Medications, Therapeutic Agents, and Illicit Substances

Dionne Benson • Lynn R. Hovda

Toxic and adverse drug reactions in large animals occur with some frequency but are not as routinely reported as occurrences in small animals. Blurred lines between toxicity and adverse reactions exists in the literature and in practice.

Adverse drug reactions can be classified in a variety of ways with six different presentations of the normal scheme.^2,3 A more simplified approach uses only two different types of reactions: dose related and idiosyncratic.⁴ In dose-related reactions the signs move from physiologic to pharmacologic to toxic as the dose is increased. Often simply stopping the medication and allowing the drug to clear the system results in cessation of the clinical signs. Anaphylactoid reactions are included in this group because they are not immune mediated and depend on mast cell degranulation to manifest effects. Idiosyncratic reactions are generally not related to a specific dose or concentration of the medication administered. Immune- mediated reactions are included in the group.

Finding accurate information on adverse or toxic medica­tion reactions in large animals is difficult. Preclinical studies are generally small and include a limited number of animals when, in fact, the medication will be used to treat thousands of animals and reactions may not show up until these numbers are reached.⁵ Clinical trials are often helpful, but again small numbers of animals may be involved.

Treatment of adverse or toxic reactions varies for each medication and route of exposure. Few antidotes exist for large animal medications, and for the most part treatment is symp­tomatic and supportive.⁶ The use of an offending medication should be discontinued as soon as a reaction is recognized. Bathing for topical exposures, gastric lavage followed by activated charcoal for most recent oral exposures, mineral oil, and intravenous fluids are all useful tools for dealing with the clinical signs.

The most commonly reported adverse or toxic drug reactions in horses are to antimicrobials (procaine benzylpenicillin), NSAIDs, anesthetic agents, sedatives, and antiparasitic drugs.⁷ Reports in cattle and swine primarily implicate antimicrobials.⁷ Some of these drugs are covered in separate chapters or dis­cussed more generally throughout this text.

Antimicrobial Drugs

It is not possible in the scope of this chapter to begin to review all the antimicrobial drug adverse or toxic reactions. Two antimicrobials, however, have specific known risk factors for large animals and are covered here.

Doxycycline

Doxycycline is a tetracycline used in large animal medicine to treat a variety of illnesses. The IV use of doxycycline in horses is not recommended and has been associated with supraventricular tachycardia, systemic arterial hypertension, discomfort, collapse, and death.⁸ The cause is unknown but may be concentration or infusion-rate dependent. Treatment is symptomatic and supportive.

Sudden death has been reported in calves accidentally receiving 3 to 10 times the recommended daily dose (5 mg/kg bid) of doxycycline.^9,10 There is no known breed or genetic predisposition. Clinical signs included lethargy, dullness, loss of appetite, cough, dysphagia from paresis or paralysis of tongue, tachycardia, and tachypnea.

Enrofloxacin

Enrofloxacin is a second-generation quinolone metabolized in the liver to ciprofloxacin, an active metabolite. Ciprofloxacin, itself a quinolone antimicrobial, should not be used orally in horses because it causes mild diarrhea to severe colitis, laminitis, and endotoxemia.¹¹

The most common adverse reactions in horses include mild diarrhea, neurologic signs, and orthopedic disorders in young animals. The neurologic signs are generally dose related (i.e., high dose, bolus route) and transient, resolving in 10 to 15 minutes after administration.¹² Diluting the drug and administering it at a slower rate prevents the development of neurologic signs. Juvenile arthropathies with associated cartilage damage have been reported in neonatal foals and other species, but the true incidence is unknown.¹³

Several other adverse or toxic reactions have been reported. Intrauterine infusion in mares resulted in acute endometrial ulceration, necrosis, and hemorrhage, as well as fibrosis with inflammation.¹⁴ Oral ulcers developed in animals treated with a gel compounded from the injectable cattle product.¹⁵ Finally, to prevent toxicosis, the dose in neonatal calves needs to be lowered to accommodate their lower amounts of body fat and different metabolic capacities.¹⁶

B₂-Adrenergic Receptor Agonists (Clenbuterol, Ractopamine, Zilpaterol)

All three of these agents have been abused in horses for their known anabolic effects.^17,18 The use of clenbuterol in food-producing animals, once similarly abused, is now completely banned due to accumulation in meat.¹⁹ Racto­pamine and zilpaterol are still allowed as feed additives and are discussed later in this chapter (see the Feed Additives section later).

Clenbuterol is labeled for the management of acute and chronic respiratory disorders in horses. The normal dosage range is 0.8 to 1.6 ug/lfor muscle partitioning in food-producing animals is estimated to be 5 to 10 times the therapeutic dose, whereas the dosage needed for repartitioning in horses is much lower at 2.4 μgτ⅛ bid.²⁰

At normal doses clenbuterol is a moderately selective β₂-adrenergic receptor agonist; at high doses all β-adrenergic receptors are stimulated, and a wide variety of signs occur. Clinical signs are dose dependent, with nervousness and mild agitation, sweating, and increased heart rate occurring in some horses 5 to 10 minutes after a therapeutic dose of 1.6 μg/kg.¹⁹ Far larger overdoses, 10 μg7lin 24 hours with supportive care.⁴²

Illicit Substances

Cobalt

Cobalt is an essential mineral for mammalian species. It is used in the creation of cobalamin (vitamin B₁₂). The dietary need for cobalt varies by species and is higher in ruminants (especially sheep) than in horses.^43-45 Toxicity in ruminants is often poorly recognized due to the lack of distinctive clini­cal signs.⁴⁶ Cobalt, however, has purportedly been used as a supplement to racing horses to induce erythropoietin creation by stabilizing hypoxia-inducible factor 1α.^47,48 Despite a lack of evidence-based medicine that this process occurs in the horse, there are allegations that this practice continues. Toxicity in the horse has been observed when high doses of cobalt are administered to research horses.⁴⁹ Toxicity has been documented in videos showing sweating, colic, and muscle fasciculations.⁴⁹ Signs resolved within hours without medical intervention.⁴⁹

Glaucine

Glaucine was recently identified in several samples collected from racehorses. Glaucine is available in injectable products that can be purchased on the Internet.

Dermorphin

Dermorphin is a peptide that bonds to mu opioid receptors.⁵⁴ It has been identified in samples collected from racing horses. It is purported to be administered for its analgesic properties. In a study investigating selected pharmacodynamic effects of dermorphin, researchers identified several responses to IV administration, including headshaking, colic-type symptoms, sweating, tachypnea, and sedation.⁵⁴ These behaviors also occurred to a lesser degree in some horses receiving IM administration. Most symptoms resolved quickly and without supportive care.⁵⁴

Nomifensine

Nomifensine was recently identified in samples collected from several racehorses. Sold as a prescription antidepressant and later removed from the United States market, nomifensine may now be used in competitive horses for its dopamine-related analgesic effects.⁵⁵ There have been no reports of nomifensine- related toxicity in horses. In a study of nomifensine in dogs, dosages in the 3 to 10 mg/kg range had slight effects on blood pressure, heart rate, and blood flow.⁵⁶ These effects were transient in nature. It was withdrawn from the U.S. human drug market due to the risk of hemolytic anemia.⁵⁷

Gamma-Aminobutyric Acid

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter present in the CNS of mammals.⁵⁸ In show and racing horses there have been allegations of inappropriate use of exogenous GABA for its calming effects. In research, IV administration caused transient sedative effects and increased heart rate.⁵⁸ In addition, purported effects of IV injection include sudden death, although this claim has not been verified. Other potential detrimental effects are unknown.