Health care providers and patients have long recog-nized that people often respond differently to the same medicine, both in terms of efficacy and ‘side effects’, or adverse drug reactions (ADRs).
Pharmacogenetics and
the Genetic Basis of ADRs
Health
care providers and patients have long recog-nized that people often respond
differently to the same medicine, both in terms of efficacy and ‘side effects’,
or adverse drug reactions (ADRs). There are many factors that contribute to
this inter-individual variability in response to medications, including the
pathogenesis and severity of the disease being treated; concomitant medications
and drug interactions; and the patient’s age, renal and liver function,
concomitant illnesses, nutrition and lifestyle (smoking, alcohol use, weight
and fitness) (Meyer, 2000). Genetic factors that affect the kinetics and
dynamics of drugs play an even greater role in determining an individual’s risk
of non-response or toxicity (Evans and Relling, 1999). Although it is difficult
to define the relative contribution of genetic and environmental effects in an
individual, it is clear that variation in genes coding for drug-metabolizing
enzymes, drug transporters and drug receptors and targets accounts for a
significant portion of the observed heterogeneity in drug response across
populations.
The
study of ADRs has been hampered by the use of ambiguous and inconsistent
terminology and reporting. Edwards and Aronson (2000) proposed the following
definition of an ADR: ‘an apprecia-bly harmful or unpleasant reaction,
resulting from an intervention related to the use of a medicinal product, which
predicts hazard from future admin-istration and warrants prevention or specific
treat-ment, alteration of the dosage regimen, or withdrawal of the product’.
ADRs may result from health care provider, pharmacy or patient error or from a
variety of genetic and environmental factors. Although defi-nitions and figures
vary, it is clear that ADRs are a significant cause of morbidity, mortality and
health care expense. Lazarou, Pomeranz and Corey (1998) performed a meta-analysis
of 39 prospective studies from US hospitals and found that 6.7% of inpatients
have a serious ADR while hospitalized, resulting in 106 000 deaths per year.
Johnson and Bootman (1995) used a cost of illness model to address the
drug-related morbidity and mortality in the ambulatory care setting in the US
from data collected in the early 1990s. Their estimate of the costs of adverse
events was $76B/year. Ernst and Grizzle (2001) updated the estimates using data
published since the 1995 study and updated values for May 2000 in dollars.
Their estimates for the cost of drug-related morbidity and mortality exceeded
$177.4B in 2000. Pirmohammed et al.
(2004) conducted a prospective analysis of all admissions to two general hospitals in the United Kingdom. They
found that 6.5% of all hospital admis-sions were due to an adverse event and
that the adverse event directly led to the hospitalization in 80% of the cases.
They projected the annual cost of such admis-sions to the National Health
Services to be $847M. The overall fatality rate was 0.15% and the most common
drugs implicated were aspirin, diuretics, warfarin and non-steroidal
anti-inflammatory drugs. GI bleeding was the most common reaction.
The
number, severity and cost of ADRs is now recognized as a significant public
health issue and has triggered interest in discovering what causes them and if
and how their occurrence can be predicted and prevented. In this chapter, we
will focus on the current state of knowledge regarding the genetic basis of
ADRs and the important role that pharmacogenet-ics will play in meeting the
ultimate goal of providing safer, more effective medicines.
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