Over-the-Counter Drug Toxicosis

David C. Dorman, Raleigh, North Carolina

According to the U.S. Food and Drug Administration (FDA) there are over 300,000 over-the-counter (OTC) drug products. These drugs represent approximately 60% of all medications purchased in the United States. The general public may assume that OTC products are safe because they do not require a prescription, thus leading to more frequent administration errors. Exposure to prescription and OTC drugs remains a significant concern for small animal owners and veterinarians. According to the Animal Poison Control Center (APCC) of the American Society for Prevention of Cruelty to Animals (ASPCA), exposure to human medications accounted for nearly 25% of all calls made to that Center in 2010. The APCC also reports that the OTC drugs ibuprofen, naproxen, and other nonsteroidal antiinflammatory drugs (NSAIDs), as well as acetaminophen and pseudoephedrine were among the 10 most frequent causes of drug-related exposure. Exposure to OTC drugs may occur from the administration of these drugs by an owner or veterinarian or through accidental ingestions in the home. Most OTC drug exposures result from ingestion, and the observed clinical signs often represent an exaggeration of the pharmacologic effects of the drug.

The formulation examples described in this chapter should not be considered comprehensive, but rather should serve to highlight some of the OTC products available. Formulations of these and other OTC products may change over time. Therefore it is critical that veterinarians clearly identify the full product name and the current formulation of the OTC in question. Certain OTC products can contain multiple active ingredients. For example, some products used to treat cold and flu-like symptoms contain combinations of aspirin, ibuprofen, acetaminophen, caffeine, diphenhydramine, and other agents. Coexposure to multiple drug formulations can dramatically complicate the management of the exposed animal. This chapter considers several of the newer OTC drugs in the marketplace and provides updates on the management of other more frequently encountered OTC drugs.

General Treatment and Diagnostic Considerations

Unless otherwise noted, the following general management recommendations can be applied to animals exposed to the OTC drugs discussed in this chapter. Initial treatment is focused on stabilizing vital signs, decreasing exposure dose through gastrointestinal decontamination and other methods, and providing symptomatic treatment. In general, induction of emesis and other means of gastrointestinal decontamination is most effective when performed within 2 hours of ingestion. Many OTC drug formulations have been designed for rapid gastrointestinal absorption and systemic delivery, resulting in a shortening of this therapeutic window. Activated charcoal (1 to 2 g/kg, PO, SID or BID to TID) combined with an osmotic or saline cathartic (e.g., sodium sulfate at 250 mg/kg PO, SID) is generally the preferred method of gastric decontamination following ingestion of a potentially toxic dose of an OTC drug. Gastric lavage, followed by activated charcoal, is indicated after massive ingestion. Certain OTC drugs undergo extensive enterohepatic recirculation; therefore repeated doses of activated charcoal are indicated. Occasionally OTC tablets or capsules form concretions in the gastrointestinal tract. Consequently adsorbents, cathartics, and lavage procedures may be of value even several hours after exposure.

