Shopping Cart

INTRODUCTION

As discussed in Module 1 (“Anatomical and Physiological Considerations for Drug Therapy in Non-Human Species”), differences between and even within animal species are numerous and often unpredictable. Each species has evolved through natural selection with various anatomical and physiological adaptations influenced by environment, diet, behavior, function, and genetic composition. These adaptations produce substantial differences in susceptibility to the toxic effects of drugs, excipients, preservatives, foods, household products, and plants. Consequently, providers (veterinarians and dispensing pharmacists) must choose drugs and adjunctive therapies very carefully when treating non-human species. Veterinary-labeled drugs may not be safe when used in all veterinary species. Even veterinary-labeled drugs can be toxic if they are administered to patients outside of the approved target species; for example, enrofloxacin generally is safe in dogs but can cause serious retinal toxicity in cats.¹

Pharmacists and pharmacy technicians often are the last line of defense in recognizing and preventing potential animal poisoning. Unfortunately, pharmacists and pharmacy technicians traditionally are trained only in human toxicology. To provide competent and confident pharmaceutical care to non-human species, pharmacists, pharmacy technicians, and veterinary technicians must possess a working knowledge of species-specific susceptibilities to toxins. Factors that affect the risk of toxicity vary greatly among species; they include (but are not limited to) differences in absorption, distribution, metabolism, and elimination; anatomical characteristics such as the inability to vomit; age and size of the animal; and seasonal and environmental influences.

The American Society for the Prevention of Cruelty to Animals (ASPCA) reported that 37.1% of pet poisonings in 2018 were attributable to human over-the-counter (OTC) (19.6%) and human prescription (17.5%) drugs.² Lack of knowledge on the part of pet owners can result in inadvertent poisonings when pets are accidentally or intentionally exposed to drugs. In some instances, pet owners attempt to treat animals with OTC products intended for humans; pharmacists and pharmacy technicians are ideally positioned to intervene in these purchases or provide valuable post-ingestion consultation.

Given that dogs and cats are the most commonly kept household pets,³ this module focuses on potentially toxic drugs, excipients, and foods in those species. However, it is critical that pharmacists and pharmacy technicians acquire the same comprehensive level of knowledge for any species for which they provide pharmaceutical care and products.

FACTORS THAT INFLUENCE TOXICITY

The clinical sequelae of toxin exposure in animals are not necessarily due to the actual dose or inherent toxicity of the offending substance. One important factor that influences toxicity is species-specific adaptation to usual diet and substances to which the species is exposed commonly. For example, some species of freshwater fish are able to induce detoxification enzymes when exposed to environmental polluntants.⁴ To further demonstrate the limitations of various species in metabolic capacity, cats have evolved as obligate carnivores. They have very little dietary exposure to phytoalexins in plant materials; as a result, cats have not developed metabolic enzyme systems to detoxify planar phenolic xenobiotics. When cats are exposed to these substances (eg, azo dyes such as phenazopyridine), they can suffer significant toxicity at any administered dose. Species-specific physiological limitations are discussed in greater detail in Module 1.

Anatomical factors also influence species’ vulnerability to toxins. For example, the ability to vomit is critical for expelling toxins from the upper gastrointestinal tract, thereby reducing absorption and distribution of the toxin. Horses, rodents, and rabbits are among the species that lack the ability to vomit. The muscles of the equine lower esophageal sphincter are very robust, preventing opening of the hiatal valve under backward pressure from the stomach. The equine esophagus joins the stomach at an angle, so that pressure from gastric distention further closes the angle. In addition, the equine stomach is located deep within the rib cage and cannot be squeezed readily by abdominal muscles. When a horse (or other species that cannot vomit) ingests a toxin, induction of emesis is not an option; other measures must be taken to prevent absorption, such as gastric lavage or administration of absorbents and cathartics. Anatomical factors are discussed in greater detail in Module 1.

Clinical Pearl Horses, rabbits, rats, and mice (as well as other small rodents) cannot vomit. This may make them particularly vulnerable to certain orally ingested toxins.

Seasonal factors also must be taken into consideration when evaluating a species’ vulnerability to toxin exposure. Mycotoxins and poisonous plants are more abundant in certain climates and during certain seasons. The incidence of chocolate toxicity in dogs increases significantly around holidays when chocolate is more abundant (eg, Halloween, Christmas, Valentine’s Day, and Easter). Similarly, plants used as holiday decorations (eg, lilies and daffodils at Easter, mistletoe and holly at Christmas) are associated with an increase in pet poisonings. Pet exposure to specific plant toxins is beyond the scope of this activity; resources for independent study are provided later in this activity.

CANINE TOXICOLOGY

As a species, dogs have evolved as opportunistic gorgers of food. Predation on live prey can be risky business, so canids have evolved to take large, infrequent meals instead of numerous small meals. In the wild, canids are known to take on prey that approximate 45% of their own body weight.⁵ The tendency to gorge all of an available food source at once causes dogs to be at higher risk of toxicity from ingestion of large amounts of potential toxin. For example, if a dog encounters a bottle of prescription medication or a bag of chocolate candy, it is likely to consume the entire amount instead of just 1 tablet or 1 piece of chocolate. This habit also makes it more likely for dogs to ingest other foreign bodies (eg, pill vials, chocolate wrappers) in addition to ingesting toxic substances, further confounding treatment of the exposure. It has also been observed that this indiscriminate eating behavior is more common in juvenile animals, including dogs, other animal species, and human children.

