Adverse drug reactions in horses (Proceedings)

The official definition of an adverse drug reaction is “any response to a drug which is noxious and unintended and which occurs at doses of an appropriately given drug used for the prophylaxis, diagnosis, or therapy, excluding therapeutic failures and occurring within a reasonable time frame of administration of the drug.”

From a practitioners' standpoint, however, it is the unpredictable severe reactions that are of greatest concern. In many instance, the signs of an adverse drug reaction are not recognized for what they are. Rather, they are often attributed to signs caused by the underlying disease process. The most important step towards recognizing and responding appropriately to an adverse drug reaction is to retain an index of suspicion that it may be present.

Adverse drug reactions are generally divided into two broad categories.  The first category might be termed the “expected” unexpected event. These are commonly termed side effects, and most practitioners administer pharmacologic agents fully aware that in rare instances unintended effects take place. These are generally patient or dose–related, and cause damage to organ systems unrelated to the drug's primary action.

An example would be the development of antibiotic-induced colitis after trimethoprin/sulfa is prescribed for a laceration. In most instances stopping administration of the causative agent with the first development of clinical signs is sufficient. Because these effects are rather common, it is important to warn clients about their possibility or to monitor the patient carefully before life threatening problems arise.

The second type of adverse drug reaction might be termed the “unexpected” unexpected event. In these instances, the reaction is not a known side effect of the drug being administered, but a unique event. Generally, unexpected reactions fit into two categories. The first reflect immunologic causes, such as hypersensitivity reactions or anaphylaxis. The second group is idiosyncratic reactions, which features a patient developing a severe reaction for no identifiable reason to a drug that is given via the appropriate route and in the appropriate dose.

Prevention

While it may seem counter-intuitive to attempt to prevent an unpredictable event, there are several steps one can take to minimize the occurrence of adverse drug reactions.  First and foremost, a thorough understanding of the drugs one administers is paramount. This includes appropriate dose and route. Accurately dosing for weight in miniature horses, small ponies, and foals is quite important.

For example, giving 0.25 gram phenylbutazone in a 200-pound foal is an overdose, and one could expect signs of NSAID toxicity if this amount is administered for longer than 2-3 days. It is important to be aware of the most common adverse effects of drugs being administered and know how to recognize and treat them. Giving multiple agents at once increases the odds of a reaction, due both to the possibility of drug-drug interactions and the fact that metabolism of one may interfere with the clearance of another. Using drugs that are approved for use in the horse means that basic safety testing has been performed in equids.

This is not the case for therapeutics labeled for other species or to be given by alternative routes. An example of an adverse reaction to a drug given by an alternative route is what can occur when DMSO is administered intravenously. DMSO is labeled for topical use, and will cause hemolytic anemia if given in too strong a concentration I.V.   The cartilage damage in growing foals caused by enrofloxacin is an example of an adverse event in a horse caused by a product that is not labeled for that species.

 Allergic drug reactions

Allergic reactions are hypersensitivity reactions that exert their effect via immunologic mechanisms. The number of allergic reactions in veterinary medicine is unknown. In humans, they constitute 10% of all drug reactions. Generally they are unanticipated unless an adverse reaction, such as hives, from a prior exposure was recognized.

There is always a lag time between the initial exposure and the development of the reaction. Unfortunately, in the vast majority of instances, the initial exposure goes unrecognized.  A relatively small number of drugs are responsible for the majority of reactions, with beta-lactam antibiotics and NSAIDs being the most common causative agents in equine patients. Whether these drugs are uniquely antigenic, or merely the drug classes most commonly prescribed, is not known. 

Allergic responses are not dose related; the patient will react similarly whether a therapeutic or small test dose is administered. The reaction does not resemble the pharmacologic action of the drug. Rather, the clinical signs relate to the type of immune response that predominates (See Table 1). Large proteins such as those found in blood products are always immunogenic. Smaller molecules, such as the ones that comprise most therapeutic agents, do not stimulate an antigenic response unless they are complexed to a larger protein.