So-called intralipid therapy has also been increasingly used in the initial management of animals exposed to certain toxicants. This therapy was first applied clinically to people to reverse the cardiotoxicity associated with bupivicaine and other local anesthetic agents. More recently, intralipids have been used by veterinarians to reverse central nervous system (CNS) signs and cardiac arrhythmias associated with lipophilic drug overdoses such as ivermectin, permethrin, and baclofen (Fernandez et al, 2011; Gwaltney-Brant and Meadows, 2012; Kaplan and Whelan, 2012). The pharmacologic basis for how intralipid therapy works remains the subject of debate. Intralipids may form a lipid sink for lipophilic drugs, resulting in reduced tissue distribution of the drug and enhanced drug clearance. The lipids may also serve as an energy source that stabilizes tissue metabolism. Administration of a bolus in the range of between 1.5 and 4 ml/kg (0.3 to 0.8 g/kg IV over 1 min), followed by a continuous rate infusion (CRI) of 0.25 ml/kg/min (0.05 g/kg/min IV over 30 to 60 min), has been suggested for dogs (Fernandez et al, 2011). At this time the use of intralipid therapy in the management of OTC drugs can not be broadly advocated but may be warranted with cardiotoxic or neurotoxic drugs or OTC drugs that are highly lipophilic. Support of vital functions is a principle of therapy. Airway control with assisted ventilation and supplemental oxygen may be required. Seizures should be treated with standard anticonvulsants such as diazepam (2.5 to 5 mg/kg IV). Intravenous fluids, inotropic agents such as dopamine (2.5 to 10 µg/kg/min) or dobutamine (5 to 20 µg/kg/min), and electrolytes should be given to control hypotension and hemorrhage, maintain renal function, and correct electrolyte imbalances. In general, the highly protein-bound OTC drugs are not amenable to enhanced elimination by forced diuresis. Additional therapeutic considerations also are provided for individual drugs discussed in this chapter. It is important to remember that clinical signs associated with OTC exposure can emerge at different times; therefore repeated reevaluation of the animal and appropriate modifications of the treatment approach are always in order.

A definitive diagnosis for toxicoses resulting from the OTC drugs described in this chapter generally relies on a known history of exposure, development of compatible clinical signs, and confirmation of drug residues using appropriate analytic chemical methods. There may be a delay in obtaining analytic results, therefore veterinarians should not delay treatment for this confirmation.

Nonsteroidal Antiinflammatory Drugs

There has been an increase in the number of NSAIDs available in the U.S. market. Several NSAIDs (e.g., aspirin, ibuprofen, and naproxen) are available OTC. Other prescription NSAIDs include celecoxib, sulindac, piroxicam, indomethacin, etodolac, meloxicam, ketoprofen, nabumetone, and ketorolac tromethamine. Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid. Aspirin irreversibly inhibits COX, while the other commonly used NSAIDs (e.g., ibuprofen, naproxen) reversibly inhibit COX. Prostaglandins mediate a variety of normal physiologic functions including regulation of renal blood flow. Prostaglandins are also vasodilatory and cytoprotective in the gastrointestinal tract.

The inhibitory activity of NSAIDs on COX activity explains not only their beneficial antiinflammatory effects, but also in part accounts for their adverse effects on platelet, gastrointestinal, and renal function. For example, piroxicam and indomethacin exert their highest activity against COX-1 and demonstrate high gastrointestinal toxicity. In comparison, the selective COX-2 inhibitors (e.g., deracoxib, robenacoxib) have less inhibitory effects on blood clotting, have better gastrointestinal tolerability, and can be less nephrotoxic than NSAIDs, which are either nonselective or selective COX-1 inhibitors.

There are significant species differences in the elimination and biotransformation of NSAIDs, resulting in variable half-lives of elimination that can influence drug toxicity. For example, the elimination half-life of aspirin in cats approaches 40 hours, compared with 7.5 to 8 hours in dogs. The plasma elimination half-life of piroxicam has been reported as 37 to 40 hours in dogs, 12 to 13 hours in cats, and 30 to 86 hours in humans. Cats are thought to be more sensitive than dogs to some of the toxic effects of NSAIDs; however, there is insufficient information available to indicate whether this is a consistent finding for all NSAIDs. Two important protective determinants in NSAID-induced toxicity are high COX-2 selectivity and short blood half-life.