Drugs

Drugs known to be potentially toxic to all canids include isoniazid, sulfonamides, estrogens, and nonsteroidal anti-inflammatory drugs (NSAIDs).

As discussed in greater detail in Module 1, increased susceptibility to drug toxicity in certain breeds of dogs is caused by a genetic polymorphism in the p-glycoprotein (P-gp) transporter protein also known as the multidrug resistant (MDR) or the ATP Binding Cassette (ABC) efflux transporter.⁶ Specifically, a 4-base pair deletion mutation in the ABCB1 gene results in failure of the P-gp pump at the blood–brain or other blood–compartment barriers. This mutation occurs at a very high incidence in many herding breed dogs, including collies, Australian shepherds, and Shetland sheepdogs.⁷ Many drugs used in veterinary medicine are substrates for P-gp, including chemotherapeutic agents (doxorubicin and vinca alkaloids), antidiarrheals (loperamide), and macrocyclic lactone heartworm preventatives (avermectins and milbemycin).

Isoniazid
As discussed in Module 1, canine species are deficient in transacetylase enzymes required for xenobiotic acetylation (eg, arylamine N-acetyltransferases). Drugs such as isoniazid that contain an aromatic amino group (-NH₂) must undergo acetylation to facilitate elimination; consequently, isoniazid may cause adverse effects or toxicity in dogs due to alternative metabolic pathways that result in toxic metabolites.

On the positive side, the inability to acetylate sulfanilamide to the less soluble and more toxic acetylsulfanilamide tends to protect dogs from the renal toxicity of sulfanilamide.⁸

Sulfonamides
Dogs also are susceptible to developing keratoconjunctivitis sicca (KCS; dry eye syndrome) from direct toxicity of sulfonamides to the acinar lacrimal glands.⁷ Because KCS sometimes can be irreversible, all dogs treated with ocular sulfonamide agents (eg, antibiotics, oral antidiabetic agents) should be monitored for squinting, ocular discharge, and conjunctivitis, and they should be examined by a veterinarian immediately if any of these signs are observed. It is important to note that although zonisamide is a sulfonamide, it is not a sulfonylarylamine—the form of sulfonamide that generates toxic nitrosyl molecules that can cause direct tissue injury and hypersensitivity reactions. For this reason, zonisamide is unlikely to cause KCS or other sulfonamide-related adverse effects in dogs (or cats, or sulfa-sensitive human caregivers).

Clinical Pearl Sulfonamides can cause keratoconjunctivitis sicca (dry eye syndrome) in dogs due to a direct toxicity to the acinar lacrimal glands. Pharmacists dispensing sulfonamide agents for canine patients should counsel pet owners to observe the dog for signs of KCS, including ocular discharge, squinting, and conjunctivitis. Dogs that exhibit any of these symptoms should be examined by a veterinarian immediately.

Estrogens
Dogs are susceptible to severe myelosuppression secondary to estrogen-induced production of a myelopoiesis-inhibitory factor in thymic stromal cells.¹⁰ The onset of myelosuppression is slow; clinical manifestations of marrow aplasia often are not evident for at least 3 weeks, giving dog owners a false sense of assurance that no toxic insult has occurred in the days following estrogen exposure. Unfortunately, by the time estrogen-exposed dogs are symptomatic, complete and often irreversible bone marrow aplasia has occurred.

Although pharmacists and pharmacy technicians rarely receive veterinary prescriptions for estrogens to be administered to dogs, they commonly dispense estrogens for human use in households with dogs. Counseling for human patients receiving prescriptions of estrogen always should include a warning to keep the medication out of the reach of children and animals. Pharmacists and pharmacy technicians can support veterinarians who need to treat estrogen exposure in animals by maintaining adequate inventories of activated charcoal, cholestyramine (to bind enterohepatically recycled estrogen in the gut) and myeloproliferative biologics (eg, epoetin, darbepoietin, filgrastim) at all times.

Clinical Pearl Estrogens cause dose-related myelosuppression in dogs often, resulting in fatal aplasia. Pharmacists, pharmacy technicians, and veterinary technicians should counsel all patients receiving estrogen therapy to keep these medications out of the reach of dogs and warn that exposure is a potentially life-threatening emergency.

NSAIDs
Selective inhibitors of cycloxygenase-1 (COX-1) such as carboxylic acids (eg, aspirin, ibuprofen) or enolic acids (eg, phenylbutazone, dipyrone) can be extremely toxic to dogs when ingested either acutely or chronically. NSAID toxicity is one of the most common forms of drug toxicity in dogs and among the 10 most common types of poisoning reported to the National Animal Poison Control Center.² Ibuprofen is the most common human medication ingested by pets; many brands have a sweet outer coating that makes them especially appealing to pets.

