This document discusses acetaminophen, including its metabolism, toxicity in cats and dogs, clinical signs of toxicity, and treatment. It notes that cats are more sensitive due to a deficiency in an enzyme that metabolizes acetaminophen. Toxicity can occur at 10-40 mg/kg in cats. Treatment involves decontamination, N-acetylcysteine to reduce toxicity and support liver function, and monitoring for methemoglobinemia or liver damage.

1. AcetaminophenAcetaminophen is a synthetic nonopiate derivative of p-aminophenol widely used in humans for its antipyretic and analgesic properties. Its use has largely replaced salicylatesdue to the reduced risk of gastric ulceration.Acetaminophen is rapidly absorbed from the GI tract. Peak plasma concentrations are usually seen within an hour, but can be delayed with extended-release formulations.It is uniformly distributed into most body tissues. Protein binding varies from 5-20%.The metabolism of acetaminophen involves 2 major conjugation pathways in most species. Both involve cytochrome P-450 metabolism, followed by glucuronidationor sulfation.

2. AcetaminophenCats are more sensitive to acetaminophen toxicosis because they are deficient in glucuronyltransferase and therefore have limited capacity to glucuronidate this drug.In cats, acetaminophen is primarily metabolized via sulfation; when this pathway is saturated, toxic metabolites are produced. In dogs, signs of acute toxicity are usually not observed unless the dosage of acetaminophen exceeds 100 mg/kg. Clinical signs of methemoglobinemiahave been reported in 3 out of 4 dogs at 200 mglkg. Toxicity can be seen at lower dosages with repeated exposures. In cats, toxicity can occur with 10-40 mg/kg.

3. AcetaminophenMethemoglobinemia and hepatotoxicity characterize acetaminophen toxicosis.Renal injury is also possible. Cats primarily develop methemoglobinemia within a few hours, followed by Heinz body formation. Methemoglobinemia makes mucous membranes brown or muddy in color, and is usually accompanied by tachycardia hyperpnea, weakness, and lethargy.

4. AcetaminophenOther clinical signs of acetaminophen toxicity include depression, weakness, hyperventilation, icterus, vomiting, hypothermia, facial or paw edema, cyanosis, dyspnea, hepatic necrosis, and death. Liver necrosis is more common in dogs than in cats. Liver damage in dogs is usually seen 24-36 hr after ingestion. Centrilobular necrosis is the most common form of hepatic necrosis seen with acetaminophen toxicity.

5. Treatment (NSAIDs)Treatment of NSAID toxicosis consists of early decontamination, protection of the GI tract and kidneys, and supportive care. Vomiting should be induced in recent exposures, followed by administration of activated charcoal with a cathartic. Activated charcoal can be repeated in 6-8 hr to prevent NSAID reabsorption from enterohepatic recirculation.Use of H2-receptor antagonists (ranitidine, famotidine, cimetidine) may not prevent GI ulcers but can be useful in treating them. Omeprazole, which is a proton pump inhibitor used for inhibiting gastric acid secretions, can be used instead of an H2-blocker at

6. Treatment0.5-1.0 mg/kg, PO, sid, in dogs. Sucralfate (dog: 0.5-1 g, PO, bid-tid; cat: 0.25-0.5 tablet, PO, bid-tid) reacts with hydrochloric acid in the stomach and forms a paste-like complex that binds to the proteins in ulcers and protects them from further damage. Becausesucralfaterequires an acidic environment, it should be given 330 min before administering H2 antagonists. Misoprostol (dog: 1-3 mg/kg, PO, tid) has recently been shown to prevent GI ulceration when used concomitantly with aspirin and other NSAID.

7. IV fluids should be given at a diuretic rate if the potential for renal damage exists.Alkalinization of the urine with sodium bicarbonate results in ion trapping of salicylatesin kidney tubules and can increase their excretion. However, ion trapping should be used judiciously and only in cases where the acid-base balance can be monitored closely.Baseline renal function should be monitored and rechecked at 48 and 72 hr. Prognosis depends on the dose ingested and how soon the animal receives treatment following exposure.

8. Treatment of AcetaminophenTreatment of Acetaminophen: The objectives of treating acetaminophen toxicosisare early decontamination, prevention or treatment of methemoglobinemia and hepatic damage, and provision of supportive care. Induction of emesis is useful when performed early. This should be followed by administration of activated charcoal with a cathartic.Activated charcoal may be repeated because acetaminophen undergoes some enterohepaticrecirculation.

9. Treatment of AcetaminophenAdministration of N-acetylcysteine (NAC), a sulfur-containing amino acid, can reduce the extent of liver injury or methemoglobinemia. NAC provides sulfhydryl groups, directly binds with acetaminophen metabolites to enhance their elimination, and serves as a glutathione precursor. It is available as a 10% or 20% solution. The loading dose is 140 mg/kg of a 5% solution IV or PO (diluted in 5% dextrose or sterile water), followed by 70 mg/kg, PO, qid for generally 7 more treatments.

