death
Historical Findings :
• Ivermectin toxicity should be considered in a dog belonging to
a susceptible breed with a history ...
CLINICAL FEATURES
Physical Examination :
 Ataxia or recumbency and altered mental state (e.g., depression,
obtundation) a...
DIFFERENTIAL DIAGNOSIS
• Differentiation from other causes of acute onset
neurologic signs is based on a history of exposu...
DIAGNOSTICS
Laboratory :
• Ivermectin and other macrolides can be detected in serum,
gastrointestinal contents, liver, and...
THERAPEUTICS
Drug(s) of Choice :
• There is no specific antidote.
• If the drug has been ingested in the past 2 hours emes...
• Picrotoxin, a GABA antagonist, has also been used to treat
ivermectin toxicity.
• Picrotoxin resulted in a rapid improve...
Supportive Care :
• Patients should receive supportive care as
appropriate for their clinical signs and must be
closely mo...
• Aspiration pneumonia due to a combination of
recumbency and a decreased gag reflex can occur.
• Patients who are unable ...
AMITRAZ TOXICITY
DEFINITION/OVERVIEW
• Amitraz is applied topically to control ticks, mites, and lice.
• Flea and tick collars contain enou...
ETIOLOGY/PATHOPHYSIOLOGY
• Amitraz affects peripheral α1 - and α2 - adrenergic
receptor sites in the cardiovascular system...
SIGNALMENT/HISTORY
• Toxicity in dogs is more commonly reported than in cats or
other species.
• Amitraz should never be u...
CLINICAL FEATURES
• Neurological signs as depression, ataxia, and weakness
• Cardiovascular collapse with bradycardia, rec...
DIFFERENTIAL DIAGNOSIS
• Recreational and prescription drugs such as marijuana,
opioids, barbiturates, benzodiazepines, ph...
DIAGNOSTICS
Complete Blood Count/Biochemistry :
• Hyperglycemia is common.
• Liver enzymes may rarely be elevated.
Imaging...
THERAPEUTICS
Drug(s) of Choice :
• Treatment of amitraz poisoning is best accomplished by
gastric decontamination and admi...
Ingestion of Collar; Asymptomatic Patient :
• Emetic as 3% USP hydrogen peroxide (2.2 m/kg PO
maximum 45 ml after feeding ...
Marked Depression :
• May require pharmacologic reversal of the α 2 - adrenergic
effects
• Yohimbine (Yobine) — 0.11 mg/kg...
CHOCOLATE TOXICITY
DEFINITION/OVERVIEW
• Ingestion of chocolate (methylxanthine alkaloids) in sufficient
quantity to cause gastrointestinal, ...
ETIOLOGY/PATHOPHYSIOLOGY
• Methylxanthine alkaloids – theobromine and caffeine from
the cocoa bean
• Methylxanthines – ade...
Incidence/Prevalence :
• More common during the holiday season due to increased
availability
• Cocoa shell mulch; increasi...
SIGNALMENT/HISTORY
• Dogs — puppies and young dogs more commonly affected
• Cats — rarely
Historical Findings :
• Recent c...
CLINICAL FEATURES
• Tachycardia
• Tachypnea
• Hypertension
• Hyperthermia
• Tachyarrhythmias
• Hyperreflexia
• Muscle trem...
DIFFERENTIAL DIAGNOSIS
• Other toxins: mycotoxins, strychnine, nicotine, pesticides,
organophosphates
• Drugs: amphetamine...
DIAGNOSTICS
• CBC and serum biochemistry: hypokalemia
• Urine specifi c gravity: low
• Stomach content analysis: presence ...
THERAPEUTICS
• The objective is to eliminate the methylxanthine toxin by
decontamination and support of clinical signs.
• ...
Drug(s) of Choice :
Emetics :
• Apomorphine: Dogs 0.02 to 0.04 mg/kg IV; 0.1 mg/kg SQ; 0.25 mg/kg
conjunctival sac; Cats 0...
Ventricular Tachycardia :
• Lidocaine: 1 to 2 mg/kg IV bolus over 30 seconds; 25 to 80 μ g/kg per
min CRI
Muscle Tremors :...
ACETAMINOPHEN TOXICITY
DEFINITION/OVERVIEW
• Acetaminophen (paracetamol) is a common over-the
counter pain medication.
• Acetaminophen possesses ...
ETIOLOGY/PATHOPHYSIOLOGY
• Metabolized by the liver via two pathways:
• The major pathway converts acetaminophen to inacti...
• Under nontoxic conditions, glutathione is conjugated to NAPQI,
which effectively detoxifies it. In toxic conditions, glu...
Systems Affected :
• Hepatobiliary: liver necrosis
• Cardiovascular: facial and
paw edema
• Hemic/lymphatic/immune:
Deplet...
