Toxicology case studies: pain medications (Proceedings)

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Aspirin (acetylsalicylic acid, ASA) is the salicylate ester of acetic acid and is a weak acid derived from phenol. Aspirin reduces pain and inflammation by reducing prostaglandin and thromboxane synthesis through inhibition of cyclooxygenase. At very high doses, aspirin and other salicylates uncouple oxidative phosphorylation leading to decreased ATP production. Salicylates also affect platelet aggregation.

Aspirin

Aspirin (acetylsalicylic acid, ASA) is the salicylate ester of acetic acid and is a weak acid derived from phenol. Aspirin reduces pain and inflammation by reducing prostaglandin and thromboxane synthesis through inhibition of cyclooxygenase. At very high doses, aspirin and other salicylates uncouple oxidative phosphorylation leading to decreased ATP production. Salicylates also affect platelet aggregation.

Aspirin is rapidly absorbed from the stomach and proximal small intestines in monogastric animals. The rate of absorption is dependent upon gastric emptying, tablet disintegration rates, and gastric pH. Absorption of large, potentially lethal doses may be slower than therapeutic doses partly due to the effect of aspirin on gastric emptying. Aspirin is metabolized in the liver and excreted through the urine. The elimination half-life increases with the dose. In dogs, the half-life at the therapeutic dose is 8.6 hours. Cats are deficient in glucuronyl transferase and have prolonged excretion of aspirin due to decreased metabolism.

Since aspirin is highly protein bound, it should be used with caution in patients with hypoproteinemia or pre-existing hepatic or renal disease. Aspirin is contraindicated in patients with bleeding GI ulcers. In dogs, toxicity has been noted at doses of 100 - 300 mg/kg/day PO for 1 - 4 weeks. Doses of 325 mg twice a day were lethal to cats.

Signs may include vomiting (+/- blood), hyperpnea, respiratory alkalosis, metabolic acidosis, gastric hemorrhage, centrilobular liver necrosis, and bleeding diathesis. Fever and seizures may be seen due to the uncoupling of oxidative phosphorylation. Renal insufficiency is uncommon with salicylate toxicoses but could develop secondary to rhabdomyolysis (from seizing) or hypotension.

The primary goal of treatment is to prevent or treat gastric ulceration, acidosis, hepatopathy, and coagulopathy. Emesis can be performed in the asymptomatic animal, unless contraindicated. Activated charcoal adsorbs aspirin and repeated doses may be used with large ingestions. A cathartic should be used, unless the animal is dehydrated or has diarrhea. Peritoneal dialysis can be effective in removing salicylate. Liver values, glucose, acid base status and electrolytes should be monitored. Maintain hydration and start GI protectants (sucralfate, H2 blockers, +/- misoprostol, +/- omeprazole) to help manage and/or prevent gastric ulcers. In the asymptomatic patient, gastric protectants should be continued for 5 - 7 days. Metoclopramide can be used to control vomiting. Bismuth subsalicylate antacid formulations and corticosteroids are contraindicated.

Alkalinization of the urine results in ion trapping of salicylate in the kidney tubule and increases its secretion. Ion trapping can have adverse effects, therefore it should be used only in cases where the acid base balance can be monitored. Assisted ventilation and supplemental oxygen may be required if the animal is comatose. Seizures should be treated with diazepam. Fluids, whole blood, and electrolytes should be given to control hypotension and hemorrhage, manage acute bleeding ulcers, and correct electrolyte abnormalities. Acid base imbalances should be corrected. Hyperpyrexia should be treated conservatively as aggressive cooling (ice baths or cold water enemas) may result in hypothermia.

Prognosis is good if the animal is treated promptly and appropriately. The development of central lobular hepatic necrosis is considered to have a poor prognosis. With hepatic damage, treatment may need to be continued for weeks.