Although NSAIDs approved for human use (eg, naproxen, ibuprofen) are particularly toxic to dogs, NSAIDs approved for use in other species also are problematic. For example, phenylbutazone—an NSAID approved for use in horses—causes gastrointestinal ulceration, nephrotoxicity, hepatotoxicity, and myelosuppression in dogs.⁹

Clinical Pearl Human-labeled NSAID toxicity is one of the most common forms of drug toxicity in dogs. Whenever pharmacists and pharmacy technicians dispense or sell NSAIDs—for use in humans or animals—they should admonish the recipient to secure NSAID medications out of the reach of all pets, especially dogs. NSAIDs should never be administered to any animal without the advice of a veterinarian.

Excipients

Drugs approved for use in humans may be used legally in companion animals pursuant to a veterinarian’s order. Pharmacists and pharmacy technicians should scrutinize prescribing information and product labeling carefully to ensure that any drug intended for administration to a dog does not contain any surfactants, preservatives, or other additives known to be toxic to dogs. Potentially toxic excipients are listed in Table 1 and discussed in greater detail below.

Clinical Pearl Pharmacists and pharmacy technicians can search for prescribing information for approved drugs on the FDA website at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Surfactants
Nonionic surfactants such as polyethoxylated castor oil (Cremophor EL, Kolliphor) and polysorbates (Tween) 20 and 80 are used commonly as surfactants for lipophilic drugs. If these surfactants are administered intravenously to dogs, they trigger histamine release and complement activation, which can culminate in severe nonimmune anaphylactic shock reactions, hypotension, and death.^11-13 Polysorbate 80 is used extensively in parenteral drug formulations. Parenteral products known to contain polyethoxylated castor oil include paclitaxel injection (Taxol), cyclosporine injection (Sandimmune), and tenoposide injection (Vumon).¹⁴

Poloxomer 188 (Flocor) is used less commonly as a solvent for lipophilic drugs. Poloxomer 188 has been associated with complement activation in humans and may cause severe adverse reactions in dogs.¹⁵

Preservatives
Thimerosal has been shown to cause a moderate to severe reaction (including death) in 50% of dogs when injected.¹⁶ For this reason, thimerosal has been removed from the majority of canine vaccines. However, thimerosal continues to be used as a preservative in many dermatologic and ophthalmic products.

Ethoxyquin is used commonly as a preservative in food; it often is added to spices to prevent color loss.¹⁷ Ethoxyquin also is used sometimes in compounding as an antioxidant. The Food and Drug Administration (FDA) started receiving reports of ethoxyquin-associated toxicities in dogs in 1998. These toxicities included liver, kidney, thyroid and reproductive dysfunction; teratogenic and carcinogenic effects; allergic reactions; and a host of skin and hair abnormalities.¹⁸

Flavorings, Colorings, and Sweeteners
As mentioned earlier, substances containing primary aromatic amine structures must undergo acetylation in order to be eliminated, and dogs do not possess the transacetylase enzymes required to safely eliminate aromatic amines. A search of the United States Pharmacopeia (USP) Food Chemicals Codex reveals at least 10 monographs for primary aromatic amines commonly used in foods, including Green S, Amaranth, Brown HT, Quinoline Yellow, Azorubine, and Patent Blue V.¹⁹

The artificial sweetener xylitol is ubiquitous in human drugs (and foods; see below). Xylitol is significantly toxic to dogs at very low doses (100-500 mg/kg). Dogs absorb xylitol from the gut (humans do not); when xylitol enters the dog’s bloodstream, it provokes insulin release that causes profound, sometimes fatal, hypoglycemia. Exposure to higher doses of xylitol can result in hepatotoxicity in dogs.

Dogs that ingest any dosage form that potentially contains xylitol should be referred to a veterinarian immediately for emergency care. The maximum amounts of xylitol permitted in dosage forms intended for human use are listed in Table 2.

Clinical Pearl The artificial sweetener xylitol is extremely toxic to dogs. Dogs that ingest any dosage form or food that potentially contains xylitol should be referred to a veterinarian immediately for emergency care.

Foods

Foods known to be toxic if ingested by dogs produce effects that range from mild gastrointestinal upset to severe adverse reactions, including death. Dogs are very curious about what their owners are cooking and eating, and they will quickly ingest any available food if given the opportunity. Foods that can be toxic to dogs even in small amounts are listed in Table 3 and discussed in greater detail below.

Methylxanthines
Methylxanthines are phosphodiesterase inhibitors. They increase cyclic adenosine monophosphate, resulting in increased muscle contraction and neurologic and cardiovascular stimulation.

The methylxanthine caffeine is found in many foods and beverages. Pet owners should take pains to keep all caffeine-containing products away from their dogs.

Chocolate is particularly dangerous for dogs because it contains two methylxanthines: caffeine and theobromine. Theobromine has a considerably longer half-life in dogs (17.5 hours) than in other species (for example, 2.5-5 hours in humans)due to extensive enterohepatic recirculation.²¹ Toxicity is dose-related and depends on the amount of methylxanthines in the chocolate, with dark chocolate (eg Baker’s chocolate)containing more theobromine and caffeine than white or milk chocolate. Pharmacists, pharmacy technicians, and veterinary technicians should never flavor any compounded medication with chocolate, even if artificial; doing so can encourage an affinity for chocolate in dogs. It also is important for pharmacists, pharmacy technicians, and veterinary technicians to counsel pet owners not to administer medications to dogs by mixing them with chocolate milk, as suggested in the labeling of many human pediatric medications. Pharmacists and technicians should also be aware that energy drinks contain significant amounts of caffeine that may result in toxicity if ingested by dogs.