Genetics :
• Toxicity is observed in cats more frequently seen
than dogs due to their smaller body size and
decreased abil...
SIGNALMENT/HISTORY
Species :
• Most frequently cats, less commonly dogs
• No known breed predilections
History :
• Adminis...
Physical Examination Findings :
• Anorexia, salivation, vomiting, abdominal pain
• Hypothermia
• Depression, weakness, com...
DIFFERENTIAL DIAGNOSIS
Other drugs/toxicities causing methemoglobinemia:
• Nitrites
• Phenacetin
• Nitrobenzene
• Phenol a...
DIAGNOSTICS
Complete Blood Count/Biochemistry/Urinalysis :
• Heinz bodies, especially in cats
• Possibly anemia due to lys...
Toxic Dose :
Dogs
• 100 mg/kg is hepatotoxicity
• 200 mg/kg and methemoglobinemia may be seen
Cats
• No safe dose for cats...
THERAPEUTICS
Drug(s) of Choice :
Induction of emesis
• Apomorphine: 0.03 mg/kg to
0.04mg/kg IV, IM, or 1.5 to 6
mg dissol...
• Xylazine: 0.44 to 1.1 mg/kg IM or SQ
• Hydrogen peroxide: 1 to 2 ml/kg PO (max dose of 30 ml). If not
successful in 10 m...
Metabolism of acetaminophen to both toxic and non - toxic by - products. In acetaminophen
toxicity, the conjugation pathwa...
Vitamin C (ascorbic acid)
• 30 mg/kg PO or SQ every 6 hours
• Questionable efficacy
• May cause gastrointestinal upset
C...
Contraindications :
• Drugs that may perpetuate clinical signs
Precautions/Interactions :
• Drugs that are metabolized by ...
RODENTICIDE TOXICITY
DEFINITION/OVERVIEW
• Ingestion of anticoagulant rodenticide compounds results
in a depletion of vitamin K and functional ...
ETIOLOGY/PATHOPHYSIOLOGY
• Vitamin K, a fat-soluble vitamin, is a crucial cofactor for
hepatic posttranslational carboxyla...
Systems Affected :
• Cardiovascular — hemopericardium, subepicardial
hemorrhage
• Gastrointestinal — sublingual or gastric...
Normal coagulation
factor synthesis.
Proteins induced by
vitamin K antagonists or
absence (PIVKAs)
formation in the presen...
SIGNALMENT/HISTORY
No specific signalment, although intact animals may be more likely
to roam and be accidentally or malic...
CLINICAL FEATURES
• Clinical features are similar for dogs and cats.
• Clinically asymptomatic if ingestion occurred < 48 ...
DIFFERENTIAL DIAGNOSIS
• Similar between dogs and cats, with the exception of
variations in inherited coagulation factor d...
DIAGNOSTICS
• Diagnosis is often made with a history, clinical
presentation, or coagulation profile that supports the
diag...
THERAPEUTICS
Treatment depends on timing of ingestion and the urgency of the
clinical presentation.
Drug(s) of Choice :
• ...
• Vitamin K 1 therapy alone is usually sufficient to reverse
the anticoagulant effect in patients with prolonged PT
withou...
Precautions/Interactions :
• Orally administered vitamin K may be insufficiently absorbed if
concomitant intestinal malabs...
Diet :
• Administration of vitamin K 1 with a high fat meal (i.e.,
canned food) improves bioavailability.
Activity :
• Wit...
REFERENCES
• Small Animal Emergency and Critical Care by Elisa M.
Mazzaferro, MS, DVM, PhD, DACVECC (Blackwell’s Five-
Min...
THANKS
Intoxication emergency (amitraz, chocolate, ivermectin, rodenticide, acetaminophen toxicity)
Intoxication emergency (amitraz, chocolate, ivermectin, rodenticide, acetaminophen toxicity)
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Intoxication emergency (amitraz, chocolate, ivermectin, rodenticide, acetaminophen toxicity)

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Intoxication emergency (amitraz, chocolate, ivermectin, rodenticide, acetaminophen toxicity)

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Intoxication emergency (amitraz, chocolate, ivermectin, rodenticide, acetaminophen toxicity)

  1. 1. INTOXICATIONEMERGENCY Presented by : Dr. Kanwarpal Singh Dhillon M.V.Sc (Medicine)  Acetaminophen Toxicity  Amitraz Toxicity  Anticoagulant Rodenticide Toxicity  Chocolate Toxicity  Ivermectin Toxicity
  2. 2. IVERMECTIN TOXICITY
  3. 3. DEFINITION/OVERVIEW Ivermectin and other macrolides, such as selamectin, dormectin, moxidectin, and milbemycin, are antiparasitic drugs that are effective against both external and internalparasites. In general, these drugs are commonly used, are very effective, and have wide margins of safety. Some collie-type breeds have a genetic mutation that causes them to develop neurotoxicity at low doses.  In other breeds toxicity occurs only with severe overdose.
