5 Adverse drug reactions
Assessing the safety of drugs
When drugs are newly introduced to the market, their safety profile will be provisional. While efficacy and evidence of safety must be demonstrated for regulatory authorities to permit marketing, it is not possible to discover the complete safety profile of a new drug prior to its launch. Pre-marketing clinical trials involve on average 2500 patients, with perhaps a hundred patients using the drug for longer than a year. Therefore, pre-marketing trials do not have the power to detect important reactions that occur at rates of 1 in 10,000, or fewer, drug exposures. Often, only pharmacologically predictable ADRs with short onset times may be identified in clinical trials, nor can pre-marketing trials detect ADRs which are separated in time from drug exposure. Additionally, patients within trials are often carefully selected, without the multiple disease states or complex drug histories of patients in whom the drug will eventually become used. Furthermore, the patient’s perspective is also frequently excluded from clinical trial safety assessments, with ADRs being assessed only by the clinicians who run them (Basch, 2010). For these reasons, rare and potentially serious adverse effects often remain undetected until a wider population is exposed to the drug. The vigilance of health professionals is an essential factor in discovering these new risks, together with regulatory authorities who continuously monitor reports of adverse effects throughout the lifetime of a marketed medicinal product.
Definitions
Having clear definitions of what constitutes an ADR is important. The World Health Organization (WHO) defines an ADR as ‘a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function’ (WHO, 1972). The use of the phrase ‘at doses normally used in man’ distinguishes the noxious effects of drugs during normal medical use from toxic effects caused by poisoning. Whether an effect is considered noxious depends on both the drug’s beneficial effects and the severity of the disease for which it is being used. There is no need to prove a pharmacological mechanism for any noxious response to be termed an ADR.
The WHO definition has been criticised for excluding the potential for contamination of a product, ADRs that include an element of error, and ADRs associated with pharmacologically inactive excipients in a product. The use of the term ‘drug’ also excluded the use of complementary and alternative treatments, such as herbal products. In an attempt to overcome these points, the following definition of an ADR was proposed, ‘An appreciably 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 regime, or withdrawal of the product’ (Edwards and Aronson, 2000).
Classification of ADRs
Rawlins–Thompson classification
The Rawlins–Thompson system of classification divides ADRs into two main groups: Type A and Type B (Rawlins, 1981). Type A reactions are the normal, but quantitatively exaggerated, pharmacological effects of a drug. They include the primary pharmacological effect of the drug, as well as any secondary pharmacological effects of the drug, for example, ADRs caused by the antimuscarinic activity of tricyclic anti-depressants. Type A reactions are most common, accounting for 80% of reactions.
Type B reactions are qualitatively abnormal effects, which appear unrelated to the drug’s normal pharmacology, such as hepatoxicity from isoniazid. They are more serious in nature, more likely to cause deaths, and are often not discovered until after a drug has been marketed. The Rawlins–Thompson classification has undergone further elaboration over the years (Table 5.1) to take account of ADRs that do not fit within the existing classifications (Edwards and Aronson, 2000).
Type of reaction | Features | Examples |
---|---|---|
Type A: Augmented pharmacological effect | Common | Bradycardia associated with a beta-adrenergic receptor antagonist |
Predictable effect | ||
Dose-dependent | ||
Low morbidity | ||
Low mortality | ||
Type B: Bizarre effects not related to pharmacological effect | Uncommon | Anaphylaxis associated with a penicillin antibiotic |
Unpredictable | ||
Not dose-dependent | ||
High morbidity | ||
High mortality | ||
Type C: Dose-related and time-related | Uncommon | Hypothalamic pituitary–adrenal axis suppression by corticosteroids |
Related to the cumulative dose | ||
Type D: Time-related | Uncommon | Carcinogenesis |
Usually dose-related | ||
Occurs or becomes apparent some time after use of the drug | ||
Type E: Withdrawal | Uncommon | Opiate withdrawal syndrome |
Occurs soon after withdrawal of the drug | ||
Type F: Unexpected failure of therapy | Common | Failure of oral contraceptive in presence of enzyme inducer |
Dose-related | ||
Often cause by drug interactions |
The DoTS system
The DoTS classification is based on Dose relatedness, Timing and patient Susceptibility (Aronson and Ferner, 2003). In contrast to the Rawlins–Thompson classification, which is defined only by the properties of the drug and the reaction, the DoTS classification provides a useful template to examine the various factors that both describe a reaction and influence an individual patient’s susceptibility.