Allium Species
Members of the Allium family—garlic, onions, leeks, and chives—contain a variety of organosulfoxide components that cause oxidative hemolysis in dogs.

Allicin and ajoene, two pharmacologically active agents in garlic, are potent cardiac and smooth muscle relaxants, vasodilators, and hypotensive agents.^22-24 Ajoene also is a potent antithrombotic agent.²⁵ The anemia and impaired oxygen transport caused by oxidative hemolysis are worsened by the hypotensive and antithrombotic effects of ajoene, resulting in severe clinical signs of depression, lethargy, and weakness.

Consumption of as little as 15 to 30 g/kg of onion in dogs has resulted in clinically important hematologic changes. Dogs that ingest approximately 0.5% of their body weight in onions experience Allium toxicosis.²⁶ Dogs with a hereditary predisposition to elevated concentrations of erythrocyte reduced glutathione and potassium are more susceptible to the hematologic effects of onions.This trait is relatively common in Japanese breeds.²⁷

Clinical Pearl Onions, garlic, leeks, chives, and other members of the Allium family are extremely toxic to dogs, causing lethargy, depression, and hemolytic anemias. These flavors—even if artificial—should never be used to flavor medications for dogs.

Grapes, Raisins, and Currants
Acute renal failure can occur in dogs following ingestion of grapes from many sources, including:²⁸

• Fresh produce
• Dried raisins or currants
• Grape skins and pressings crushed for juice or winemaking.

The specific mechanism of acute renal failure is not known, but it is thought to be attributable to damage in the proximal renal tubular epithelium. The response to grape exposure varies widely from dog to dog and cannot be predicted for an individual dog. Reported toxic doses have been as low as 0.32 oz/kg for grapes and 0.65 oz/kg for raisins.²⁸ Onset of clinical signs usually begins within 6 to 12 hours of ingestion but may occur as late as 2 days after ingestion. Typical signs include nausea, vomiting, diarrhea, and anorexia, and laboratory findings indicate onset of acute renal failure.

Hops
Many dog owners know that alcohol is toxic to dogs, but few appreciate that the constituents of fermented spirits (ie, grapes in wine and hops in beer) are even more toxic to dogs. Hops toxicity is similar to grape toxicity in that the toxic element is unknown and there is no established threshold for toxicity; the response of individual dogs varies considerably, and any exposure to hops is potentially life-threatening. Although initial reports of hops toxicity were primarily in Greyhounds, it is now recognized that many breeds of dogs are affected. ²⁹ The onset of clinical signs varies from 30 minutes to 12 hours following ingestion. Vomiting may be followed by panting, agitation, injected (brick red) mucous membranes, significantly elevated body temperature (malignant hyperthermia), and eventually death.

Macadamia Nuts
Macadamia nuts have only recently been recognized as a nonfatal toxin in dogs. The exact mechanism of toxicity is not understood. Nonedible species of Macadamia contain cyanogenic glycosides; it is possible that these glycosides are present in edible Macadamia species in amounts that cause adverse effects in dogs. Toxic doses have been reported in the range of 2.4 g/kg to 62.4 g/kg.³⁰ This very broad range indicates that dogs exhibit individual sensitivity to macadamia nut toxicity.

Clinical signs of macadamia nut toxicity include vomiting, hyperthermia, abdominal pain, joint pain, limping, inability to stand, fever, pale mucous membranes, weakness, tremors, and ataxia.³¹ They usually occur within 12 hours of ingestion.³¹ These signs usually are not fatal— most pets fully recover without treatment—but they can be quite distressing to both the dog and the dog owner.

Xylitol
The dangers of xylitol were discussed in the Excipients section. It is important to note that xylitol often is used as an artificial sweetener in sugar-free foods, especially peanut butter and other nut butters. Dog owners commonly use peanut butter to hide medications for administration to dogs, so it is important that they check labels of nut butters and any other foods used to facilitate medication administer medication. When xylitol is added to foods, it often is expressed generically on the Nutrition Facts label as “sugar alcohols (polyols)” and not specifically as xylitol.

Benzocaine
Benzocaine is a local anesthetic commonly used in topical products and cough drops intended for use on humans. Benzocaine can cause methemoglobinemia in dogs after both topical and oral exposure.³²

Sodium Chloride
Ingestion of large amounts of salt (sodium chloride) by dogs can lead to hypernatremia and cerebral edema. Ironically, one of the most common causes of sodium chloride poisoning in dogs is administration of salt by the dog owner in an attempt to induce emesis after ingestion of another suspected toxin. Another common source of salt intoxication is from ingestion of the salt dough used to make homemade Christmas ornaments. Pet owners should be encouraged to seek immediate veterinary care whenever a toxic exposure is suspected, rather than resort to home treatment.

Most dogs love the flavor of meat-based bouillons. Unfortunately, many bouillons contain extremely high amounts of sodium chloride (1 gram of salt per 4 gram cube). Bouillons should not be used in the compounding of medications for dogs.

FELINE TOXICOLOGY

In contrast to dogs, cats have evolved as finicky picnickers of meals rather than opportunistic gorgers. Consequently, cat poisonings from drugs usually result from intentional administration of toxic substances by well-intended cat owners, not accidental self-ingestion by the cat. Plant ingestions, on the other hand, are usually the result of voluntary ingestion from cats grazing on houseplants or other available greenery.