  4. 4. ETIOLOGY/PATHOPHYSIOLOGY  Ivermectin and other similarly acting drugs act as GABA agonists at the neuromuscular junction in the peripheral nervous system of nematode and arthropod parasites.  GABA is an inhibitory neurotransmitter.  In mammals, GABA - containing neurons are limited to the CNS where the blood - brain barrier protects them from exposure to many drugs, including ivermectin.  The multiple drug resistance gene, MDR1, encodes for P - glycoprotein, a principal component of the blood - brain barrier. The mutation, mmdr1 - 1 δ , results in loss of P - glycoprotein function, and thereby allows access to the brain by ivermectin and some other drugs that are also substrates of P - glycoprotein. Dogs with this mutant allele are susceptible to ivermectin toxicity at low doses. Systems Affected : The toxic effect is on the neurologic system; other organ systems are affected indirectly.
  5. 5. SIGNALMENT/HISTORY Genetic Basis : oAnalysis of the history of the canine mutation shows that dogs carrying the mutant allele mmdr1 - 1 δ are descendants of a dog that lived in Great Britain before 1873 o7 Collie-type breeds and 2 Sighthound breeds were identified as carrying this allele. These modern - day breeds are: Collie, Shetland sheepdog, old English sheepdog, McNab cattledog, Australian shepherd, miniature Australian shepherd, and English shepherd. Two other breeds of sighthound type but descended from the common ancestor are silken windhound and longhaired whippet. oIvermectin sensitivity has been reported in border collie, bearded collie, and Australian cattle dog.
  6. 6. Signs :  Toxicity is to the CNS with other systems affected secondarily.  Ataxia  Tremors  Seizures  Coma  Death
  7. 7. Historical Findings : • Ivermectin toxicity should be considered in a dog belonging to a susceptible breed with a history of acute onset of neurologic signs combined with recent exposure to drugs in this group. • In dogs with the mutant allele, doses of ivermectin of 100 to 500 μ g/kg have caused toxicity. • In other breeds, toxicity occurs only with severe overdoses ( > 2000 μ g/kg) usually caused by miscalculation using equine or bovine preparations. The median lethal dose for experimental beagle dogs was 80,000 μ g/kg. • Exposure can also occur from dogs eating feces of treated large animals because the drug is eliminated in the feces. • Young animals are more susceptible to toxicity because their blood - brain barrier is not fully developed. • Toxicity has been reported in kittens at doses of 300 to 400 μ g/kg.
  8. 8. CLINICAL FEATURES Physical Examination :  Ataxia or recumbency and altered mental state (e.g., depression, obtundation) are the primary neurologic signs with stupor, coma, and even death occurring in severely affected dogs.  Those with depressed mentation may also have decreased gag reflex.  Muscle tremors, seizures, and loss of menace and pupillary light response may occur.  Spinal cord reflexes may be normal or increased.  Other signs include bradycardia, mydriasis, miosis, hypersalivation and vomiting.  Clinical signs in dogs can range in severity, even with ingestion/exposure to similar doses.  Onset of signs can be within a few hours after administration of a single dose.  Animals being treated daily may develop signs of toxicity only after several days.
  9. 9. DIFFERENTIAL DIAGNOSIS • Differentiation from other causes of acute onset neurologic signs is based on a history of exposure to the drug in a susceptible canine breed or severe overdose in other animals.
  10. 10. DIAGNOSTICS Laboratory : • Ivermectin and other macrolides can be detected in serum, gastrointestinal contents, liver, and fat but levels in tissues do not correlate with toxicity because it is the concentration of the drug in the brain that determines toxicity. Other : • Reversal of neurologic signs in response to the anticholinesterase physostigmine supports but does not confirm a diagnosis. Its use for this purpose is not recommended because of adverse side effects. • A DNA-based test for the mutant genotype is available and could be used to confirm that a dog is at increased risk of toxicity. Pathological Findings : • No specific lesions are directly caused by these drugs.
  11. 11. THERAPEUTICS Drug(s) of Choice : • There is no specific antidote. • If the drug has been ingested in the past 2 hours emesis should be induced, provided that the patient is alert enough to protect its airway. If the patient is not able to protect its airway, orogastric lavage under general anesthesia with intubation should be performed. • Orogastric lavage should be followed by activated charcoal and a sorbital cathartic. • Repeat doses of activated charcoal are indicated because of the potential for enterohepatic recirculation. • Anticholinesterase drugs have been administered as a diagnostic test or for short - term improvement of clinical signs. Physostigmine may result in partial improvement of signs but the effect lasts less than 1 hour. The potential toxicities of physostigmine are tremors, seizures, ptyalism, lacrimation, urination, and defecation. It does not target ivermectin toxicity directly and is not recommended.
