Toxicity of pain medications (Proceedings)

Aspirin

Aspirin (acetylsalicylic acid, ASA) is the salicylate ester of acetic acid and is a weak acid derived from phenol. It is available as tablets and capsules (65, 81, 325, and 500 mg), 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 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 monogastrics. Aspirin is metabolized in the liver and excreted through the urine. The elimination half life increases with the dose. Cats are deficient in glucuronyl transferase and have prolonged excretion due to decreased metabolism. Elimination is also slower in neonates and geriatric animals.

Aspirin should be used with caution in patients with hypoproteinemia or pre-existing hepatic or renal disease and is contraindicated in patients with bleeding GI ulcers. In dogs, single doses over 150 mg/kg should be decontaminated. Signs may include vomiting (+/- blood), hyperpnea, respiratory alkalosis, metabolic acidosis, gastric hemorrhage, central lobular 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.

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. Liver values, glucose, acid base status and electrolytes should be monitored. Maintain hydration and start GI protectants (sucralfate, H2 blockers, +/- misoprostol, +/- omeprazole). Gastric protectants should be continued for 5 - 7 days, longer in the symptomatic patient. Antiemetics should be used to control vomiting.

Alkalinization of the urine results in ion trapping of salicylate in the kidney tubule and increases its secretion. Ion trapping should only be used 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 may be needed 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 hepatic necrosis is considered to have a poor prognosis. With hepatic damage, treatment may need to be continued for weeks.

Other salicylates

Salicylates are found in many products. Bismuth subsalicylate (Pepto-Bismol®, Kaopectate®) contains 9 mg of salicylate in 1 ml (2 tablespoons = 325 mg aspirin). Topically applied salicylates (arthritis, psoriasis, teething, wart removal) can be absorbed through the skin and cause systemic problems. Oil of wintergreen is used as a flavoring for candy and contains approximately 98% methyl salicylate.

Acetaminophen

Acetaminophen (Tylenol®, non-aspirin pain reliever, APAP) is a synthetic non-opiate derivative of p-aminophenol. APAP's exact mechanism of action is unknown, but it is 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 APAP is achieved by blocking the effects of endogenous pyrogens by inhibiting prostaglandin synthesis. It is available in tablets, liquid preparations, and long-acting compounds. Tablet strengths vary from 80 to 650 mg. Liquids are available in 160 mg/5 ml, 100 mg/ml, and 120 mg/2.5 ml.

Acetaminophen is rapidly and almost completely absorbed from the GI tract. Peak plasma levels are seen at 10-60 minutes (60-120 min for extended release). APAP is distributed into most body tissues with the highest concentrations in the peri-portal zone of the liver and the renal medulla. Elimination is capacity-limited. Two major conjugation pathways are used to metabolize APAP by most species (P-450 metabolism followed by glucuronidation or sulfation). Acetaminophen-induced hepatoxicity and nephrotoxicity is due to the formation of the oxidative metabolite, N-acetyl-para-benzoquinoneimine (NAPQI). Glutathione can conjugate and neutralize NAPQI, but when glutathione stores are depleted, NAPQI binds to sulfhydryl groups on the hepatic cell membrane and damages the lipid layer. Another metabolite, PAP (para-aminophenol), appears to be responsible for methemoglobinemia and Heinz body formation.

Methemoglobin values increase within 2-4 hours, followed by Heinz body formation. Clinical signs include depression, weakness, hyperventilation, icterus, vomiting, methemoglobinemia, hypothermia, facial or paw edema, death, cyanosis, dyspnea, and hepatic necrosis. Liver necrosis is less common in cats than in 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. Therapeutic doses have resulted in KCS 72 hours after ingestion. No dose is safe in cats since they are deficient in glucuronyl transferase. Cats develop clinical signs at doses > 10 mg/kg. Ferrets are considered to be as sensitive as cats.

Early decontamination is most beneficial. Emesis is usually unrewarding. Activated charcoal adsorbs APAP 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.