Cats also have evolved as meticulous groomers, of both themselves and others. Ingestion of topically applied substances during grooming can result in unintended toxicity in cats as well as by other species that are known to groom.

Drugs

As described previously, cats express physiological variations that increase their susceptibility to substances generally not toxic to other species. Table 4 lists drugs known to be toxic to cats.

Analgesics
As discussed in Module 1, cats have a relatively limited ability to conjugate with glucuronyl transferase compared to other mammals and thus have limited capacity to conjugate with glucuronide. Substances that must be conjugated with glucuronide for elimination exert toxicity through either accumulation or generation of toxic metabolites through alternative metabolic pathways (or both). These substances include acetaminophen and NSAIDs.

Acetaminophen should never be given to cats at any dose. Because of slow formation of the glucuronide conjugate, the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite is produced by an alternate metabolic pathway. Available glutathione stores are not sufficient to remove the large concentrations of NAPQI, and unconjugated NAPQI exerts its damage on hemoglobin. Doses as low as 10 mg/kg have resulted in methemoglobinemia and death; doses of 40 mg/kg have resulted in hepatotoxicity and death.³⁴

Clinical Pearl Acetaminophen must never be administered to cats. Ingestion of amounts as low as 10 mg/kg can cause methemoglobinemia and death.

Limited capacity to conjugate with glucuronide also leads to accumulation of NSAIDs, including aspirin and other salicylates. This resultant higher serum concentration of NSAIDs results in loss of protective prostaglandins in the gastric tract and kidneys. Acute renal failure, gastric ulceration, and gastric perforation may occur within 12 hours of exposure or up to 3 to 5 days later.

Chloramphenicol, Oral Diazepam, and Griseofulvin
Deficiencies in demethylation and hydroxylation in cats are responsible for serious adverse events following administration of chloramphenicol, griseofulvin, or oral diazepam.³⁵ Adverse events occur subsequent to accumulation of drug and (in some cases) formation of toxic metabolites. Chloramphenicol can cause myelosuppression in cats. Orally administered diazepam is associated with idiosyncratic hepatic failure,³³ although diazepam apparently does not cause this response after parenteral routes of administration. Griseofulvin is reported to cause pancytopenia in cats through direct suppression of hematopoiesis after accumulation;³⁴ this drug generally is not recommended for cats due to safety concerns.

Propylthiouracil
Approximately 10% of geriatric cats (> 10 years of age) will develop hyperthyroidism.³⁸ Many of these cats will not be able to tolerate treatment with methimazole. Unfortunately, treatment with propylthiouracil carries a high risk of immune-mediated hemolytic anemia. Propylthiouracil is rarely, if ever, prescribed for cats.³⁹

Clinical Pearl Because propylthiouracil carries a high risk of immune-mediated hemolytic anemia in cats, pharmacists and pharmacy technicians should verify all prescriptions for propylthiouracil intended for cats. Pharmacists and pharmacy technicians also should take care to avoid misinterpreting handwritten or telephoned prescriptions for drug names that are similar to propylthiouracil (eg, ponazuril, propranolol, prazosin HCl).

Venlafaxine
Although cats often are treated with selective serotonin reuptake inhibitors (SSRIs), nonselective serotonin reuptake inhibitors (NSSRIs) can cause severe adverse effects, even in small doses. For example, venlafaxine causes dose-related sedation, tremors, serotonin syndrome, and cardiac arrhythmias.⁴⁰ Unfortunately, cats appear to willingly ingest venlafaxine (Effexor) capsules; cat owners should be cautioned to store this medication well out of the reach of their pets.

Alpha Lipoic Acid (ALA)
Although the mechanism is not clear, cats are considerably (approximately 10 times) more susceptible to neurological and hepatotoxicity from alpha lipoic acid (ALA) than either humans or dogs.⁴¹ Clinical signs may develop within 30 minutes to several hours following ingestion; they include hypersalivation, vomiting, ataxia, tremors and seizures, and death.

The minimum toxic dose of ALA in cats is 13 mg/kg. Neurologic signs, hepatotoxicity, and death occur at 30 mg/kg. ALA typically is available as a 600-mg capsule; ingestion of even one-fourth of the contents of 1 capsule is potentially lethal to an average 5-kg cat.

Clinical Pearl Cats are 10 times more susceptible to neurological and hepatic toxicity from alpha lipoic acid, and exposure to even small amounts can be fatal. Pharmacists, pharmacy technicians, and veterinary technicians should counsel cat owners not to attempt use of human adjunctive therapies in their pets—especially cats that are obese or have diabetes—without first consulting a veterinarian.

Enrofloxacin
As discussed in Module 1, failure of the ABCG2 P-gp pump in cats at the ocular blood barrier results in accumulation of photoreactive fluoroquinolones in the retina. Exposure of the retina to natural light (through the pupil) generates reactive oxygen species that cause retinal degeneration and blindness. This effect usually occurs at doses > 5 mg/kg; however, it may occur at lower doses.