  12. 12. • Picrotoxin, a GABA antagonist, has also been used to treat ivermectin toxicity. • Picrotoxin resulted in a rapid improvement in mental state followed by a seizure. • If treatment for seizures or tremors is required it may be advisable to avoid the use of Benzodiazepines, such as diazepam, because the binding sites for benzodiazepine, GABA, and ivermectin are closely associated. It has been proposed, but not proven that enhancement of the toxic effects might occur. Barbiturates may be preferable because their binding site in the brain is not as closely associated with the ivermectin binding site.
  13. 13. Supportive Care : • Patients should receive supportive care as appropriate for their clinical signs and must be closely monitored. • Deterioration from the initial presenting signs for approximately the next 6 days followed by gradual improvement over the next 6 to 18 days is expected. Longer courses have been reported. • Special attention should be paid to the respiratory and cardiovascular systems because hypoventilation that requires mechanical ventilation and bradycardia that requires treatment with an anticholinergic agent such as glycopyrrolate have been reported.
  14. 14. • Aspiration pneumonia due to a combination of recumbency and a decreased gag reflex can occur. • Patients who are unable to eat and drink normally must receive fluid and electrolyte therapy and nutritional support. Oral intake of food or water should not be attempted in patients with altered mental states because they may have decreased gag reflexes and be unable to properly protect their airway. In these patients, nasogastric or gastric tube feeding is preferred but intravenous nutrition may be preferred. • Severely affected patients are recumbent and meticulous care for the recumbent patient is needed. Prognosis : • The prognosis for recovery without long - term sequelae is good even in severely affected patients provided that aggressive intensive care support is administered.
  15. 15. AMITRAZ TOXICITY
  16. 16. DEFINITION/OVERVIEW • Amitraz is applied topically to control ticks, mites, and lice. • Flea and tick collars contain enough amitraz to cause clinical signs of intoxication in a twenty-five - pound dog.
  17. 17. ETIOLOGY/PATHOPHYSIOLOGY • Amitraz affects peripheral α1 - and α2 - adrenergic receptor sites in the cardiovascular system and α 2 - adrenergic receptor sites in the CNS, thus it is a α 2 - adrenergic agonist. • Toxic exposure can occur either through the oral or dermal route. • After high dose, oral ingestion peak plasma concentration is reached at 6 hours and elimination half - life is as long as 24 hours. • The metabolites are excreted in the urine.
  18. 18. SIGNALMENT/HISTORY • Toxicity in dogs is more commonly reported than in cats or other species. • Amitraz should never be used in cats. Risk Factors/Causes : • Increased predilection for toxicity in geriatric, sick, or toy breed animals. Historical Findings : • Signs of sudden collapse, depression, vomiting, and diarrhea.
  19. 19. CLINICAL FEATURES • Neurological signs as depression, ataxia, and weakness • Cardiovascular collapse with bradycardia, recumbency, and hypotension • Gastrointestinal signs of vomiting, diarrhea, and abdominal pain
  20. 20. DIFFERENTIAL DIAGNOSIS • Recreational and prescription drugs such as marijuana, opioids, barbiturates, benzodiazepines, phenothiazines, antihypertensive drugs, skeletal muscle relaxants, and other depressive drugs • Ivermectin or milbemycin in very high doses to sensitive breeds • Alcohols such as ethanol, ethylene glycol (antifreeze), methanol (wind shield washer fluid), isopropyl alcohol (rubbing alcohol) • Tick paralysis, botulism • Head trauma • Cardiovascular collapse
  21. 21. DIAGNOSTICS Complete Blood Count/Biochemistry : • Hyperglycemia is common. • Liver enzymes may rarely be elevated. Imaging : • Abdominal radiology may reveal a collar buckle in the gastrointestinal tract. Pathological Findings : • High - dose and prolonged exposure shows increased liver weight; slight enlargement of hepatocytes; thinning of the zonae fasciculata and reticularis; slight hyperplasia of the zona glomerulosa of the adrenal glands
  22. 22. THERAPEUTICS Drug(s) of Choice : • Treatment of amitraz poisoning is best accomplished by gastric decontamination and administration of antidotes (yohimbine or atipamezole). Precautions/Interactions : • Do not administer atropine, even if bradycardia occurs. Atropine may relieve some clinical signs, however may cause other clinical signs to worsen, and may contribute to hypertension. • Do not induce emesis if the toxic substance was Mitaban ® dip, due to risk of aspiration pneumonia.