The final aspect of the DoTS classification system is susceptibility, which includes factors such as genetic predisposition, age, sex, altered physiology, disease and exogenous factors such as drug interactions (Table 5.2)
Dose relatedness | Time relatedness | Susceptibility |
---|---|---|
Toxic effects: ADRs that occur at doses higher than the usual therapeutic dose Collateral effects: ADRs that occur at standard therapeutic doses Hypersusceptability reactions: ADRs that occur at sub-therapeutic doses in susceptible patients |
Time-independent reactions: ADRs that occur at any time during treatment. Time-dependent reactions: Rapid reactions occur when a drug is administered too rapidly. Early reactions occur early in treatment then abate with continuing treatment (tolerance). Intermediate reactions occur after some delay, but if reaction does not occur after a certain time, little or no risk exists. Late reactions risk of ADR increases with continued-to-repeated exposure, including withdrawal reactions. Delayed reactions occur some time after exposure, even if the drug is withdrawn before the ADR occurs. |
Raised susceptibility may be present in some individuals, but not others. Alternatively, susceptibility may follow a continuous distribution – increasing susceptibility with impaired renal function. Factors include: genetic variation, age, sex, altered physiology, exogenous factors (interactions) and disease. |
Factors affecting susceptibility to ADRs
Co-morbidities and concomitant medicines use
Reductions in hepatic and renal function substantially increase the risk of ADRs. A recent study examining factors that predicted repeat admissions to hospital with ADRs in older patients showed that co-morbidities such as congestive cardiac failure, diabetes, and peripheral vascular, chronic pulmonary, rheumatological, hepatic, renal, and malignant diseases were strong predictors of readmissions for ADRs, while advancing age was not. Reasons for this could be pharmacokinetic and pharmacodynamic changes associated with pulmonary, cardiovascular, renal and hepatic insufficiency, or drug interactions because of multiple drug therapy (Zhang et al., 2009).
Ethnicity
Examples of ADRs linked to ethnicity include the increased risk of angioedema with the use of ACE inhibitors in black patients (McDowell et al., 2006), the increased propensity of white and black patients to experience central nervous system ADRs associated with mefloquine compared to patients of Chinese or Japanese origin, and differences in the pharmacokinetics of rosuvastatin in Asian patients which may expose them to an increased risk of myopathy. However, susceptibility based on ethnicity could be associated with genetic or cultural factors and ethnicity can be argued to be a poor marker for a patient’s genotype.
Pharmacogenetics
The narrow therapeutic index of warfarin, its high inter-individual variability in dosing and the serious consequences of toxicity have made it a major target of pharmacogenomic research. Studies of genetic polymorphisms influencing the toxicity of warfarin have focused on CYP2C9, which metabolises warfarin and vitamin K epoxide reductase (VKOR), the target of warfarin anticoagulant activity. Genetic variation in the VKORC1 gene, which encodes VKOR, influences warfarin dosing by a threefold greater extent than CYP2C9 variants. In 2007, the U.S. Food and Drug Administration (FDA) changed the labelling requirement for warfarin, advising that a lower initial dose should be considered in people with certain genetic variations. However, concerns remain because genetic variation only accounts for a proportion of the variability in drug response and clinicians may obtain a false sense of reassurance from genetic testing leading to complacency in monitoring of therapy. In addition, there appears to be little evidence of additional benefit (Laurence, 2009), in terms of preventing major bleeding events, compared to careful monitoring of the INR (see chapter 23)
A success story for pharmacogenetics is the story of the nucleoside analogue reverse transcriptase inhibitor (NRTI) abacavir. Hypersensitivity skin reactions to abacavir are a particular problem in the treatment of human immunodeficiency virus (HIV) infection. Approximately 5–8% of patients taking abacavir develop a severe hypersensitivity reaction, including symptoms such as fever, rash, arthralgia, headache, vomiting and other gastro-intestinal and respiratory disturbances. Early reports that only a subset of patients was affected, a suspected familial predisposition, the short onset time (within 6 weeks of starting therapy), and an apparent lower incidence in African patients led to suspicion of a genetic cause. Subsequent research revealed a strong predictive association with the human leukocyte antigen HLA-B*5701 allele in Caucasian and Hispanic patients. The presence of the allele can be used to stratify the predicted risk of hypersensitivity as high risk (>70%) for carriers of HLA-B*5701 and low risk (<1%) for non-carriers of HLA-B*5701. Evidence from the practical use of HLA-B*5701 screening has shown substantial falls in the incidence of hypersensitivity reactions, as well as a more general improved compliance with the medication (Lucas et al., 2007).