Other Drugs
Estrogens can cause bone marrow suppression and blood dyscrasias in cats as well as dogs. Pharmacists, pharmacy technicians, and veterinary technicians should counsel all patients receiving estrogen therapy to keep these medications out of the reach of cats and warn that exposure is a potentially life-threatening emergency.

Benzoic acid derivatives (eg, benzocaine) and drugs that contain azo moieties (eg, phenazopyridine) require conjugation with glucuronide and can cause toxic effects in cats. Possible toxicities are described in greater detail in the next section.

Excipients

Pharmacists, pharmacy technicians, and veterinary technicians should also scrutinize product labeling carefully to ensure that any drug intended for administration to a cat does not contain any surfactants, preservatives, or other additives known to be toxic. Potentially toxic excipients are listed in Table 5. Most of these substances must be conjugated with glucuronide for elimination. Substances known to require conjugation with glucuronide typically contain specific functional groups (-OH, -COOH, NH_2, =NH, or -SH moieties) attached to either phenolic (ring) or alcoholic (straight-chain) bases.

Azo Dyes
Azo dyes are synthetic dyes that are used to color the majority of foods, drugs, and cosmetics throughout the world. They contain phenolic moieties that must be conjugated with glucuronide. In cats, accumulation of azo dyes and production of toxic metabolites through alternate pathways results in Heinz body formation and anemias.

In the United States, color additives for foods, drugs, and cosmetics are strictly regulated by the FDA. The FDA currently lists 40 dyes that are approved for use.⁵³ Once a dye is approved for use, it is given an FDA-certified color additive name; for example, the yellow tartrazine (an azo dye) is certified as FD&C Yellow No. 5. Many certified colors are azo dyes, but neither the FD&C number nor the traditional name indicates whether the dye is an azo dye. Pharmacists, pharmacy technicians, and veterinary technicians should consult an appropriate reference (eg, USP Food Chemicals Codex¹⁹) to determine whether a dye contains azo moieties.

Benzoic Acid Derivatives
Benzoic acid derivatives used as excipients include benzyl alcohol and benzoic acid. They must be conjugated with glucuronide or glycine. Multiple incidents of toxicity in cats have been reported.^43-46

It is interesting to note that metronidazole benzoate has not been reported to cause methemoglobinemia in cats when administered on a short-term basis. It is considered to be a safe short-term therapy for cats.

Essential Oils
Essential oils (eg, eucalyptus oil, tea tree oil, pennyroyal oil, peppermint oil) are volatile oils that give plants their characteristic odors. They are used primarily in perfumes and flavorings and also for aromatherapy. It is thought that plants produce essential oils largely as a mechanism of defense from pests; because these oils are “natural” products, they have found favor for use as insect repellents.

Although essential oils are safe for topical use on humans, cats are likely to groom and consequently ingest topically applied substances. Use of essential oils on cats has resulted in a number of feline poisonings and adverse events including lethargy, weakness, hypotension, tremors, renal failure, seizures, coma, and death.^47-49 Essential oils should not be used to compound products intended for cats, and pet owners should be cautioned not to use any “natural” product on a cat without first consulting a veterinarian.

Alcohols
Ethanols and other alcohols are toxic to cats by the same mechanisms as they are to dogs. However, cats are much less tolerant of propylene glycol than dogs are. Propylene glycol was commonly added to semi-moist cat food and treats in concentrations of 5% to 10% until it was recognized that this level of exposure often resulted in Heinz body anemias in cats.⁵⁰ As a result, the FDA banned the use of propylene glycol in cat foods in 1996;⁵¹ however, propylene glycol still is permitted in drugs approved for use in cats. Injectable solutions of drugs approved for use in humans may contain up to 82.043% propylene glycol.⁵² Although no threshold for propylene glycol has been established for drug products intended for cats, it is logical to assume that chronic exposure to concentrations of 5% to 10% or greater could be problematic, and feline exposure to propylene glycol should be minimized.

Foods

Foods known to be toxic to cats are listed in Table 6. Many of these foods also are toxic to dogs.

Allium species toxicity in cats is well-documentedand produces the same adverse sequellae as in dogs: depression, lethargy, weakness, and death due to anemia and inefficient oxygen transport.⁵⁴ Consumption of as little as 5 g/kg of onions in cats has resulted in clinically important hematologic changes.²⁶

Although there currently are no published reports of toxicity due to ingestion of grapes, raisins, or currants by cats, the ASPCA advises against feeding these substances to cats.⁵⁵ Other foods that the ASPCA recommends not feeding to cats include chocolate, coffee, and tomato leaves.⁵⁴

Hypernatremia from excessive sodium chloride intake poses the same risks for cats as it does for dogs. Similar precautions should be taken to avoid exposure of cats to excess sodium chloride.

TOXICOLOGY INFORMATION RESOURCES

A comprehensive discussion of the information necessary for pharmacists and pharmacy technicians to be well-informed about toxicological considerations in non-human species is beyond the scope of this activity. The list of non-human species is long, and the list of newly recognized toxic drugs, excipients, and foods grows every year. Pharmacists, pharmacy technicians, and veterinary technicians providing care, products, and compounds for non-human species are encouraged to develop an information support system that is both contemporary and credible and can be accessed easily and rapidly when the need arises.

