Any harmful and undesirable phenomenon occurring during treatment of a patient is termed an adverse event (AE). When drug treatment is associated with an adverse event it is termed an adverse drug reaction (ADR). Although no universally accepted definition exists, most medical and veterinary authorities concur that an ADR is a reaction which is harmful, unintended and which occurs at doses normally used for prophylaxis, diagnosis or treatment of disease or the modification of physiological function.

Classification of Adverse Drug Reactions

Type A (augmented) ADRs are expected but exaggerated pharmacologic or toxic responses to a drug. They may be an exaggeration of the intended response to the drug, a secondary response affecting an organ other than the target organ but predictable based on the pharmacology of the drug, or at the extreme, a toxic response.

Most ADRs of this type are attributable to differences in drug disposition that result in higher plasma and tissue drug concentrations arising from dysfunction of organs of metabolism and excretion, or inappropriate dosage, for example the administration of a non-lipid soluble drug to an obese dog with no dose adjustment. Type A ADRs are usually dose-dependent and avoidable if sufficient drug and patient information is available and considered.

Type B (bizarre) reactions are unexpected or aberrant responses that are unrelated to the drug's pharmacological effect, are not dose dependent and are unpredictable and idiosyncratic. Type B ADRs include allergic and pseudoallergic (non immunological) reactions, direct toxic effects on organs that are associated with actions unrelated to any desired therapeutic effect (the mechanisms for which may be complex and obscure), and aberrant responses in different species.

Type C (chronic) ADRs occur only during prolonged treatment programs, for example the induction of iatrogenic Cushing's syndrome with chronic use of prednisolone.

Type D (delayed) ADRs are experienced remote from the time of treatment and therefore may be difficult to diagnose in the absence of an astute clinician and an excellent history. Second cancers developing in patients treated with alkylating agents are classical examples, as is human phocomelia following thalidomide administration.

Type E (end of treatment) ADRs occur in specific situations when drug treatment is terminated suddenly, for example withdrawal seizures manifested on terminating anticonvulsant therapy, or adrenocortical insufficiency subsequent to interrupting glucocorticoid treatment.

Type F (failure) ADRs occur when the expected response to treatment is not achieved. Although there are myriad examples of clinical failure, critical analysis reveals primary drug failure to be an infrequent principal cause.

Type G (gaffes) ADRs result from human error, either delayed or inaccurate diagnosis, withholding treatment, prescribing an inappropriate drug, administering an incorrect dosage regimen, or failure to monitor the response to treatment.

Factors That Influence Type A ADRS

It is important to understand the factors that modify the effects of drugs and their dosage in order to anticipate when a patient may be at increased risk of a Type A ADR. Many factors modify the effects of drugs in the individual patient. Some factors result in qualitative differences in the effects of the drug and may preclude its safe use in that patient. Other factors may produce a quantitative change in the usual effects of the drug that can be offset by appropriate adjustment in dose. Factors that may be important in modifying the effects of a drug in an individual include species, body size and percentage fat, age, sex, pathology, drug interactions and pharmacogenomic differences.

Pharmacogenomics refers to the study of the effect of genetic and genomic differences between individuals on the pharmacological behaviour of drugs. Genetic variability in the proteins responsible for drug transport, biotransformation (the enzymes of phase I and II processes) and receptors can be heritable and is determined by specific changes in the nucleotide sequences of specific genes. Genes in which particular nucleotide differences are present in at least 1% of the population are termed polymorphic. While heritable differences in a number of important hepatic enzymes have been well known in humans for decades, the application of pharmacogenomics to the dog is very recent with even fewer studies in cats. Examples of enzymes, genes or proteins that may be affected by pharmacogenomic differences and the drugs they affect include N-acetyltransferase (sulphonamides), thiopurine S-methyltransferase (azathioprine), immune response genes (vaccine response), P-glycoprotein (P-gp) or multidrug resistance protein 1 (Mdr1)--several breeds and many drugs--see Table 1.

Table 1. P-gp polymorphism in dogs and P-gp substrates.

Type B Adverse Drug Reactions (Hypersensitivity)

Type B ADRs are unrelated to dose, are hard to predict and difficult to avoid. The major example of these idiosyncratic ADRs are allergic or hypersensitivity reactions. Drug hypersensitivity reactions are more common in patients with a prior history of allergic reactions to the drug or atopic patients. However, they can occur in any individual.

Allergic drug reactions may occur as a result of a number of different immunological mechanisms including immediate hypersensitivity (Type I), cytotoxic hypersensitivity (Type II), immune complex formation (Type III), and delayed hypersensitivity (Type IV). However, the pathophysiology of many drug reactions eludes precise characterization and some immune reactions are a result of a combination of mechanisms.

Relatively few drugs are responsible for inducing allergic drug reactions as most drugs are not capable of covalently bonding with proteins, a requisite step to render a molecule immunogenic. The drug/drug metabolite-protein complex must have multiple antigenic combining sites to stimulate a drug-specific immune response and to elicit an allergic reaction. For those drugs that are capable of inducing an immunologic response, it is generally the metabolites of the drug that are chemically reactive and easily form covalent bonds with macromolecules.

Drug hypersensitivity may manifest in different ways. Acute anaphylaxis is associated with IgE and mast cell degranulation. It is characterised by one or all of the following clinical signs: hypotension, bronchospasm, angioedema, urticaria, erythema, pruritis, pharyngeal and/or laryngeal oedema, vomiting and colic. The main shock or target organ for anaphylactic reactions varies between species, e.g., hepatic veins are the main target in dogs and the bronchi, bronchioles and pulmonary vein in cats.

A systemic allergic reaction may also occur associated with drug use related to deposition of immune complexes in tissues and activation of complement. Drug hypersensitivity should be considered in the differential diagnosis of any apparent immune-mediated disease, for example polyarthropathy, haemolytic anaemia and vesicular/ulcerative dermatitis.

Prior exposure to the drug is not essential as hypersensitivity may develop within the course of repeated drug administration. For example, in humans, drug hypersensitivity can develop within as little as 5-7 days in a patient previously un-exposed to the drug.

Allergic drug reactions should be managed by withdrawing the drug and treating with corticosteroids if needed. Adrenaline and fluid therapy may be needed to successfully manage acute anaphylactic reactions.