Ibuprofen

Ibuprofen (Motrin®, Advil®, Midol®, etc.) is a nonsteroidal anti-inflammatory agent. Ibuprofen inhibits prostaglandin synthesis by blocking the conversion of arachidonic acid to various prostaglandins. Ibuprofen decreases secretion of the protective mucous layer in the stomach and small intestine and causes vasoconstriction in gastric mucosa. Ibuprofen inhibits renal blood flow, glomerular filtration rate, tubular ion transport, renin release and water homeostasis. Ibuprofen may also affect platelet aggregation and possibly hepatic function. Serious hepatotoxicosis does not appear to be a common problem with ibuprofen.

Absorption of ibuprofen is rapid (0.1 to 1.5 h). Plasma half-life in the dog has been reported to be 2-2.5 hours, but the elimination half-life is considerably longer. Ibuprofen is metabolized in the liver (conjugation, oxidation and hydroxylation) and undergoes significant enterohepatic recirculation before being excreted in the urine. Fifty to sixty percent is excreted in the urine as metabolites within 24 hours, with less than 10% excreted in the urine unchanged. The remainder of the drug is eliminated in feces both as metabolites and as unchanged drug. Geriatric animals and neonates are at higher risk of toxicosis as acute renal insufficiency, liver disease, and hypoalbuminemic states can decrease plasma protein binding, decrease metabolism and increase volume of distribution. Administration of ibuprofen in combination with glucocorticoids, salicylates, phenylbutazone, indomethacin, or other NSAIDS could potentiate the adverse effects of these drugs.

Ibuprofen has a narrow margin of safety. Even at the therapeutic dog dosage of 5 mg/kg, ibuprofen may cause gastric ulcers and perforations with chronic use. In dogs, an acute exposure of 50-125 mg/kg can result in gastrointestinal signs (vomiting, diarrhea, nausea, abdominal pain, anorexia), > 175 mg/kg can result in more severe GI signs (hematemesis, melena) plus renal damage (pu/pd, oliguria, uremia). Doses of > 400 mg/kg in the dog result in GI and renal signs, plus CNS signs (seizure, ataxia, coma, shock). Cats are thought to be twice as sensitive to ibuprofen's toxic effects as dogs due to their limited glucuronyl-conjugating capacity. Ferrets that ingest ibuprofen are at high risk for CNS depression and coma, with or without GI upset.

The onset of GI upset is generally within the first 2-6 hours after ingestion, with the onset of GI hemorrhage and ulceration occurring 12 hours to 4 days post ingestion. Lesions associated with ibuprofen overdose include perforations, erosions, ulcers, and hemorrhages in the upper (stomach and duodenum) and, on occasion, lower (colon) gastrointestinal tract. The onset of renal failure often occurs within the first 12 hours after massive exposure to an NSAID but may be delayed until 3-5 days after exposure.

Emesis can be performed in the asymptomatic animal. Activated charcoal adsorbs ibuprofen and may need to be repeated, since ibuprofen undergoes enterohepatic recirculation. A cathartic should also be used, unless the animal is dehydrated or has diarrhea. In the asymptomatic patient, gastric protection should be continued for 5-7 days. Animals should be started on IV fluids at twice maintenance for 48 hours if renal failure is expected. Monitor BUN, creatinine, and urine specific gravity (baseline level, 24, 48, and 72 h). The animal may also need to be monitored for acidosis and electrolyte changes. Acid-base disturbances are rare and usually transient. Peritoneal dialysis may be necessary if unresponsive oliguric or anuric renal failure develops.

For symptomatic animals, GI protectants are very important. Mild gastrointestinal irritation may be treated symptomatically with antacids, such as magnesium or aluminum hydroxide. Misoprostal is helpful for treating or preventing gastric ulceration caused by NSAIDS as it stimulates mucus and bicarbonate secretion and increases gastric mucosal blood flow (contraindicated during pregnancy due to its abortifacient activity). H2 blockers, sucralfate and omeprazole can also be used to manage and/or prevent gastric ulcers. Assisted ventilation and supplemental oxygen may be required if animal is comatose. Seizures should be treated with diazepam. Fluids, whole blood, inotropic agents, and electrolytes should be given to control hypotension and hemorrhage, maintain renal function, and correct electrolyte abnormalities.