Table 7 lists selected databases, textbooks, professional organizations, and websites that contain veterinary toxicological information. All of these sources are authored or staffed by credible experts in the field of veterinary toxicology and pharmacology. Plumb’s Veterinary Drugs monographs contain detailed information on overdose and acute toxicity for each drug.

REFERENCES

1. Gelatt KN, Van Der Woerdt A, Ketring KL, Andrew SE, Brooks DE, Biros DJ, Denis HM, Cutler TJ. Enrofloxacin‐associated retinal degeneration in cats. Vet Ophthalmol. 2001;4(2):99-106.
2. American Society for the Prevention of Cruelty to Animals. Ten most common pet toxins of 2018. https://www.aspca.org/news/just-announcing-top-10-toxins-2018. Accessed October 27, 2019.
3. American Veterinary Medical Association. U.S. pet ownership statistics. https://www.avma.org/KB/Resources/Statistics/Pages/Market-research-statistics-US-pet-ownership.aspx. Accessed October 27, 2019.
4. Van den Hurk P, Gerzel LE, Calomiris P, Haney DC. Phylogenetic signals in detoxification pathways in Cyprinid and Centrarchid species in relation to sensitivity to environmental pollutants. Aquat Toxicol. 2017;188:20-25.
5. Van Valkenburgh B. Deja vu: the evolution of feeding morphologies in the Carnivora. Integr Comp Biol. 2007;47(1):147-163.
6. Mealey KL, Bentjen SA, Gay JM, et al. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001;11(8):727-733.
7. Washington State University College of Veterinary Medicine Veterinary Clinical Pharmacology Laboratory. Affected breeds. http://vcpl.vetmed.wsu.edu/affected-breeds. Accessed October 27, 2019.
8. Sipes IG, Gandolfi AJ. Biotransformation of toxicants. In: Amdur MO, Doull J, Klaasen CD, eds. Cassarett & Doull’s Toxicology: The Basic Science of Poisons. 4^th New York, NY: Pergamon Press; 1991.
9. Riviere JE, Papich MG, eds. Veterinary Pharmacology and Therapeutics. 10^th Ames, IA: Wiley-Blackwell; 2017.
10. Sontas HB, Dokuzeylu B, Turna O, et al. Estrogen-induced myelotoxicity in dogs: a review. Can Vet J. 2009;50(10):1054-1058.
11. Qiu S, Liu Z, Hou L, et al. Complement activation associated with polysorbate 80 in beagle dogs. Int Immunopharmacol. 2013;15(1):144-149.
12. Szebeni J, Muggia F, Gabizon A, et al. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev. 2011;63(12):1020-1030.
13. Weiszhár Z, Czúcz J, Révész C, et al. Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20. Eur J Pharm Sci. 2012;45(4):492-498.
14. Katdare A, Chaubal M, eds. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. New York, NY: Informa Healthcare; 2006:278.
15. Moghimi SM, Hunter AC, Dadswell CM, et al. Causative factors behind poloxamer 188 (Pluronic F68, Flocor)-induced complement activation in human sera. A protective role against poloxamer-mediated complement activation by elevated serum lipoprotein levels. Biochim Biophys Acta. 2004;1689(2):103-113.
16. Subcommittee on Human Rights and Wellness of the Committee on Government Reform, U.S. House of Representatives. Mercury in medicine—taking unnecessary risks. http://www.gpo.gov/fdsys/pkg/CREC-2003-05-21/html/CREC-2003-05-21-pt1-PgE1011-3.htm. Published May 21, 2003. Accessed October 27, 2019.
17. United States Environmental Protection Agency. EPA R.E.D. FACTS: Ethoxyquin. EPA-738-F-04-006. November 2004. https://archive.epa.gov/pesticides/reregistration/web/pdf/0003fact.pdf. Accessed October 27, 2019.
18. Dzanis DA. Safety of ethoxyquin in dog foods. J Nutr. 1991;121(11Suppl):S163-164.
19. S. Pharmacopeial Convention. Food Chemicals Codexonline. http://online.foodchemicalscodex.org. Accessed October 27, 2019.
20. S. Food and Drug Administration. Inactive ingredient search for approved drug products (search term “xylitol”). http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm. Accessed October 27, 2019.
21. Baggott MJ, Childs E, Hart AB, et al. Psychopharmacology of theobromine in healthy volunteers. Psychopharmacology. 2013;228(1):109-118.
22. Mayeux PR, Agrawal KC, Tou JS, et al. The pharmacological effects of allicin, a constituent of garlic oil. Agents Actions. 1988;25:182-190.
23. Martin N, Bardisa L, Pantoja C, et al. Experimental cardiovascular depressant effects of garlic (Allium sativum) dialysate. J Ethnopharmacol. 1992;37:145-149.
24. Malik ZA, Siddiqui S. Hypotensive effect of freeze-dried garlic (Allium sativum) sap in dog. J Pak Med Assoc.1981;31:12-13.
25. Apitz-Castro R, Badimon JJ, Badimon L. Effect of ajoene, the major antiplatelet compound from garlic, on platelet thrombus formation. Thromb Res.1992;68:145-155.
