Lecture 16 - Acetaminophen Toxicosis Flashcards
Each week, about ___% of American adults use a medicine
containing acetaminophen
23
Acetaminophen is an ______ and ______
derivative of ?
analgesic and antipyretic
derivative of N-acetyl-p-aminophenol (APAP)
Acetaminophne is Present in > 200 prescription and over-the- counter (OTC) formulations for ?
fever, pain, sinus, cold and flu
Acetaminophen is used as an _________ and __________ drug but has little ________ action.
When dealing with potential exposure to acetaminophen, it is important to
verify the exact _________ in a product, because many medications have ____ drugs.
Additionally, many of the other ingredients found in combination products
(e.g., ?) may also contribute to the toxicosis and their adverse effects need to be addressed.
Acetaminophen is used as an analgesic and antipyretic drug but has little anti-
inflammatory action.
When dealing with potential exposure to acetaminophen, it is important to
verify the exact ingredients in a product, because many medications have
nonsteroidal anti-inflammatory drugs.
Additionally, many of the other ingredients found in combination products
(e.g., antihistamines, decongestants) may also contribute to the toxicosis and
their adverse effects need to be addressed.
Acetaminophen is not commonly used in dogs and cats because of its ___ safety margin
However, out of all the drug toxicoses, this is the most common one in which species?
low
– The most common drug toxicosis in cats
Most Acetaminophen toxicoses result from?
Other times?
well-meaning but
ill-informed admin. of acetaminophen-
containing medications to cats by owners
Accidental ingestion of owner’s medications
(esp. in dogs)
Acetaminophen is contraindicated in ______. _______ are possibly as sensitive as cats.
cats, Ferrets
What is the ADME of Acetaminophen toxicosis?
- Most poisonings result from ____ exposure
- Acetaminophen undergoes ___ and almost complete _____ tract absorption
– Peak plasma concentration in ___-___ min - ______ protein binding and ____ distribution
- Metabolized in the ___, some in the _______
- Excreted primarily in _____, some in ___
Elimination t½ in cats increases with ____
- Most poisonings result from oral exposure
- Acetaminophen undergoes rapid and almost complete GI tract absorption
– Peak plasma concentration in 10-60 min - Poor protein binding and wide distribution
- Metabolized in the liver, some in the kidney
- Excreted primarily in urine, some in bile
Elimination t½ in cats increases with dose
How is acetaminophen metabolized in the liver?
1. Glucuronidation: ____-dependent, ___ in cats
2. Sulfation: dose-dependent in both ___ and ____. Main pathway in ___
• Glucuronidation and sulfation pathways are _______ limited. The higher the dose, the _______ it takes for the biotransformation process to occur.
3. Cytochrome P450: 5-10% APAP metabolized to _____, a toxic electrophile but is conjugated by ?
Acetaminophen is also deacetylated to ____ by carboxylesterases, which causes oxidative damage to _____ _____ cells resulting in methemoglobinemia.
* Cats and dogs are deficient in ____-_______ (enzyme that converts PAP back to acetaminophen) –> buildup of ___ levels of PAP –> methemoglobinemia
• Acetaminophen is also deacetylated to p-
aminophenol (PAP) by carboxylesterases
– PAP causes oxidative damage to red blood
cells resulting in methemoglobinemia
• Cats and dogs are deficient in N-
acetyltransferase (enzyme that converts
PAP back to acetaminophen) –> buildup of
high levels of PAP –> methemoglobinemia
- What is the main metabolic pathway in dogs, but cats are deficient in?
- What is the main pathway in cats?
- Which is the toxic pathway?
- What are the toxic metabolites produced as a result of each pathway?
- The first pathway is glucuronidation and it results in the formation of glucuronides that are non-toxic. It is the main pathway in dogs, but it is deficient in cats.
- The second pathway is sulfation which is used by both dogs and cats. It is the main pathway in cats and results in the formation of sulfates which are non-toxic.
- CYP450 is the other pathway, and it results in the formation of a reactive metabolite known as N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is initially conjugated by GSH to form mercapturic acid which is non-
toxic but when in excess it binds to cellular macromolecules resulting in toxicity.
Metabolism by both glucuronidation and sulf pathways is dose dependent and
capacity-limited, more dose enters the p450 pathway, gsh is depleted, synthesis
of gsh suppressed by high conc. of acetaminophen leading to elevated napqi
What is the MOT of acetaminophen toxicosis?
• Toxicity occurs when _________ pathways
and ______ scavenging capacity are exceeded
resulting in accumulation of ________.