  23. 23. Ingestion of Collar; Asymptomatic Patient : • Emetic as 3% USP hydrogen peroxide (2.2 m/kg PO maximum 45 ml after feeding a moist meal); apomorphine, and especially xylazine, not recommended • Endoscopic retrieval of collar if large segments within the stomach; usually numerous small pieces are located throughout the gastrointestinal tract, making endoscopic removal difficult or unrealistic. • Surgical removal of collar from gastrointestinal tract • Activated charcoal (2 g/kg PO) containing sorbitol
  24. 24. Marked Depression : • May require pharmacologic reversal of the α 2 - adrenergic effects • Yohimbine (Yobine) — 0.11 mg/kg IV, administered slowly; reverses depression and bradycardia within minutes; objective is to keep the patient in a state of low – level depression with normal heart rate, blood pressure, body temperature, and blood glucose concentrations • Collar ingestions — monitor for recurrence of clinical signs; may need additional yohimbine until collar segments appear in the stool • Atipamezole (Antisedan) — 0.05 mg/kg IM; reported to reverse poisoning within 10 minutes; repeated as needed; can be used an alternative when yohimbine is unavailable • Yohimbine and atipamezole may require initial repeated administration every 4 to 8 hours because half - life in dogs is short and elimination half - life of amitraz is longer.
  25. 25. CHOCOLATE TOXICITY
  26. 26. DEFINITION/OVERVIEW • Ingestion of chocolate (methylxanthine alkaloids) in sufficient quantity to cause gastrointestinal, neurologic, and cardiac abnormalities
  27. 27. ETIOLOGY/PATHOPHYSIOLOGY • Methylxanthine alkaloids – theobromine and caffeine from the cocoa bean • Methylxanthines – adenosine receptor antagonist in the CNS; causing stimulation and cerebral vasoconstriction; direct myocardial stimulator — tachycardia; increased calcium entry into the sarcoplasmic reticulum — increased skeletal and myocardial contractility • Caffeine — phosphodiesterase inhibitor; increased cAMP and the release of catecholamines • Theobrominine — undergoes enterohepatic recirculation • Theobromine and caffeine LD50 = 100 to 200 mg/kg, however, clinical signs can be seen as low as 20 mg/kg
  28. 28. Incidence/Prevalence : • More common during the holiday season due to increased availability • Cocoa shell mulch; increasing in popularity for landscaping Systems Affected : • Gastrointestinal — vomiting and diarrhea • Urologic — polyuria, polydipsia • Nervous — hyperactivity, CNS stimulation, seizures • Musculoskeletal — tremors, hyperreflexia • Cardiovascular — tachycardia, increased myocardial contractility
  29. 29. SIGNALMENT/HISTORY • Dogs — puppies and young dogs more commonly affected • Cats — rarely Historical Findings : • Recent chocolate ingestion reported • Gastrointestinal signs; vomiting and diarrhea (2 – 4 hours) • Polyuria/polydipsia • Hyperactivity and anxiety • Neurologic signs — tremors, seizures
  30. 30. CLINICAL FEATURES • Tachycardia • Tachypnea • Hypertension • Hyperthermia • Tachyarrhythmias • Hyperreflexia • Muscle tremors • Ataxia • Seizures • Coma/death
  31. 31. DIFFERENTIAL DIAGNOSIS • Other toxins: mycotoxins, strychnine, nicotine, pesticides, organophosphates • Drugs: amphetamines, digitalis • Seizure disorder • Electrolyte/metabolic abnormality; hypomagnesemia and hypocalcemia
  32. 32. DIAGNOSTICS • CBC and serum biochemistry: hypokalemia • Urine specifi c gravity: low • Stomach content analysis: presence of chocolate and methylxanthine • Plasma, serum, and urine: theobromine levels
  33. 33. THERAPEUTICS • The objective is to eliminate the methylxanthine toxin by decontamination and support of clinical signs. • Induce emesis if alert • Orogastric lavage • Activated charcoal • Intravenous fluid diuresis: intravenous crystalloid fluids; high rates as tolerated by the patient • Urinary catheter; theobromine is reabsorbed in the bladder
  34. 34. Drug(s) of Choice : Emetics : • Apomorphine: Dogs 0.02 to 0.04 mg/kg IV; 0.1 mg/kg SQ; 0.25 mg/kg conjunctival sac; Cats 0.04 mg/kg IV; 0.08 mg/kg IM or SQ • Hydrogen peroxide: 1 to 5 ml/kg PO • Xylazine : Dogs 0.2 mg/kg IV; 0.5 to 1 mg/kg IM or SQ; Cats 0.44 mg/kg IM Toxin Binding : • Activated charcoal: 2 to 8 g/kg PO every 6 to 8 hours Seizures : • Diazepam: Dogs 0.5 to 2 mg/kg IV; Cats 0.5 to 1 mg/kg IV
  35. 35. Ventricular Tachycardia : • Lidocaine: 1 to 2 mg/kg IV bolus over 30 seconds; 25 to 80 μ g/kg per min CRI Muscle Tremors : • Methocarbamol: 44 mg/kg IV; administer half slowly until relaxation and continue to effect Precautions/Interactions : • Do not induce vomiting if obtunded, having seizures, or otherwise unable to protect airway • Cats: Lidocaine use caution; apomorphine is controversial; diazepam may induce liver failure • Avoid corticosteroids and erythromycin; reduced methylxanthine excretion • Methylxanthines are excreted in milk and cross the placenta
  36. 36. ACETAMINOPHEN TOXICITY
  37. 37. DEFINITION/OVERVIEW • Acetaminophen (paracetamol) is a common over-the counter pain medication. • Acetaminophen possesses antipyretic and analgesic properties similar to NSAIDs, although it does not have any anti-infl ammatory properties. • Acetaminophen is found in over two hundred over-the- counter and prescription medications.