26. Cope RB. Toxicology Brief: Allium species toxicity in dogs and cats. http://veterinarymedicine.dvm360.com/toxicology-brief-allium-species-poisoning-dogs-and-cats. Accessed October 27, 2019.
27. Yamoto O, Maede Y. Susceptibility to onion-induced hemolysis in dogs with hereditary high erythrocyte reduced glutathione and potassium concentrations. Am J Vet Res. 1992;53:134-137.
28. Mazzaferro EM. Acute renal failure associated with raisin or grape ingestion in 4 dogs. J Vet Emerg Crit Care. 2004;14(3):203-212.
29. Duncan KL, Hare WR, Buck WB. Malignant hyperthermia-like reaction secondary to ingestion of hops in five dogs. J Am Vet Med Assoc. 1997;210(1):51-53.
30. Hansen SR, Buck WB, Meerdink G, et al. Weakness, tremors, and depression associated with macadamia nuts in dogs. Vet Hum Toxicol. 2000;42(1):18-21.
31. Hansen SR. Macadamia nut toxicosis in dogs. Veterinary Medicine. April 2002. http://aspcapro.org/sites/pro/files/x-toxbrief_0402_0.pdf. Accessed October 27, 2019.
32. Harvey JW, Sameck JH, Burgard FJ. 1979. Benzocaine-induced methemoglobinemia in dogs. J Am Vet Med Assoc. 1979;175(11):1171-1175.
33. Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract. 2013;43(5):1039-1054.
34. Poppenga RH, Gwaltney-Brant SM, eds. Small Animal Toxicology Essentials. Ames, IA: Wiley-Blackwell; 2011.
35. Boothe DM, ed. Small Animal Clinical Pharmacology and Therapeutics. 2^nd St. Louis, MO: Elsevier Saunders; 2011.
36. Center SA, Elston TH, Rowland PH, et al. Fulminant hepatic failure associated with oral administration of diazepam in 11 cats. J Am Vet Med Assoc. 1996;209(3):618-625.
37. Helton KA, Nesbitt GH, Cariolo PL. Griseofulvin toxicity in cats: literature review and report of seven cases. J Am Anim Hosp Assoc. 1986;22:453-458.
38. Peterson M. Hyperthyroidism in cats: what’s causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg. 2012;14(11):804-818.
39. Aucoin DP, Peterson ME, Hurvitz AI, et al. Propylthiouracil-induced immune-mediated disease in the cat. J Pharmacol Exp Ther. 1985;234(1):13-18.
40. Dunayer ED, Merola V. Toxicology Brief: The 10 most common toxicoses in cats. Veterinary Medicine. June 1, 2006. http://veterinarymedicine.dvm360.com/toxicology-brief-10-most-common-toxicoses-cats. Accessed October 27, 2019.
41. Hill AS, Werner JA, Rogers QR, et al. Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats. J Anim Physiol Anim Nutr. 2004;88(3-4):150-156.
42. Ramirez CJ, Minch JD, Gay JM, et al. Molecular genetic basis for fluoroquinolone-induced retinal degeneration in cats. Pharmacogenet Genomics. 2011;21(2):66-75.
43. Bedford PGC, Clarke MA. Suspected benzoic acid poisoning in the cat. Vet Rec. 1971;88:599-601.
44. Cullison EA. Toxicosis in cats from use of benzyl alcohol in lactated Ringers solution. J Am Vet Med Assoc. 1983;182(1):61.
45. Krake AC, Arendt TD, Teachout DJ, et al. Cetacaine-induced methemoglobinemia in domestic cats. J Am Anim Hosp Assoc. 1985;21:527-534.
46. Wilkie DA, Kirby R. Methemoglobinemia associated with dermal application of benzocaine cream in a cat. J Am Vet Med Assoc. 1988;21:85-86.
47. Villar D. Toxicity of melaleuca oil and related essential oils applied topically on dogs and cats. Vet Hum Toxicol. 1994;36(2):139-142.
48. Richardson JA. Potpourri hazards in cats. Veterinary Medicine. December 1999. http://aspcapro.org/sites/pro/files/zh-toxbrief_1299_0.pdf. Accessed October 27, 2019.
49. Genovese AG, McLean MK, Khan SA. Adverse reactions from essential oil‐containing natural flea products exempted from Environmental Protection Agency regulations in dogs and cats. J Vet Emerg Crit Care. 2012;22(4):470-475.
50. Christopher MM, Perman V, Eaton JW. Contribution of propylene glycol-induced Heinz body formation to anemia in cats. J Am Vet Med Assoc. 1989;194(8):1045-1056.
51. S. Department of Health and Human Services. Substances prohibited from use in animal food or feed. 21 CFR §589.1. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=589&showFR=1. Accessed October 27, 2019.
52. S. Food and Drug Administration. Inactive ingredient search for approved drug products (search term “propylene glycol”). http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm. Accessed October 27, 2019.
53. Barrows JN, Lipman AL, Bailey CJ. Color additives: FDA’s regulatory process and historical perspectives. Food Safety Magazine. Oct/Nov 2003. http://www.fda.gov/ForIndustry/ColorAdditives/RegulatoryProcessHistoricalPerspectives. Accessed October 27, 2019.
54. Kobayashi K. Onion poisoning in the cat. Feline Pract. 1981;11(1):22-27.
55. American Society for the Prevention of Cruelty to Animals. Cat care. 2010. https://www.aspca.org/sites/default/files/cat_edu.pdf. Accessed October 27, 2019.

Back to Top