Introduction
Introduction
Pharmacogenomics explains how the genetic make-up of individual patients may influence the effectiveness and safety of commonly used medicines. The variability in the therapeutic effects of codeine, for example, is due to pharmacogenomics (PGx).
While the age, weight, height and sex of a person may influence the choice and dose of medicines, knowledge about how the genetic make-up of individual patients might affect their response to drugs is less well understood.
PGx testing has been available from community pharmacies in the USA, Canada and Australia for several years. A number of DNA tests sold in the UK now also give information on drug response and some pharmacy chains have said they intend to introduce a service to support their use.
Common situations where pharmacogenomics are implicated:
One of the first disorders where genetic factors were found to affect drug metabolism is glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the 1950s G6PD deficiency was identified in people with an illness related to the consumption of fava beans (a variety of broad beans) and an X-linked inherited association was determined.
G6PD is an enzyme involved in carbohydrate metabolism and protects red blood cells from potentially harmful oxidative toxins. Fava beans contain toxins which are readily broken down in people with the enzyme but can cause severe haemolysis in those with relative deficiency of G6PD.
Certain drugs also become ‘toxic’ if red blood cells are not protected from oxidation by G6PD: primaquine, nitrofurantoin, quinolones and some sulphonamides (such as co-trimoxazole) should be avoided in those with known G6PD deficiency as their use may precipitate a haemolytic crisis, requiring blood transfusion.
Aspirin, quinine, chloroquine, hydroxychloroquine and sulfonylureas are less toxic but should still be used with caution. These drugs are flagged up in the British National Formulary (BNF). In several countries G6PD deficiency is screened for by blood spot tests in newborn babies, but this is not done routinely in the UK.
Some patients tolerate codeine very poorly and become nauseous on small doses while others may fail to get pain relief at even high doses. Codeine is an opioid prodrug that is converted to its active form, morphine, by a liver enzyme that is part of the CYP2D6 pathway of cytochrome P450 enzymes.
There are over 100 genetic variants of CYP2D6, of which several result in ultra-rapid, high activity and some in reduced or no enzyme activity. Those with ultra-rapid activity (one to two per cent of the population) tolerate the drug poorly as they then suffer from a morphine ‘overdose’.
At the other extreme, in patients who are ‘poor’ or ‘intermediate’ metabolisers (as many as five to 10 per cent of the population), the analgesic effects of codeine may be inadequate due to lower levels of active morphine. In these patients dihydrocodeine may prove to be effective as well as the use of low-dose morphine may be required. At present the UK has no consensus guidelines on how to screen patients for CYP2D6 variants.
Warfarin is another example where there is a wide range of responses to different doses of treatment. While two enzymes have been identified as possible reasons for this, many factors which are non-genetic are also thought to be the cause so the additional benefits from testing may be marginal for many people.