  38. 38. ETIOLOGY/PATHOPHYSIOLOGY • Metabolized by the liver via two pathways: • The major pathway converts acetaminophen to inactive metabolites through conjugation to inactive glucuronide and sulfate metabolites. • The minor pathway metabolizes acetaminophen by the p - 450 mixed function oxidase to a highly reactive toxic metabolite, NAPQI. (N - acetyl - para – benzoquinoneimine) • Under normal circumstances this minor route produces little NAPQI, but in the event of acetaminophen toxicity, the glucuronidation pathway becomes saturated and metabolism shifts to the production of NAPQI
  39. 39. • Under nontoxic conditions, glutathione is conjugated to NAPQI, which effectively detoxifies it. In toxic conditions, glutathione stores quickly become depleted, leaving NAPQI free to bind to lipid in the hepatocyte membrane and causing hepatocellular necrosis. • NAPQI also causes severe oxidative damage to red blood cells by causing the oxidation of hemoglobin to metHb, a compound that does not carry oxygen. Oxidation of hemoglobin also causes the formation of Heinz bodies. • Cats lack glucuronyl transferase, which decreases the amount of metabolism through the major pathway. • In cats, relatively smaller amounts of acetaminophen will produce more toxic metabolite and therefore cause more severe toxicity compared to dogs. • Feline hemoglobin is also unique and contains eight sulfhydryl groups. Because of this unique property, feline hemoglobin is more sensitive to oxidation and can form metHb more rapidly with smaller amounts of acetaminophen. • In cats, methemoglobinemia may happen rapidly and become fatal before they show signs of hepatotoxicosis.
  40. 40. Systems Affected : • Hepatobiliary: liver necrosis • Cardiovascular: facial and paw edema • Hemic/lymphatic/immune: Depletion of glutathione causes oxidative damage to red blood cells and converts hemoglobin to metHb Facial edema may be seen in dogs, but it is more commonly seen in cats with acetaminophen toxicity.
  41. 41. Genetics : • Toxicity is observed in cats more frequently seen than dogs due to their smaller body size and decreased ability to glucoronidate and eliminate acetaminophen. Incidence/Prevalence : • Most common drug toxicity in cats • Less common in dogs
  42. 42. SIGNALMENT/HISTORY Species : • Most frequently cats, less commonly dogs • No known breed predilections History : • Administration of acetaminophen or history of ingestion of acetaminophen. Owners may not be aware that acetaminophen has potentially life - threatening effects in dogs and cats. • Owners may notice clinical signs within 1 to 4 hours after ingestion or signs may be delayed until after metHb or hepatotoxicity occurs.
  43. 43. Physical Examination Findings : • Anorexia, salivation, vomiting, abdominal pain • Hypothermia • Depression, weakness, coma in severe cases • Methemoglobinemia • Brown or cyanotic mucous membranes • Tachypnea • Respiratory difficulty/distress • Dark, chocolate - colored blood and urine • Edema of the face and paws (most commonly in cats, observed more rarely in dogs) • Death Risk Factors/Causes : • Acetaminophen overdose
  44. 44. DIFFERENTIAL DIAGNOSIS Other drugs/toxicities causing methemoglobinemia: • Nitrites • Phenacetin • Nitrobenzene • Phenol and cresol compounds • Sulfites • Naphthalene • Resorcinol in cats • Pyridium • Local anesthetics • Garlic or onions
  45. 45. DIAGNOSTICS Complete Blood Count/Biochemistry/Urinalysis : • Heinz bodies, especially in cats • Possibly anemia due to lysis of affected red blood cells • Elevated ALT, Alk Phos • Liver values may increase 24 to 36 hours post - ingestion. • Elevated total and direct bilirubin • Serum may be icteric • Large doses may be nephrotoxic; may see increases in BUN and creatinine • May see orange or dark colored urine with hemoglobinuria or methemoglobinuria
  46. 46. Toxic Dose : Dogs • 100 mg/kg is hepatotoxicity • 200 mg/kg and methemoglobinemia may be seen Cats • No safe dose for cats; 10 mg/kg has produced toxic signs, although generally not seen until 30 to 40 mg/kg. Cats generally show severe signs of methemoglobinemia rather than hepatotoxicosis.
