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Toxicity of pain medications (Proceedings)

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Apr 01, 2010

Aspirin

Aspirin (acetylsalicylic acid, ASA) is available as tablets, capsules, powders, effervescent tablets and oral liquid preparations. Aspirin reduces pain and inflammation by reducing prostaglandin and thromboxane synthesis through inhibition of cyclooxygenase. At very high dosages, aspirin and other salicylates uncouple oxidative phosphorylation, leading to decreased ATP production. Salicylates also impair platelet aggregation.

Aspirin is rapidly absorbed from the stomach and proximal small intestines in monogastric animals. Aspirin is metabolized in the liver and excreted through the urine. The elimination half-life increases with the dosage. In dogs, the half-life at the therapeutic dosage is 8.6 hours. Cats are deficient in glucuronyl transferase and have prolonged excretion of aspirin due to decreased metabolism. Feline dosages of 5-12 mg/kg have a half-life of 22 - 27 hours, while dosages of 25 mg/kg have a half-life of approximately 44 hours. Elimination is also slower in neonates and geriatric animals.

In dogs, toxicosis has occurred at dosages of 100 - 300 mg/kg/day PO for 1 - 4 weeks. Dosages 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 seizuring) or hypotension.

The primary goal of treatment is to prevent or treat gastric ulceration, acidosis, hepatopathy, and coagulopathy. Decontamination of asymptomatic patients would include induction of emesis and administration of activated charcoal (repeat dosages with large exposures) and cathartic. Peritoneal dialysis can be effective in removing salicylates. 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. 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.

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. Unlike salicylates, serious hepatotoxicosis does not appear to be a common problem with acute ibuprofen overdosages.

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 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, and anorexia), > 175 mg/kg can result in more severe GI signs (hematemesis, melena) plus renal damage (pu/pd, oliguria, uremia). Dosages of > 400 mg/kg in the dog may result in CNS signs (seizure, ataxia, coma, shock). Cats are about twice as sensitive to ibuprofen's toxic effects as dogs. 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 usually occurs within the first 12 hours after massive exposure to an NSAID but may be delayed until 3-5 days after exposure.

Decontamination of asymptomatic patients would include induction of emesis and administration of activated charcoal (repeat dosages with large exposures) and cathartic. In asymptomatic patients, gastric protection should be continued for 5-7 days. Animals should be started on IV fluids at twice maintenance for a minimum of 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. Misoprostol 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 for comatose patients. 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.