1.2.1 Defining an adverse drug reaction.
In 1969, the World Health Organisation (WHO) defined an ADR as “a response to a drug that is noxious, unintended or undesired, occurring at doses normally used for the prophylaxis, diagnosis or treatment of disease, or for modification of physiological function”(Edwards and Aronson, 2000).
Despite this definition being unchanged for the last 45 years, specific adaptations have been suggested for several reasons. First, this definition is restricted and does not apply to reactions elicited by inactive excipients or herbal medicines. Second, the word noxious applies through its very definition only to reactions which are harmful or hurtful to the patient, however many ADRs are not harmful but perhaps irritating such as the dry, tickling cough sometimes associated with angiotensin-converting enzyme (ACE) inhibitors. Third, it does not account for medication errors in dosing (Edwards and Aronson, 2000; Fogari et al., 2011). Independent of the exact ADR definition, these
29 reactions are often severe and subsequently represent a significant burden on clinicians, pharmaceutical companies, and most importantly patients.
1.2.2 Adverse drug reaction reporting, prevalence, and health
burden.
Pharmacovigilance, the observation and subsequent recording of potential ADRs, plays a large role in identifying problematic drugs post-marketing. Many countries operate spontaneous reporting systems whereby reports of a drug-specific ADR can be monitored, with overly frequent ADRs from a particular drug leading to the drug being flagged as a potential issue. In the UK, a yellow card system has allowed clinicians to monitor and report ADRs since 1964, which was recently updated in 2005 to allow patients themselves to submit ADR reports (McLernon et al., 2010). If it is deemed that a substantial risk is posed to patients then either a black flag warning can be imposed on that drug, or to prevent any further ADRs, the drug may be withdrawn from the market altogether. A total of 22 drugs were withdrawn from use in patients during a ten year period from early 1990 to late 1999 due to the potential to cause an ADR, the majority of which were due to cardiac or hepatic toxicity (Arnaiz et al., 2001).
In the US alone, it is estimated that 100,000 deaths occur annually due to serious ADRs (Wilke et al., 2007). In a 1995, Boston based drug surveillance program, 6.1% of hospitalised patients developed an ADR and 1.2% of these reactions resulted in patient death (Bates et al., 1995). Substantially higher hospitalised patient ADR incidence rates have been reported such as the 15.1% recorded by Lazarou and colleagues (Lazarou et al., 1998). While primarily of concern as they are detrimental to patient health, this prevalence of ADRs additionally means that hospitals have more in-patients. Estimates have put the number of extra hospital bed days for in-patients due to ADRs at 2000 at
30 any one time. When combined with total bed-days for patients in hospital because of an ADR, the authors nicely illustrate this as the equivalent of ten 800-bed hospitals (Davies et al., 2009). This strain on hospital beds translates into financial burden, with ADRs approximated to cost an extra £5000 per bed per year. This, along with other figures estimating the financial cost of hospital admissions due to ADRs at 5-9% of total inpatient costs, equates to a total annual financial burden of ADRs on the National Health Service (NHS) of approximately £637 million for England alone (Davies et al., 2009; Kongkaew et al., 2008). However, the actual figure could be much higher due to the under reporting of ADRs as a 2001 nationwide survey in the Netherlands found that only 1% of ADRs were reported (van der Hooft et al., 2006).
1.2.3 General adverse drug reaction risk factors.
Although the term ADR describes a wide variety of responses, of differing degrees of severity, to an abundance of drugs, there are several generalised factors which are linked to their onset. Some of these relate directly to the drug. These include an increased potential for ADRs when drugs are administered repeatedly, perhaps with sporadic intervals in contrast to a continuous dosing regimen, but also the route of administration, with orally administered drugs deemed less sensitising to those given via a parenteral route (Thong and Tan, 2011).