Toxicoses from NSAIDs can occur from either a single high-dose exposure or following repeated exposure to lower doses. In many cases even a small increase in the recommended therapeutic NSAID dose (e.g., a 25% to 100% dose increase) can lead to adverse effects. Common clinical signs observed with NSAID toxicosis include vomiting, CNS depression, anorexia, diarrhea, and ataxia. Dogs are particularly sensitive to the ulcerogenic effects of NSAIDs, especially when combined with corticosteroid use. The onset of gastrointestinal signs often occurs within the first 2 to 6 hours after ingestion, with the onset of gastrointestinal hemorrhage and ulceration occurring 12 hours to 4 days after ingestion. Severe gastric lesions may occur, however, with only minimal overt clinical signs. Lesions associated with NSAID gastroenteropathy include perforations, ulcers, and hemorrhages in the upper (stomach and duodenum) and, on occasion, lower (colon) gastrointestinal tract. Once ulceration has occurred, bleeding into the lumen of the gut may be exacerbated if blood clotting is inhibited. Blood loss, anemia, iron deficiency, and melena may be observed. Gastric erosions, ulcers, and evidence of hemorrhage may be detected by endoscopy. Recent studies have shown that dogs with NSAID-induced gastric lesions develop a marked elevation in plasma C-reactive protein (CRP), serum amyloid-A (SAA), haptoglobin, fibrinogen concentrations, and white blood cell counts. This rapid acute phase protein response occurs in concert with gastric mucosal injury and may be potentially useful together with rectal examination of fecal contents and gastroscopy in the diagnosis and monitoring of gastric injury.

Massive NSAID ingestion is also associated with renal failure characterized by oliguria and azotemia initially, followed by either an oliguric or anuric clinical course. The onset of renal failure often occurs within the first 12 hours after NSAID exposure but may be delayed 3 to 5 days. The liver is another target organ for certain NSAIDs (e.g., carprofen); however, it remains unknown whether this effect is idiosyncratic, dose related, or both. Other clinical effects that have been reported include decreased platelet aggregation leading to increased bleeding time, bone marrow depression, allergic reactions, and seizures.

Therapeutic considerations for NSAID toxicosis variably include gastrointestinal decontamination and, when needed, administration of crystalloid fluids (such as 0.45% saline and 2.5% dextrose, IV), whole blood, inotropic agents such as dopamine (2.5 µg/kg/min) or dobutamine (5 to 20 µg/kg/min), and electrolytes to control hypotension and hemorrhage, manage acute bleeding ulcers, maintain renal function, and correct electrolyte abnormalities. A variety of pharmacologic approaches have been used in humans to reduce the risk of NSAID-induced gastrointestinal toxicity. These approaches include the use of histamine (H₂)-receptor antagonists (ranitidine, famotidine, and cimetidine) and proton pump inhibitors (PPIs) (e.g., omeprazole). The effectiveness of these drugs following an acute massive dose NSAID exposure in veterinary medicine has not been fully evaluated, but they are often prescribed.

Sucralfate (0.5 to 1 g q8-12h PO [dog]; 0.25 g q8-12h PO [cat]), cimetidine (10 mg/kg q8h IM, IV, PO), ranitidine (2 mg/kg q8h IV, PO [dog]; 2.5 mg/kg q12h IV [cat] or 3.5 mg/kg q12h PO [cat]), and omeprazole (0.7 mg/kg q24h PO [dog]) have proved beneficial in the management of gastric ulcers. Misoprostol (2 to 5 µg/kg, PO, q8h, dog), a synthetic prostaglandin E₁ analog, prevents aspirin-induced gastric ulcers in dogs (Ward et al, 2003) but is generally less effective after an ulcer forms. Misoprostol also is associated with adverse side effects such as abdominal pain, vomiting, and diarrhea. Studies in humans suggest that PPIs (e.g., omeprazole) may be more effective in treating NSAID-related dyspepsia (indigestion) and also in healing gastric and duodenal ulcers in patients that continue to receive an NSAID. Metoclopramide (0.2 to 0.4 mg/kg q6-8h PO or SC) may be helpful in the control of vomiting. Mild gastrointestinal irritation may be treated symptomatically with nonabsorbable antacids such as magnesium or aluminum hydroxide. Bismuth subsalicylate antacid formulations are contraindicated. The NSAID should also be discontinued and other analgesic options considered if needed.