Adverse drug reactions

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5 Adverse drug reactions

J. Krska, A.R. Cox

Key points

• An adverse drug reaction is an unintended noxious response occurring after the normal use of a drug, which is suspected to be associated with the drug.
• Adverse drug reactions can be classified as type A, which are most common and related to the drug’s pharmacological effect, or type B, which are rare and unpredictable, although other classes of reaction can be identified.
• Few adverse reactions are identified during pre-marketing studies; therefore, pharmacovigilance systems to detect new adverse drug reactions are essential.
• Spontaneous reporting schemes are a common method of pharmacovigilance which depend primarily on health professionals.
• Patients are encouraged to contribute to post-marketing surveillance schemes in some countries.
• Adverse drug reactions are a significant cause of morbidity and mortality, are responsible for approximately 1 in 20 hospital admissions and are a considerable financial burden on health systems.
• Predisposing factors for adverse drug reactions include age, female gender, ethnicity, genetic factors, co-morbidities and concomitant medication.
• Many adverse drug reactions may be preventable through rational prescribing and careful monitoring of drug therapy.
• Health professionals need to be able to identify and assess adverse drug reactions and play a major role in preventing their occurrence.
• Patients want to receive information about adverse drug reactions; therefore, communicating the risks of using medicines is an important skill for health professionals.

Introduction

All medicines with the ability to produce a desired therapeutic effect also have the potential to cause unwanted adverse effects. Health professionals should have an awareness of the burden that adverse drug reactions (ADRs) place on health services and the public, the identification and avoidance of ADRs and their important role in post-marketing surveillance of medicines to ensure their continued safety.

Risks associated with medicinal substances are documented throughout history; for example, William Withering’s 1785 account provides a meticulous description of the adverse effects of digitalis. However, it was the thalidomide disaster that captured public attention and brought about major regulatory changes in drug safety. Thalidomide was first marketed by Chemie Grünenthal in 1957 and distributed in the UK by Distillers Ltd, whose chief medical advisor stated, ‘If all the details of this are true, then it is a most remarkable drug. In short, it is impossible to give a toxic dose.’ In 1958, thalidomide was recommended for use in pregnant and nursing mothers without supporting evidence. An Australian doctor, Jim McBride, and a German doctor, Widukund Lenz, independently associated thalidomide exposure with serious birth defects and thalidomide was withdrawn in December 1961. Thalidomide left behind between 8000 and 12,000 deformed children and an unknown number of deaths in utero.

The 1970s saw another unexpected and serious adverse reaction. The cardioselective beta-adrenergic receptor blocker practolol, launched in June 1970, was initially associated with rashes, some of which were severe. A case series of psoriasis-like rashes linked to dry eyes, including irreversible scarring of the cornea, led other doctors to report eye damage, including corneal ulceration and blindness, to regulators. Cases of sclerosing peritonitis, a bowel condition associated with significant mortality, were also reported. Practolol had remained on the market for 4 years; over 100,000 people had been treated and hundreds were seriously affected.

Some adverse effects can be more difficult to differentiate from background events occurring commonly in the population. The COX-II selective non-steroidal anti-inflammatory drugs (NSAIDs), celecoxib (introduced 1998) and rofecoxib (introduced 1999), were marketed on the basis of reduced gastro-intestinal ADRs in comparison to other non-selective NSAIDs. Apparent excesses of cardiovascular events, which were noted during clinical trials and in elderly patient groups, were ascribed to the supposed cardio-protective effects of comparator drugs. However, in September 2004, a randomised controlled trial of rofecoxib in the prevention of colorectal cancer showed the drug to be associated with a significantly increased risk of cardiovascular events. Celecoxib was also associated with a dose-related increased risk of cardiovascular events in clinical trials. Rofecoxib was voluntarily withdrawn from the market. Further research has provided evidence of thrombotic risk with non-selective NSAIDs, in particular diclofenac. This risk appears to extend to all NSAID users, irrespective of baseline cardiovascular risk.

Not all drug safety issues are related to real effects. In 1998, a widely-publicised paper by Andrew Wakefield and co-authors, later retracted, alleged a link between MMR vaccine and autism, and led to a crisis in parental confidence in the vaccine. This had a detrimental effect on vaccination rates, resulting in frequent outbreaks of measles and mumps, despite epidemiological and virological studies showing no link between MMR vaccine and autism. The MMR vaccine controversy illustrates how media reporting of drug safety information can influence patients’ views of medicines and can cause significant harm. Poor presentation of drug safety issues in the media often creates anxiety in patients about medicines which they may be using, regardless of their benefits.

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.

As a result of this monitoring, the safety profile of established drugs is often well known, although new risks are occasionally identified. However, an important part of the therapeutic management of medical conditions is the minimisation of these well-known risks through rational prescribing and careful monitoring of drug therapy. Current evidence suggests that this could be improved.

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 terms ADR and adverse drug effect can be used interchangeably; adverse reaction applies to the patient’s point of view, while adverse effect applies to the drug. The terms suspected ADR or reportable ADR are commonly used in the context of reporting ADRs to regulatory authorities, for example, through the UK’s Yellow Card Scheme, operated by the Medicines and Healthcare Regulatory Authority (MHRA). Although the term ‘side effect’ and ADR are often used synonymously, the term ‘side effect’ is distinct from ADR. A side effect is an unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment.

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).

