Introduction & module overview
Introduction & module overview
Pharmacogenetics/pharmacogenomics can explain how the genetic make-up of individual patients may influence the effectiveness and safety of commonly used medicines. Examples are the variability in therapeutic effects of codeine and in the occurrence of severe adverse effects of, say, carbamazepine and allopurinol.
The age, weight, height and sex of a person may influence the choice and dose of medicines. We already accept that checking liver or renal function using blood tests is important in determining which drugs, and what doses, are safe to use in some patients, and in subsequent monitoring and dose titration. These features are known as pharmacodynamic and pharmacokinetic factors.
Knowledge about how the genetic make-up of individual patients might affect their response to drugs (through their expression of pharmacodynamic or pharmacokinetic factors) is less well advanced.
Genetic differences in the response to drugs are described as pharmacogenetic and pharmacogenomic factors. Although describing subtly different things, these two terms are often used interchangeably. This CPD module will mainly refer to pharmacogenomics (PGx).
Many pharmacists may not have been taught about PGx in their initial training, so this module introduces the subject to enable informed responses to questions from patients.
Clopidogrel non-responders
Clopidogrel is a prodrug activated by CYP2C19, a cytochrome P450 enzyme (CYP) in the liver. CYP2C19 varies in its activity related to variation in genetic expression.
As many as 10-20 per cent of people with gene expression that reduce enzymatic activity do not convert enough clopidogrel to the active form to reduce clotting. If prescribed after a stroke they are therefore at an increased risk of further strokes.
The NHS in Tayside launched a programme in August 2022 to screen stroke patients who were being considered for clopidogrel treatment for the gene coding for the variants. The specialist clinical pharmacist for stroke plays a key role in reviewing test results and advising on subsequent prescribing. It is likely that this type of screening will become more commonplace in the NHS over time.
Another concern flagged up by the MHRA in 2009 is that the metabolism of clopidogrel is impaired by proton pump inhibitors (PPIs) such as omeprazole. This drug-drug interaction is important as PPIs are often co-prescribed with clopidogrel. The PPIs compete with clopidogrel for metabolism by CYP2C19.
Evidence now suggests this is mainly of clinical significance with omeprazole and esomeprazole. The MHRA clarified advice in 2014 that concomitant use of clopidogrel and omeprazole, or esomeprazole, is to be discouraged unless considered essential.