CHAPTER 1 Adverse Drug Reactions
Any pharmacologic agent has the potential to cause an adverse reaction in a patient. In some instances, a reaction is inherent, dose-dependent, and predictable. In others, it is considered idiosyncratic and may occur even when the drug is administered at recommended doses. To prevent or treat any adverse drug reaction, it is important to use drugs properly as well as to diagnose and treat problems promptly and appropriately.
DEFINITIONS
An adverse drug reaction (ADR) can be broadly defined as any “appreciable harmful or unpleasant reaction resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.” This definition includes both toxic effects and side effects, which have very different meanings. Toxic effects are considered harmful and occur via the same mechanism as the therapeutic effects, but are associated with higher doses. Side effects occur via a separate mechanism of action, might not be dose-related, and may be harmful or beneficial. The terms adverse drug reaction and adverse drug effect are often used interchangeably, the only difference being that an adverse reaction relates to the change in the patient, and the adverse effect relates to the effect of the drug. An adverse event, however, should be considered separate from the other term because it defines an adverse outcome that occurs while a patient is receiving a drug but for which causality has not been determined and may or may not be related to the drug being administered.
CLASSIFICATION OF ADVERSE DRUG REACTIONS
Adverse drug reactions can manifest in various ways. Therefore, they are often difficult to diagnose. The different presentations of ADRs are described below.
Dose-Related Reactions
Dose-related reactions are the most commonly seen ADRs. These reactions are related to the pharmacologic effect of the drug and are predictable and expected. They typically develop as the drug reaches steady-state concentrations in the plasma (i.e., after 5 half-lives of the drug). Because of this predictability, dose-related reactions are the most frequently diagnosed and are preventable, resulting in a low mortality rate. Examples of dose-related drug toxicoses in equine medicine include aminoglycoside-induced nephrotoxicosis and digoxin-induced arrhythmias.
Non–Dose-Related (Idiosyncratic) Reactions
Non–dose-related reactions are much less common than dose-related ADRs. They are not related to the pharmacologic action of the drug and are therefore not predictable. Additionally, they can arise anytime after drug administration has begun. Unfortunately, these reactions are often severe and are associated with a much higher mortality rate. Examples of non–dose-related drug toxicoses in equine medicine include allergic reactions, such as those seen with penicillins, and malignant hyperthermia, which can be associated with inhalant anesthetics.
Dose- and Time-Related (Chronic) Reactions
Dose and time-related (chronic) reactions develop with chronic administration of a drug and are related to the total cumulative dose of the drug being administered. They are relatively rare but can be predicted in some instances. Temporally, they tend to occur after the drug has been administered for a long period (weeks to months). Examples include gastrointestinal ulceration associated with nonsteroidal anti-inflammatory drug (NSAID) administration or alterations in cardiac function with chronic clenbuterol administration.
Time-Related (Delayed) Reactions
Time-related (delayed) reactions become apparent only after treatment has been discontinued for a prolonged period. Because of this, they can be difficult to associate with drug administration. The teratogenic effects in horses caused by drugs such as griseofulvin, trimethoprim-sulfonamide-pyrimethamine combinations, or cambendazole are examples of delayed ADRs. In this instance, diagnosis involves associating drug administration with the appropriate gestational period of system development.
Withdrawal
Withdrawal reactions occur shortly after discontinuation of drug use and are often related to physical dependency on the drug. They are uncommon in horses. The best example in equine medicine is adrenal exhaustion after prolonged administration of corticosteroids.
DIAGNOSIS OF ADVERSE DRUG REACTIONS
The determination of causality in cases of potential ADRs can be difficult. Definitive diagnosis often involves consideration of the timing of drug administration, the mechanism of the drug’s known toxicity, and the effects of drug withdrawal and reintroduction of drug administration. The effect of reintroduction of the drug is not always possible to determine, particularly in the clinical setting, and depends on the severity of the reaction. Similarly, withdrawing the drug may not be possible, particularly if it is an essential drug and there is no suitable substitute drug available from a different class. In these instances, a reduction in drug dosage may be the only possible route. Therefore, most instances of clinical ADRs are diagnosed on the basis of temporal relationship and the likelihood of the drug causing that effect.
If this approach is used, one must take into account the background frequency of the event and other confounding factors, such as the actual disease process being treated and the effects of concurrently administered drugs. For instance, a horse that develops signs of colic while receiving misoprostol may be developing colic secondary to misoprostol’s effects on smooth muscle contractility, or the colic may be a result of an unrelated gastrointestinal disturbance, such as an impaction, or the primary disease process being treated, such as gastric ulceration or right dorsal colitis. Because colic is such a frequent occurrence in horses, attributing this sign to a drug would require large numbers of horses to develop similar signs during a similar period during or after administration of the given drug. Ventricular arrhythmias, on the other hand, are infrequent in horses, and if arrhythmia develops after initiation of treatment with digoxin, it is most likely related to administration of the drug.
Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM) can be an extremely useful tool for diagnosing dose-related ADRs. The purpose of TDM is to relate plasma concentrations in the patient with the known therapeutic or toxic concentrations of the drug. The most common methods used in TDM are high-pressure liquid chromatography, fluorescence polarization immunoassay, and radioimmunoassay. High-pressure liquid chromatography can be used to detect the largest number of drugs and can accurately and specifically quantitate a drug and its metabolites in plasma or other media. It is also expensive and time consuming. The fluorescence polarization immunoassay method is very easy to perform and has been used for TDM in veterinary practice. Drugs commonly monitored via this method include aminoglycosides, cyclosporin, digoxin, phenobarbital, procainamide, quinidine, and theophylline. One drawback to this analytic method is that these assays have been developed and validated for human plasma, and their sensitivity and specificity in veterinary species may vary, particularly with the production of drug metabolites, such as cyclosporine, that cross-react with the immunoassay. Radioimmunoassay kits have been used for TDM, particularly with opiate drugs and corticosteroids, which are therapeutic at very low plasma concentrations that may be difficult to detect with other methods. TDM is most effective if the therapeutic and toxic plasma concentrations are known, but this information is scarce in veterinary medicine. Available data are summarized (Table 1-1).
Table 1-1 Therapeutic and Toxic Plasma Drug Concentrations Used for Therapeutic Drug Monitoring in Veterinary Medicine
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| Drug | Therapeutic Concentrations | Toxic Concentrations |
|---|---|---|
| Amikacin | 40 μg/mL (peak) | ≥3 μg/mL (trough) |
| Bromide | 100-200 mg/dL (monotherapy) | N/A |
| 200-300 mg/dL (combination therapy) | ||
| Cyclosporine∗ | 300-600 ng/mL (trough) | N/A |
| Digoxin | 0.5-2 ng/mL (6-8 h after dose) | ≥2.5 ng/mL |
| Gentamicin | 20-40 μg/mL (peak) | ≥2 μg/mL (trough) |
| Lidocaine | 1-3 μg/mL (for prokinetic effects) | 2-4 μg/mL |
| Phenobarbital | 15-40 μg/mL (peak) | ≥40 μg/mL |