It is important also to avoid confusion with the term adverse drug event (ADE). An ADR in a patient is an adverse outcome that is attributed to a suspected action of a drug, whereas an ADE is an adverse outcome that occurs after the use of a drug, but which may or may not be linked to use of the drug. It therefore follows that all ADRs are ADEs, but that not all ADEs will be ADRs. This distinction is important in the assessment of the drug safety literature, since the term ADE can be used when it is not possible to suggest a causal link between a drug treatment and an adverse outcome. The suspicion of a causal relationship between the drug and the adverse effect is central to the definition of an ADR.

Classification of ADRs

Classification systems for ADRs are useful for educational purposes, for those working within a regulatory environment and for clarifying thinking on the avoidance and management 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).

Table 5.1 Extended Rawlins–Thompson classification of adverse drug reactions

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.

DoTS first considers the dose of the drug, as many adverse effects are clearly related to the dose of the drug used. For example, increasing the dose of a cardiac glycoside will increase the risk of digitalis toxicity. In DoTS, reactions are divided into toxic effects (effects related to the use of drugs outside of their usual therapeutic dosage), collateral effects (effects occurring within the normal therapeutic use of the drug) and hyper-susceptibility reactions (reactions occurring in sub-therapeutic doses in susceptible patients). Collateral effects include reactions not related to the expected pharmacological effect of the drug or off-target reactions of the expected therapeutic effect in other body systems. It is worth noting that approximately 20% of newly marketed drugs have their dosage recommendations reduced after marketing, often due to drug toxicity.

The time course of a drug’s presence at the site of action can influence the likelihood of an ADR occurring. For example, rapid infusion of furosemide is associated with transient hearing loss and tinnitus, and a constant low dose of methotrexate is more toxic than equivalent intermittent bolus doses. DoTS categorises ADRs as either time-independent reactions or time-dependent reactions. Time-independent reactions occur at any time within the treatment period, regardless of the length of course. Time-dependent reactions range from rapid and immediate reactions, to those reactions which can be delayed.

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)

Table 5.2 DoTS system of ADR classification

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

Awareness of the factors which increase the risk of ADRs is key to reducing the burden on individual patients by informing prescribing decisions. The risk that drugs pose to patients varies dependent on the population exposed and the individual characteristics of patients. Some reactions may be unseen in some populations, outside of susceptible subjects. Other reactions may follow a continuous distribution in the exposed population. Although many susceptibilities may not be known, a number of general factors which affect susceptibility to ADRs and others which affect the propensity of specific drugs to cause ADRs have been elucidated.

Age

Elderly patients may be more prone to ADRs, with age-related decline in both the metabolism and elimination of drugs from the body. They also have multiple co-morbidities and are, therefore, exposed to more prescribed drugs. Chronological age is, therefore, arguably a marker for altered physiological responses to drugs and for the presence of co-morbidities and associated drug use rather than a risk per se. As the population ages, the mitigation of preventable ADRs in the elderly will become increasingly important.

Children differ from adults in their response to drugs. Neonatal differences in body composition, metabolism and other physiological parameters can increase the risk of specific adverse reactions. Higher body water content can increase the volume of distribution for water-soluble drugs, reduced albumin and total protein may result in higher concentrations of highly protein bound drugs, while an immature blood–brain barrier can increase sensitivity to drugs such as morphine. Differences in drug metabolism and elimination and end-organ responses can also increase the risk. Chloramphenicol, digoxin, and ototoxic antibiotics such as streptomycin are examples of drugs that have a higher risk of toxicity in the first weeks of life.

Older children and young adults may also be more susceptible to ADRs, a classic example being the increased risk of extrapyramidal effects associated with metoclopramide. The use of aspirin was restricted in those under the age of 12, after an association with Reye’s syndrome was found in epidemiological studies. Additionally, children can be exposed to more adverse effects due to the heightened probability of dosing errors and the relative lack of evidence for both safety and efficacy.

Gender

Women may be more susceptible to ADRs. In addition, there are particular adverse reactions that appear to be more common in women than men. For example, impairment of concentration and psychiatric adverse events associated with the anti-malarial mefloquine are more common in females.

Females are more susceptible to drug-induced torsade de pointes, a ventricular arrhythmia linked to ventricular fibrillation and death. Women are also over-represented in reports of torsades de pointes associated with cardiovascular drugs (such as sotalol) and erythromycin. This increased susceptibility in women is thought to be due to their longer QTc interval compared to men.

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

Ethnicity has also been linked to susceptibility to ADRs, due to inherited traits of metabolism. It is known, for example, that the cytochrome P450 genotype, involved in drug metabolism, has varied distribution among people of differing ethnicity. For example, CYP2C9 alleles associated with poor metabolism can affect warfarin metabolism and increase the risk of toxicity. This occurs more frequently in white individuals compared to black individuals.

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

Pharmacogenetics is the study of genetic variations that influence an individual’s response to drugs, and examines polymorphisms that code for drug transporters, drug-metabolising enzymes and drug receptors. A greater understanding of the genetic basis of variations that affect an individual’s response to drug therapy has promised to lead to a new era of personalised medicine. Arguably, pharmacogenetics has yet to deliver on an appreciable scale, the reduction in ADRs that was predicted. However, there are some important examples of severe ADRs that may be avoided with knowledge of a patient’s genetic susceptibility.

As already noted, major genetic variation is found in the cytochrome CYP450 group of isoenzymes. This can result in either inadequate responses to drugs, or increased risk of ADRs. Clinically relevant genetic variation has been seen in CYP2D6, CYP2C9, CYP2C19 and CYP3A5. A large effect on the metabolism of drugs can occur with CYP2C9, which accounts for 20% of total hepatic CYP450 content.

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).

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