Immediate hypersensitivity – anaphylaxis

Anaphylaxis occurs in individuals that have been sensitized to an antigen and have circulating IgE. Exposure to the antigen causes IgE-mediated and non-IgE mediated degranulation of mast cells and basophiles. The inflammatory mediators released cause the clinical signs seen with anaphylaxis. In horses, clinical signs occur shortly after parenteral administration of an inciting agent. Signs may be delayed if the agent is inhaled, ingested, or given in a depot form that is slowly absorbed. Signs include the rapid development of hives, tachycardia, tachypnea, collapse, and death.  Treatment is often not successful.

Rapid administration of epinephrine 1:1000 or 1 mg/ml at a dose of 0.01-0.02 mg/kg IV (5 ml per 1000 pound horse), followed by dexamethasone at a dose of 0.2 mg/kg IV, can be attempted. If no response is seen after 20 minutes, a second course of therapy is indicated.  If no improvement in clinical signs is noted after 2 doses of epinephrine, suspect that something other than anaphylaxis is responsible for the problem. Confirming that a suspected agent is responsible for the development of anaphylaxis can be hazardous as reactions are not dose-dependent, and even a small test dose or intradermal administration can trigger another attack. Purchasing a medic alert tag at a pharmacy and attaching it to the horse's halter should be considered to prevent future administration of the causative agent.

Reporting an adverse drug reaction

In the case of a suspected adverse reaction, the veterinarian can report the problem to either the manufacturer, the Food and Drug Administration, or the United States Pharmacopeia's (USP) Veterinary Practitioner Reporting Program. The manufacturer is unlikely to respond if the drug in question is not labeled for horses. In general, a veterinarian can expect no support from the manufacturer if the drug in question is compounded. The USP forwards the information it receives to the correct regulatory agency and to the manufacturer.

Table 1. Factors that are known to influence the development of adverse drug reactions Patient factors Individual variation in pharmacokinetic behavior or bioavailability Presence of other drugs Incidence increases with number of drugs given simultaneously Age Younger than 30 days or aged Sex Females more frequently affected than males Pregnancy   Concurrent disease Dehydration, fever, organ dysfunction etc. cause alterations that influence drug disposition Immunologic status Patients with prior history of adverse reactions. Previous administration of plasma or blood products may sensitize horse to foreign proteins

Table 2. Immunologic and Non immunologic Drug Reactions TYPE EXAMPLE Immunologic   Type I (IgE-mediated) Anaphylaxis from β-lactam antibiotic Type II (cytotoxic) Hemolytic anemia from penicillin Type III (immune complex) Serum sickness Type IV (delayed hypersensitivity) Contact dermatitis from topical drug Fas/Fas ligand-induced apoptosis Toxic epidermal necrolysis     Nonimmunologic   Predictable   Pharmacologic side effect Colic from atropine Secondary pharmacologic side effect Drug-induced enterocolitis Drug toxicity Renal failure from gentamicin Drug-drug interactions Increased absorption reserpine due to oral corticosteroids Drug overdose Seizure from excessive lidocaine Unpredicatable   Pseudoallergic Anaphylactoid reaction after radio contrast media Idiosyncratic Hemolytic anemia in patient with G6PD deficiency

Intolerance

GUD after low dose phenylbutazone

Table 3. Cutaneous Symptoms of Drug Hypersensitivity Reactions TYPE OF LESIONS MECHANISM Urticaria IgE antibody-mediated or direct mast cell stimulation Purpura Vasculitis or drug-induced thrombocytopenia Blistering lesions with mucous membrane involvement Toxic epidermal necrolysis Inflammation and necrosis in unpigmented areas Photoallergic reaction Solitary circumscribed erythematous raised lesions Fixed drug eruption Papulovesicular, scaly lesion Contact dermatitis