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 a precursor in the synthesis of glutathione and can be oxidized to organic sulfate providing sulfhydryl groups that bind with APAP metabolites to enhance elimination. An initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water) is given, followed by 70 mg/kg PO QID for 7 treatments, or longer if still symptomatic. If the animal is already symptomatic, a loading dose of 280 mg/kg is given. A two-to-three hour wait between activated charcoal and PO administration of NAC is needed, since activated charcoal will adsorb NAC. Adverse effects of the oral route include nausea and vomiting. Some brands of NAC are labeled for IV use. Dilute to 5%, and give slow IV over a period of 15 to 20 minutes. Fluid therapy is used to correct dehydration and for maintenance needs, not for diuresis. Whole blood transfusion may be necessary to increase oxygen carrying capacity, but the cat must be monitored for volume overload.

Ascorbic acid provides a reserve system for the reduction of methemoglobin back to hemoglobin; however, ascorbic acid has questionable efficacy and may irritate the stomach. Cimetidine is an inhibitor of cytochrome p-450 oxidation system but takes several days to become effective and should be avoided in cats. It has now been demonstrated that cimetidine blocks one of the only pathways that cats have to convert methemoglobin back to hemoglobin. For hepatic injury, s-adenosylmethionine (SAMe, Denosyl-SD4®) at 20 mg/kg/day shows a positive effect for treatment of APAP toxicosis. Prognosis is good if the animal is treated promptly. Animals with severe signs of methemoglobinemia or with hepatic damage have poor to guarded prognosis.

Ibuprofen

Ibuprofen (Motrin®, Advil®, Midol®, etc.) is a nonsteroidal anti-inflammatory agent. It is available over the counter in 50, 100, 200 mg tablets and 100 mg/5 ml suspension. Prescription strength tablets are 400, 600, and 800 mg. 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 is not 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 and undergoes significant enterohepatic recirculation before being excreted in the urine. Geriatric animals and neonates, as well as animals with acute renal insufficiency, liver disease, and hypoalbuminemia are at higher risk of toxicosis. Administration of ibuprofen in combination with glucocorticoids, salicylates, 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 mg/kg can result in gastrointestinal signs (vomiting, diarrhea, abdominal pain, anorexia) and GI ulcers. Dose of > 125 mg/kg can result in renal damage (PU/PD, oliguria, uremia). Doses of > 400 mg/kg in the dog cause CNS signs (seizure, ataxia, coma). 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 GI hemorrhage and ulceration occurring 12 hours to 4 days post ingestion. Renal failure often occurs within the first 12 hours after massive exposure to an NSAID but may be delayed for 3-5 days.

Emesis can be performed in the asymptomatic animal. Activated charcoal adsorbs ibuprofen and may need to be repeated (enterohepatic recirculation). A cathartic should also be used, unless the animal is dehydrated or has diarrhea. GI protectants are very important. A combination of misoprostal, H2 blockers, sucralfate and omeprazole can be used to manage and/or prevent gastric ulcers. 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). Acid-base disturbances are rare and usually transient. Dialysis may be necessary if unresponsive oliguric or anuric renal failure develops.

Fluids, whole blood, inotropic agents, and electrolytes should be given to control hypotension and hemorrhage, maintain renal function, and correct electrolyte abnormalities. Assisted ventilation and supplemental oxygen may be required if animal is comatose. Seizures should be treated with diazepam.

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, but development of papillary necrosis is generally considered irreversible.

Opiods 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, but 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 (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, naloxone (0.1-0.2 mg/kg IV, IM or SQ) can be administered. As the duration of action of naloxone is much shorter than that of the opioids, repeat dosages may be necessary. 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.

Fentanyl

Fentanyl suckers, lozenges and transdermal patches are becoming more frequently used in both human and veterinary medicine. The lozenges or suckers contain fentanyl citrate in a sucrose and liquid glucose base and are attractive to animals. The patches have poor absorption from the GI tract, but can be absorbed transmucosally while the animals are chewing on them. Signs are similar to other opioids with depression, bradycardia, hypotension, weakness, and pallor predominating. Treatment is as for other opioids.

Tramadol

Tramadol (synthetic analog of codeine) is an effective opioid-type analgesic possessing both opioid agonist and monoamine reuptake inhibition effects. It is an uncontrolled, oral analgesic gaining popularity in veterinary medicine (1-2 mg/kg PO BID to QID). Do not use with TCAs, SSRIs, or MAOIs due to the risk of serotonin syndrome.