10. Treatment of AcetaminophenVomiting can occur with oral NAC. NAC is not labeled for IV use; however, it canbeadministered as a slow IV (over 15-20 min) with a O. 2 micron bacteriostatic filter.Activated charcoal and oral NAC should be administered 2 hr apart as activated charcoal could adsorb NAC. Liver enzymes should be monitored and rechecked at 24 and 48 hr. The animal should also be monitored for methemoglobinemia, Heinz body anemia, and hemolysis. Fluids and blood transfusions should be given as needed. Ascorbic acid (30 mg/kg, PO or injectable, bid-qid) may further reduce methemoglobin levels.Cimetidine (5-10 mglkg, PO, 1M, or IV), a cytochrome P-450 inhibitor, may help reduce formation of toxic metabolites and prevent liver damage.

11. GASTROINTESTINAL DRUGSH2-Receptor AntagonistsH2-receptor antagonists are structural analogs of histamine, commonly used to treat GI ulcers, erosive gastritis, esophagitis, and gastric reflux. They act at the H2 receptors of parietal cells to competitively inhibit histamine, reducing gastric acid secretions during basal conditions and when stimulated by food, amino acids, pentagastrin, histamine, or insulin. Cimetidine, famotidine, and ranitidine are examples of this group, also commonly referred to as H2 blockers. These drugs are rapidly absorbed, reaching peak plasma concentrations within 1-3 hr. Ranitidine is widely distributed throughout the body.

12. H2-Receptor AntagonistsH2 blockers are primarily metabolized in the liver. Famotidine and ranitidine are excreted in the urine as metabolites and unchanged drug, while cimetidine is eliminated in feces. The elimination half-life for all 3 drugs is ̴2. 2 hr in dogs. Because cimetidinemay inhibit the hepatic microsomal enzyme system, ingestion of an H2 blocker may result in reduced metabolism of certain drugs, including β- blockers, calcium channel blockers, diazepam, metronidazole, and theophylline.

13. H2-Receptor AntagonistsH2 blockers have a wide margin of safety, with acute oral overdoses typically resulting in minor effects such as vomiting, diarrhea, anorexia, and dry mouth. Serious adverse effects, such as tremors, hypotension, and bradycardia, are more likely to occur with IV H2-blocker overdoses. The minimum lethal dose of famotidine in dogs is >2 g/kg, PO, and 300 mg/kg, IV. Most exposures require only monitoring and supportive care, although massive overdoses may also warrant decontamination.

14. AntacidsAntacids come in pill and liquid forms, and are frequently used to treat GI upset. Common antacids include calcium carbonate, aluminum hydroxide, and magnesium hydroxide (milk of magnesia). These agents are poorly absorbed orally. Calcium- and aluminum-containing antacids generally cause constipation, while magnesium containing antacids tend to cause diarrhea. Some products contain both aluminum and magnesium salts in an attempt to balance their constipating and laxative effects. Acute single ingestion of calcium salts may cause transient hypercalcemia, but is unlikely to be associated with significant systemic effects. Induction of emesis within 2-3 hr of exposure may be helpful in preventing severe GI upset.

15. Multivitamins and IronThe common ingredients in multivitamins include: ascorbic acid (vitamin C), cyanocobalamin(vitamin B12), folic acid, thiamine (vitamin Bl), riboflavin (vitamin B2), niacin (vitamin B3), biotin, pantothenic acid, pyridoxine (vitamin B6), calcium, phosphorus, iodine, iron, magnesium, copper, zinc, and vitamins A, D, and E. Among these ingredients, iron and vitamins A and D may cause significant systemic signs. Acute ingestion of other listed ingredients in companion animals can result in self-limiting GI upset (e.g, vomiting, diarrhea, anorexia, lethargy). However, toxicity is typically rare in pets.

16. MultivitaminsMultivitamin preparations contain varying amounts of iron. Unless otherwise listed; iron should be assumed to be elemental iron. Various iron salts may contain 12-48% elemental iron. Iron has direct caustic or irritant effects on the GI mucosa. It can also be a direct mitochondrial poison.

17. Multivitamins and ironOnce the iron-carrying capacity of serum has been exceeded, free iron is deposited in the liver where it damages mitochondria, leading to necrosis of periportalhepatocytes. Signs of iron toxicosis usually develop within 6 hr. Initial vomiting and diarrhea, with or without blood, may be followed by hypovolemic shock, depression, fever, acidosis, and liver failure 12-24 hr later, often with a period of apparent recovery in between.Oliguria and anuria secondary to shock-induced renal failure may also occur. Ingestion of >20 mg/kg of elemental iron generally warrants decontamination and administration of GI protectants. Additional treatment and monitoring will be necessary for patients that have ingested >60 mg/kg of elemental iron.

18. Multivitamins and ironMilk of magnesia can complex with iron to decrease its absorption from the GI tract. Serum iron levels and the total iron binding capacity should be checked at 3 hr and again at 8-10 hr post-exposure. If serum iron is >300 mg/dL, or greater than the total iron binding capacity, chelation therapy may be needed. Desferoxamine (40 mg/kg, 1M, every 4-8 hr) is a specific iron chelator and is most effective within the first 24 hr post ingestion, before iron has been distributed from blood to tissues. Other signs should be treated symptomatically.