  47. 47. THERAPEUTICS Drug(s) of Choice : Induction of emesis • Apomorphine: 0.03 mg/kg to 0.04mg/kg IV, IM, or 1.5 to 6 mg dissolved in the conjunctival sac Vomitus containing Tylenol PM that contains acetaminophen.
  48. 48. • Xylazine: 0.44 to 1.1 mg/kg IM or SQ • Hydrogen peroxide: 1 to 2 ml/kg PO (max dose of 30 ml). If not successful in 10 minutes give another dose once.  Gastric lavage • If emesis is unsuccessful or contraindicated (if animal is neurologically inappropriate or has decreased gag reflex) Activated charcoal • Repeat every 3 to 4 hours; acetaminophen undergoes enterohepatic recirculation • 2 to 5 g/kg N - acetylcysteine (Mucomyst) • 140 mg/kg PO or IV loading dose • 70 mg/kg PO or IV every 6 hours for seven treatments • Consider giving 240 mg/kg PO or IV as a loading dose in severe cases • Activated charcoal inactivates N - acetylcysteine if it is given PO. Wait at least 30 to 60 minutes between treatments • Provides sulfhydryl source to bind NAPQI, and thus protects hepatocytes and red blood cells.
  49. 49. Metabolism of acetaminophen to both toxic and non - toxic by - products. In acetaminophen toxicity, the conjugation pathways become saturated and lead to increased p450 metabolism to N - acetyl - parabenzoquinoneimine (NAPQI), the toxic metabolite. Toxicity also leads to glutathione depletion which perpetuates hepatic damage and also contributes to oxidative damage of red blood cells. N - acetylcysteine helps get rid of NAPQI through conjugation to nontoxic by - product.
  50. 50. Vitamin C (ascorbic acid) • 30 mg/kg PO or SQ every 6 hours • Questionable efficacy • May cause gastrointestinal upset Cimetidine • 5 to 10mg/kg every 6 to 8 hours IV, IM • Reduces metabolism of acetaminophen by the cytochrome p - 450 oxidative system in the liver • Use as adjunct to N - acetylcysteine Supportive therapy • Intravenous fluids • ± O2 therapy • ± Packed red blood cells or whole blood if necessary • Feed cats kitten food due to increased sulfhydryl group substrates S - adenosyl methionine (sAMe; denosyl) • 18 mg/kg PO every 24 hours on an empty stomach • Chronic treatment until liver enzymes are within normal limits
  51. 51. Contraindications : • Drugs that may perpetuate clinical signs Precautions/Interactions : • Drugs that are metabolized by the liver may have prolonged half - lives; drugs that are biotransformed by the liver may be less effective. Activity : • Activity should be restricted. Appropriate Health Care : • Evaluate immediately when presented with brown or cyanotic mucous membranes, Nursing Care : • Gentle handling is imperative for clinically affected animals. It is important to minimize stress as much as possible, especially in cats. • Animals presenting in respiratory distress may require immediate oxygen supplementation.
  52. 52. RODENTICIDE TOXICITY
  53. 53. DEFINITION/OVERVIEW • Ingestion of anticoagulant rodenticide compounds results in a depletion of vitamin K and functional vitamin K - dependent coagulation factors and causes an acquired coagulopathy.
  54. 54. ETIOLOGY/PATHOPHYSIOLOGY • Vitamin K, a fat-soluble vitamin, is a crucial cofactor for hepatic posttranslational carboxylation of coagulation factors II, VII, IX, and X (and protein C and protein S) • Anticoagulant rodenticide ingestion inhibits the hepatic enzyme, vitamin K epoxide reductase, and prevents the recycling of the vitamin K metabolite, vitamin K epoxide, back to its functional form • Once hepatic vitamin K stores are depleted, production of functional vitamin K-dependent coagulation proteins ceases and causes the formation of PIVKAs (proteins induced by vitamin K antagonists or absence) • PIVKAs are incapable of chelating calcium and therefore are unable to successfully partake in secondary hemostasis.
  55. 55. Systems Affected : • Cardiovascular — hemopericardium, subepicardial hemorrhage • Gastrointestinal — sublingual or gastric hemorrhage, hemoabdomen • Hemic/Lymphatic/Immune — active coagulation factor deficiency, anemia, hypoproteinemia • Musculoskeletal — hemarthrosis, lameness • Nervous — intracranial hemorrhage, seizures, paresis, paralysis • Respiratory — hemothorax, parenchymal hemorrhage • Skin/Exocrine — SQ hemorrhage
  56. 56. Normal coagulation factor synthesis. Proteins induced by vitamin K antagonists or absence (PIVKAs) formation in the presence of an anticoagulant rodenticide.