Prognosis is good if the animal is treated promptly and appropriately. Gastrointestinal ulceration usually responds to therapy. Acute renal insufficiency resulting from ibuprofen administration has been considered reversible, however, the development of papillary necrosis is generally considered irreversible.

Acetaminophen

Acetaminophen (Tylenol®, non-aspirin pain reliever, APAP) is a synthetic non-opiate derivative of p-aminophenol. Acetaminophen's exact mechanism of action is unknown but it is believed to block production of prostaglandins from arachidonic acid by inhibiting COX-3. Acetaminophen acts primarily in the CNS to increase the pain threshold and may also inhibit chemical mediators that sensitize the pain receptors to mechanical or chemical stimulation. The antipyretic activity of acetaminophen is achieved by blocking the effects of endogenous pyrogens by inhibiting prostaglandin synthesis.

Acetaminophen is rapidly and almost completely absorbed from the GI tract. Peak plasma levels are seen at 10-60 minutes for regular products and at 60-120 minutes for extended release forms. Two major conjugation pathways are used to metabolize acetaminophen by most species (P-450 metabolism followed by glucuronidation or sulfation). Acetaminophen-induced hepatoxicity and nephrotoxicity is due to the formation of the metabolite, N-acetyl-para-benzoquinoneimine (NAPQI), in the liver and to a lesser degree in the kidney. NAPQI binds covalently to sulfhydryl groups on tissue macromolecules leading to cell necrosis. Glutathione can conjugate and neutralize NAPQI, but when glutathione stores are depleted, NAPQI binds to the hepatic cell membrane and damages the lipid layer. Large doses of APAP can cause nephrotoxicity characterized by proximal tubule necrosis. Another metabolite, para-aminophenol (PAP), has been show to damage the RBCs leading to methemoglobinemia and Heinz body formation.

Methemoglobin values increase within 2-4 hours, followed by Heinz body formation. Clinical signs seen with acetaminophen toxicity include depression, weakness, hyperventilation, icterus, vomiting, methemoglobinemia, hypothermia, facial or paw edema, death, cyanosis, dyspnea, and hepatic necrosis. Other possible clinical signs include metabolic acidosis, renal insufficiency/damage, myocardial damage, coma, thrombocytopenia, and vomiting. Liver necrosis is less common with cats than with dogs. Clinical signs of methemoglobinemia may last 3-4 days. Hepatic injury may not resolve for several weeks. Hepatotoxicity has been reported in dogs at 100 mg/kg and 200 mg/kg caused clinical methemoglobinemia in 3 out of 4 dogs. Doses of 40 mg/kg have resulted in KCS 72 hours after ingestion. Cats develop clinical signs at doses >40 mg/kg. No dose is safe in cats since they are deficient in glucuronyl transferase. Ferrets are considered to be as sensitive as cats.

Early decontamination is most beneficial. Emesis can be performed in the asymptomatic animal, unless contraindicated. Activated charcoal adsorbs acetaminophen and may need to be repeated, due to enterohepatic recirculation. A cathartic should also be used, unless the animal is dehydrated or has diarrhea. Monitor liver values and for the presence of methemoglobinemia. ALT, AST and bilirubin may rise within 24 hours after ingestion and peak within 48 to 72 hours. Serum albumin concentrations decrease significantly after 36 hours and continue to decrease during liver failure, providing a true index of liver function.