19. Multivitamins and ironEven though vitamin A toxicity following consumption of large amounts of fish oil or bear's liver has been well documented, it is less likely to occur following acuteingestion of multivitamins. The amount of vitamin A needed to cause toxic effects is 10-1, 000 times the dietary requirements for most species. The vitamin A requirement for cats is 10, 000 IU/kg of diet fed, with levels up to 100, 000 IU/kg of diet considered to be safe. For dogs, the requirement is 3, 333 IU/kg of diet fed, with up to 333, 300 IU/kg of diet considered to be safe. Signs associated with acute vitamin A toxicity include general malaise, anorexia, nausea, peeling skin, weakness, tremors, convulsions, paralysis, and death.

20. Multivitamins and ironVitamin D is included in many calcium supplements to aid the absorption of the calcium. Most vitamins contain cholecalciferol (vitamin D3). After consumption, cholecalciferolis converted into 25-hydroxycholecalciferol (calcifediol) in the liver, which is subsequently converted to the active metabolite 1, 25-dihydroxycholecalciferol (calcitriol) in the kidneys. One IU of vitamin D3 is equivalent to o0. 025 μg of cholecalciferol. Even though the oral LD50 of cholecalciferol in dogs has been reported as 88-mg/kg, signs have been seen at dosages as low as O. 5 mg/kg. Vomiting, depression, polyuria, polydipsia, and hyperphosphatemia may be seen within 12 hr of a significant vitamin D exposure, followed by hypercalcemia and acute renal failure 24-48 hr postexposure.

21. Multivitamins and ironIn addition to renal failure, the kidneys, heart, and GI tract may show signs of necrosis and mineralization. Initial treatment should include decontamination and assessment of baseline calcium, phosphorus, BUN, and creatinine. Multiple doses of activated charcoal with a cathartic should be administered. If clinical signs of toxicosisdevelop, treatment consists of saline diuresis and the use of furosemide, corticosteroids, and phosphate binders. Specific agents such as (salmon) calcitonin or pamidronatemay be needed for patients that remain hypercalcemic despite symptomatic treatment.Stabilization of serum calcium may require days of treatment due to the long half-life of calcifediol (16-30 days).

22. MethemoglobinRed blood cells contain 4 hemoglobin chains. Each hemoglobin molecule is composed of 4 polypeptide chains associated with 4 heme groups. The heme group contains an iron molecule in the reduced or ferrous form (Fe2+). In this form, iron can combine with oxygen, by sharing an electron, to form oxyhemoglobin. When oxyhemoglobin releases oxygen to the tissues, the iron molecule is restored to its original ferrous state. Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous form. When hemoglobin loses an electron and becomes oxidized, it is converted to the ferric state (Fe3+) or methemoglobin. Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport. Because red blood cells are continuously exposed to various oxidant stresses, blood normally contains approximately 1% methemoglobin levels.

23. Activated charcoalActivated charcoal is estimated to reduce absorption of poisonous substances up to 60%.It works by adsorbing chemicals, thus reducing their toxicity (poisonous nature), through the entire length of the stomach and small and large intestines (GI tract). Activated charcoal itself is a fine, black powder that is odorless, tasteless, and nontoxic. Activated charcoal is often given after the stomach is pumped (gastric lavage). Gastric lavage is only effective immediately after swallowing a toxic substance (within about one-half hour) and does not have effects that reach beyond the stomach as activated charcoal does.

24. Catharticcathartic /ca·thar·tic/ (-tik) 1. causing emptying of the bowels.2. an agent that empties the bowels.3. producing emotional catharsis.bulk cathartic one stimulating bowel evacuation by increasing fecal volume.lubricant cathartic one that acts by softening the feces and reducing friction between them and the intestinal wall.saline cathartic one that increases fluidity of intestinal contents by retention of water by osmotic forces and indirectly increases motor activity.stimulant cathartic one that directly increases motor activity of the intestinal tract.

25. Chelationchelation.The combination of a metal ion with a chemical compound to form a ring. Chelation is used in the industrial separation and extraction of metals and to treat metal poisoning.Chelation therapy is the administration of chelating agents to remove heavy metals from the body. For the most common forms of heavy metal intoxication—those involving lead, arsenic or mercury—the standard of care in the United States dictates the use of dimercaptosuccinic acid (DMSA).[citation needed] Other chelating agents, such as 2,3-dimercapto-1-propanesulfonic acid (DMPS) and alpha lipoic acid (ALA), are used in conventional and alternative medicine. No approved medical research has found any benefits to chelation therapy for other diseases or ailments.[1][2]

26. A chemical peel is a body treatment technique used to improve and smooth the texture of the facial skin using a chemical solution that causes the dead skin to slough off and eventually peel off. The regenerated skin is usually smoother and less wrinkled than the old skin. Thus the term chemical peel is derived. Some types of chemical peels can be purchased and administered without a medical license, however people are advised to seek professional help from a dermatologist, esthetician, plastic surgeon, or otolaryngologist on a specific type of chemical peel before a procedure is performed.