  57. 57. SIGNALMENT/HISTORY No specific signalment, although intact animals may be more likely to roam and be accidentally or maliciously exposed to toxins. Risk Factors/Causes : • The presence of vitamin K antagonist rodenticides in the immediate environment. Historical Findings : • May reveal possible exposure to or ingestion of anticoagulant rodenticides • Ingestion of an animal that consumed anticoagulant rodenticide (relay toxicosis) • Vomit or feces with green - or turquoise - colored granules in it • Respiratory difficulty or hemorrhage
  58. 58. CLINICAL FEATURES • Clinical features are similar for dogs and cats. • Clinically asymptomatic if ingestion occurred < 48 hours previously. • Clinical signs associated with deep tissue hemorrhage (hemoptysis, hemothorax, hemoabdomen, hemarthrosis, intracranial, pericardial, sublingual or subcutaneous hemorrhage) most frequently develop between 2 and 6 days following consumption. • In the acutely bleeding patient, hypoproteinemia will generally develop prior to the anemia; anemia may develop simultaneously or before hypoproteinemia in the face of slow and sustained hemorrhage.
  59. 59. DIFFERENTIAL DIAGNOSIS • Similar between dogs and cats, with the exception of variations in inherited coagulation factor deficiencies • Hepatic failure • Disseminated intravascular coagulation • Dilutional coagulopathy • Congenital factor deficiency • Massive heparin overdose • Absolute vitamin K deficiency (malnourished patients receiving broad – spectrum antibiotic therapy, posthepatic biliary obstruction, or exocrine pancreatic insufficiency or intestinal malabsorption)
  60. 60. DIAGNOSTICS • Diagnosis is often made with a history, clinical presentation, or coagulation profile that supports the diagnosis, all in the face of a rapid response to vitamin K 1 therapy. Pathological Findings : • Presence of nonclotting blood found on aspiration of body cavity or swelling. • Hemorrhage in the airways; uncommonly hemorrhage from mucosal surfaces
  61. 61. THERAPEUTICS Treatment depends on timing of ingestion and the urgency of the clinical presentation. Drug(s) of Choice : • Emesis is induced if ingestion occurred within previous 2 hours. • Activated charcoal administration is ideal if ingestion occurred within previous 2 hours; this however may delay efficacy of orally administered vitamin K 1. • Vitamin K 1 : 2.5 to 5 mg/kg per day PO for up to 6 weeks (dependent on agent ingested) is indicated for all patients with confirmed or even suspected ingestion; oral administration is generally more rapidly effective ( < 12 hours) than SQ (12 – 24 hours) and safer than intravenous dosing (risk of anaphylaxis).
  62. 62. • Vitamin K 1 therapy alone is usually sufficient to reverse the anticoagulant effect in patients with prolonged PT without hemorrhage. • In more urgent cases (i.e., presence of hemorrhage) plasma (fresh frozen or frozen) 10 to 15 ml/kg or whole blood (fresh or stored) up to 20 ml/kg are administered, concurrently with oral or SQ vitamin K 1 to promptly (although temporarily) reverse anticoagulation. • Cautious intravenous fluid administration to reverse shock, while minimizing exacerbation of further hemorrhage with unnecessary or excessive increases in blood pressure. • Oxygen therapy if hypoxemia is present or in an attempt to ease respiratory distress; avoid nasal oxygen cannulation due to risk of inducing hemorrhage/epistaxis.
  63. 63. Precautions/Interactions : • Orally administered vitamin K may be insufficiently absorbed if concomitant intestinal malabsorption or extrahepatic biliary obstruction is present; hepatic dysfunction tempers the response to vitamin K 1 therapy. • Allergic reactions (i.e., urticaria, angioneurotic edema) may occur with SQ vitamin K 1 therapy, whereas anaphylaxis is a concern with intravenous administration. • Vitamin K 1 administered IM may result in hematoma formation and therefore is contraindicated. • Small - gauge needles should be used for SQ administration of vitamin K 1 (or any other parenteral medications) in several different sites to expedite absorption. • Gastroenteric lavage is not indicated due to rapidly reversible nature of toxicity. Alternative Drugs : • Oxyglobin ® may be utilized to temporarily improve oxygen - carrying capacity if blood products are not readily available, providing time for vitamin K1 therapy to become effective.
  64. 64. Diet : • Administration of vitamin K 1 with a high fat meal (i.e., canned food) improves bioavailability. Activity : • With complicated toxicity, activity should be limited to avoid exacerbation of hemorrhage. Surgical Considerations : • Thoracocentesis may be indicated if the development of a hemothorax sufficiently compromises respiration. • Preferably avoid unnecessary procedures until coagulation ability has normalized.
  65. 65. REFERENCES • Small Animal Emergency and Critical Care by Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC (Blackwell’s Five- Minute Veterinary Consult)
  66. 66. THANKS

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