There are also a number of “patient factors” which have partly been observed thanks to the detailed reporting of ADRs alongside statistical analysis allowing for the identification of specific demographic groups which are more susceptible to ADRs. In hospitalised patients, 5.3% of the general population will develop an ADR, but this prevalence increases with age, with elderly patients having more than double the admission rate
31 (10.7%) for ADRs than children (4.1%)(Kongkaew et al., 2008). However, this value varies from one report to the next, an explanation for which is at least partly down to differing methods to detect and report ADRs. Women are also more likely than men to develop an ADR, which was verified in 2008 using a multivariate regressional analysis (OR: 1.596, p= < 0.0001). There are a number of reasons for this inter-gender differentiation such as differences in organ blood flow and function, menstruation, and metabolism among others (Zopf et al., 2008).
Indeed drug metabolism can be classified as a risk factor by itself, and although this may partly be a drug-related risk factor as particular metabolic routes are more vulnerable to ADRs than others, it is perhaps better classified as a patient-factor as the development of a reaction may reflect an individual patients metabolic genotype. The issue here is raised by the presence of multiple variants of particular metabolising enzymes within a population caused by small genetic mutations known as single nucleotide polymorphisms (SNPs). This may mean that one variant has a faster or slower metabolic rate than another, perhaps so much so that a variant may be considered a functional knock-out. Perhaps the best example of the extent of this variation is seen within the cytochrome (CYP)-450 family of enzymes involved in the metabolism of numerous drugs. One of these is CYP2D6 which is highly utilised in drug metabolism. This particular isoform has > 550 associated SNPs of which, 341 are non-coding and have no functional relevance, while 134 are non-synonymous variants with some having enhanced, and others reduced, metabolic capacities (Zanger et al., 2014).
The final major predisposing factor for ADR development is patient disease state. A simple example of this is where a patient with pre-existing liver disease develops a liver- based reaction which can be pinned to the diseased liver’s incompetent detoxification and removal of drug (Uetrecht, 2007). Another important example of the influence of
32 patient disease state is viral infection. In patients with human immunodeficiency virus (HIV), drug hypersensitivity reactions have been reported to be up to 100 times more prevalent (Coopman et al., 1993). This is thought to be partly related to an already disrupted immune system due to HIV virus, glutathione depletion which is normally required for drug detoxification, and increased immune signalling due to concomitant bacterial infection which is experienced by HIV positive patients (Phillips and Mallal, 2007). This is also the case for other viruses such as the herpes virus family, which includes human herpes virus (HHV) 6 and 7, cytomegalovirus, and Epstein-Barr virus (EBV) (Thong and Tan, 2011).
1.2.4 Adverse drug reaction classification system.
Despite recent extension of the ADR classification system, reactions are most commonly categorised as type A (augmented) or type B (bizarre).
Type A (on-target) reactions are pharmacologically predictable and account for the majority of ADRs. They may relate to the desired pharmacological effect but at a site other than that at which the drug was intended for, a larger response than was anticipated, or a secondary pharmacological effect (Gomes and Demoly, 2005; Lee, 2005). These reactions often occur due to incorrect dosing but may also be susceptible to metabolism and drug interactions if the patient is undergoing multiple drug therapy. Type B (off-target) reactions are responsible for 10-15% of ADRs with many now linked with immunological and genetic aetiologies. Although they are rarer than type A reactions, they are more likely to cause serious illness or death due to their pharmacologically unpredictable nature. Due to this unpredictability they are also called idiosyncratic reactions (Gomes and Demoly, 2005; Lee, 2005). The concern surrounding
33 these reactions is evident in that black box warnings or complete drug withdrawals were issued to 10% of newly approved drugs in the US between 1975 and 2000 due to idiosyncratic reactions alone (Uetrecht, 2007).
There are also four more classifications; type C, D, E, and F reactions. Type C (chronic) reactions are dose and time-related, while type D (delayed) are purely time-dependent. Type E (end of use) reactions are associated with cessation of drug administration such as withdrawal syndrome after stopping opiate use. Finally, type F (failure) relates to failed therapy which may be caused by drug-drug interactions.
More recently, an extended classification of these reactions was drafted to include additional parameters of a reaction such as timing, severity, and individual susceptibility of the patient. This extended version is known as DoTS for dose, timing, and susceptibility and has been introduced as some reactions were dose dependent but not related to the pharmacology of the drug (Aronson and Ferner, 2003).