Symptomatic patients need initial stabilization, including oxygen if dyspneic. Treatment involves replenishing the glutathione stores and converting methemoglobin back to hemoglobin. N-acetylcysteine (Mucomyst®, NAC) is hydrolyzed to cysteine and becomes a precursor in the synthesis of glutathione or can also be oxidized to organic sulfate needed for the sulfation pathway. This provides sulfhydryl groups which bind with acetaminophen metabolites to enhance elimination. NAC is available in 10% and 20% solutions. An initial oral loading dose for NAC would be 140 mg/kg of a 5% concentration (can be diluted in 5% Dextrose or sterile water) and then 70 mg/kg PO QID for generally 7 treatments. With ingestion of massive quantities some authors suggest using 280 mg/kg for a loading dose and continuing treatment for 12 to 17 doses. Adverse effects of the oral route of NAC include nausea and vomiting. Not all NAC is labeled for IV use however the loading dose (diluted to 5%) could be given slow IV over a period of 15 to 20 minutes with use of a bacteriostatic filter (0.2 micron) in life-threatening cases. A two-to-three hour wait between activated charcoal administration and PO administration of NAC is recommended, since activated charcoal could adsorb NAC as well as acetaminophen. Fluid therapy is used to correct dehydration and for maintenance needs, not for diuresis. Whole blood transfusions or oxyglobin may be necessary to increase oxygen carrying capacity.

For hepatic injury, a new therapy that shows potential is s-adenosylmethionine (SAMe, Denosyl-SD4®) at 20 mg/kg/day. Early studies and anecdotal reports show a positive effect for treatment of acetaminophen toxicosis. OTC formulations of SAMe have variable potency; use a prescription quality, enteric coated product (round the dose to nearest whole pill and do not break pill). Steroids and antihistamines are contraindicated.

Prognosis is good if the animal is treated promptly. Animals with severe signs of methemoglobinemia or with hepatic damage have poor to guarded prognosis. Treatment may continue for weeks.

Opioids and opiates

There are many opiods and opiates used in human and veterinary medicine. Opioids and opiates are synthetic or natural compounds derived from the opium poppy, Papaver somniferum, and are generally classified (agonist or partial agonist) by their ability to exert effects at the different opioid receptors (mu, kappa, delta, sigma). Partial agonists are agonists at one (or more receptors) and antagonists at others. Opioids act centrally to elevate the pain threshold and to alter the psychological response to pain. Most of the clinically used opioids exert effect at the mu receptor (mu1 subtype mediates analgesic effects, mu2 mediates respiratory depression).

Opioids are well absorbed from the GI tract. Bioavailability is variable as some opioids have a large first pass effect (i.e. fentanyl). These opioids are administered in other manners (CRI, buccal, transdermal) to reach therapeutic blood levels. Metabolism varies, but opioids generally undergo hepatic metabolism with some form of conjugation, hydrolysis, oxidation, glucuronidation, or dealkylation. This glucuronidation may account for the sensitivity of cats (who are deficient in glucuronyl-S-transferase) to opioids.

In dogs, CNS signs include depression, ataxia, and seizures. Respiratory depression, vomiting, bradycardia, and hypotension may be seen. Cats may show excitatory behavior and urinary retention. Detection of opioids can be made from urine or serum samples.

Treatment in an asymptomatic animal may include emesis if the ingestion is recent. Activated charcoal with cathartic should be administered and the patient monitored for up to 12 hours. If the animal becomes symptomatic, respiratory support may need to be given. If severe respiratory depression is seen, naloxone (a pure competitive antagonist with activity at the mu receptors) at a dose of 0.1-0.2 mg/kg IV, IM or SQ can be administered to reverse respiratory effects. As the duration of action of naloxone is much shorter than that of the opioids, repeat dosages may be necessary. Naloxone may not result in the animal regaining full consciousness. Partial agonists/antagonists (i.e. butorphanol) may be used to partially reverse pure agonists if no naloxone is available. Monitor temperature, cardiac function and blood gases. Treatment times will vary with the half-life of the opioid. If respiratory and cardiovascular function can be maintained then prognosis is good. For those cases that are seizuring, prognosis is guarded.

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