– _______ depletes GSH and decreases GSH
production –> ^ susceptibility to ______ ____
– _______ covalently binds to _______-containing proteins esp. in mitochondria –> decreased ___ –> cell _____ (primarily in the liver)
– Other NAPQI targets include ?
- NAPQI and PAP oxidize hemoglobin to _________ –> ____ _____ formation –> ^ fragility and decreased survival time of ____ –>
________ anemia and cyanosis - Oxidative hepatic damage predominates in ____
- Erythrocyte injury predominates in ____
- NAPQI and PAP oxidize hemoglobin to
methemoglobin –> Heinz body formation –> ^ fragility and
decreased survival time of RBC –>
hemolytic anemia and cyanosis - Oxidative hepatic damage predominates in dogs
- Erythrocyte injury predominates in cats
What are the confounding factors of acetaminophen toxicosis?
• Fasting/starvation: depletes _____ –> ^toxicity
• Barbiturates: induce _______ –> ^ _____
formation –> ^toxicity
• Cimetidine: inhibits ______ –> decreases ____ formation –> decreases toxicity
• Young animals are more ________ due to
immaturity of enzyme systems and more _____ GSH synthesis
See below
Why Are Cats Highly Susceptible to acetaminophen toxicosis?
- Cats have _____ threshold for dose-dependent biotransformation
* Cats are deficient in ________
– Low levels of the high affinity ?
* Capacity of the sulfation pathway is ___
– Dose-dependency of biotransformation occurs at lower doses in cats compared with dogs - Cats’ hemoglobin is more susceptible to _______: it has __ reactive sulfhydryl groups per Hb tetramer compared with __ in
dogs and __ in humans - Cats have lower levels of methemoglobin
reductase –> _______ and more prominent _________ - ________ ______ in wet food (banned in cat
food) contributes to increased sensitivity of
cats’ RBCs (formation of Heinz bodies)
- Cats have low threshold for dose-dependent
biotransformation
* Cats are deficient in glucuronidation
– Low levels of the high affinity acetaminophen-
uridine diphosphate glucuronosyltransferase
* Capacity of the sulfation pathway is low
– Dose-dependency of biotransformation occurs
at lower doses in cats compared with dogs - Cats’ hemoglobin is more susceptible to
oxidation: it has 8 reactive sulfhydryl
groups per Hb tetramer compared with 4 in
dogs and 2 in humans - Cats have lower levels of methemoglobin
reductase earlier and more prominent
methemoglobinemia - Propylene glycol in wet food (banned in cat
food) contributes to increased sensitivity of
cats’ RBCs (formation of Heinz bodies)
List the clinical signs of acetaminophen toxicosis in dogs?
- Signs appear ____ hr after exposure and most commonly reflect _______ injury with ________ necrosis.
– Nausea, vomiting, abdominal pain, depression, anorexia, chemosis, shock, elevated liver enzymes (ALT, AST), icterus - Methemoglobinemia occurs at _______ doses
– Hemoglobinuria, hematuria, anemia, hemolysis, cyanosis, lethargy, tachypnea, recumbency - Facial & paw _____ are commonly reported
- Signs appear 36h after exposure and most
commonly reflect hepatic injury with
centrilobular necrosis
– Nausea, vomiting, abdominal pain, depression,
anorexia, chemosis, shock, elevated liver
enzymes (ALT, AST), icterus - Methemoglobinemia occurs at higher doses
– Hemoglobinuria, hematuria, anemia, hemolysis,
cyanosis, lethargy, tachypnea, recumbency - Facial & paw edema are commonly reported
What are the clinical signs of acetaminophen toxicosis in cats?
- Appear ___-___h after exposure
- Prominent _____________
- Anorexia, vomiting, salivation, diarrhea,
depression, weakness, tachycardia, dyspnea,
cyanosis, facial and paw edema, anemia,
hematuria, icterus, Heinz bodies and
methemoglobinuria - Signs of hepatotoxicity are seen at high doses mostly in ____ cats
- Appear 1-2h after exposure
- Prominent methemoglobinemia
- Anorexia, vomiting, salivation, diarrhea,
depression, weakness, tachycardia, dyspnea,
cyanosis, facial and paw edema, anemia,
hematuria, icterus, Heinz bodies and
methemoglobinuria - Signs of hepatotoxicity are seen at high doses mostly in male cats
Acetaminophen Poisoning
Facial & paw edema –> Possibly due to vascular endothelial damage
Acetaminophen Poisoning
Methemoglobinuria
