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Genetics and pharmacodynamics

Professor Yoon Loke explains individual variation in the effects of drugs
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Welcome. In this session, we will look at genetics and pharmacodynamics. In particular, we will discuss individual variation in the effects of drugs. To start with, we will look at mechanisms by which drugs act on the body and we will also discuss how responses can vary amongst different individuals. In particular, we will look at areas where genetic variation can affect the drug’s effect on the body or on human physiological responses. Finally, we will discuss how drug therapy can be personalised through knowledge of the drug action in man. Now, there are numerous sites where drugs and act and genetic variation can affect all of these sites.
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Most drugs account receptors in the body and genetic variation can affect the number of receptors available, the configuration of the receptor, and the drug binding, as well as the extent of the physiological process triggered by drug binding. Equally some drugs act on enzymes and there may be variation within individuals as to the intrinsic activity of the enzyme, as well as how well the drug binds to this enzyme. There are also drugs that act on ion channels within the body, and genetic variation may affect the numbers of channels, as well as a confirmation of these channels.
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So, some of the underlying principles that we need to remember are that genetic variation has the potential to influence drug effects at receptor sites, or through enzyme activity, or through different configurations or ion channels and transporters. Now some of these genetic variations may be inherited, however, there are examples in cancer, where the tumors may develop de novo mutations. The end result of this genetic variation is that we may find that some patients do not have a good response to the treatment, even though clinical trials have shown significant benefit for most people. Equally, other patients may develop adverse reactions even though the clinical trials have shown that a majority of patients are safe from harm.
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Let’s now look at a genetic condition that may have an impact on the choice of treatment. This relates to the pharmacodynamic failure of statins. Statins are widely used throughout the world for treatment of cardiovascular disease and act by reducing cholesterol levels. Now, there’s a condition known as homozygous familial hypercholesterolemia, where the patients have a genetic mutation leading to low levels or complete absence of LDL cholesterol receptors. The effectiveness of the statin relies partly on up regulation of LDL receptor function and in patients who have low numbers of LDL receptors or absent LDL receptors then statins have a far more limited target to work on, which means that they may not have the same efficacy.
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So, when treating these patients, alternative drug targets have been recommended for the patient, rather than targeting the LDL receptor which is absent in these patients. And some of these alternative methods include reducing intestinal absorption of cholesterol or preventing VLDL assembly in the liver.
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Now, we mentioned enzyme activity a little bit earlier on. Genetic variation can affect the enzyme activity for certain important physiological processes in the body. The vitamin k epoxide reductase protein is an important component in the production of clotting factors. Warfarin, which is a very widely known drug inhibits VKORC1. All of us are aware that warfarin is a very difficult drug to use because the dosing is complicated by huge intra and Inter individual variation. It’s very difficult to get the right dose of warfarin and close monitoring is required. Polymorphisms in the VKORC1 gene have been shown to have an effect in creating heterogeneity and variation in the warfarin dosing.
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It has been suggested that 25% of the variation in warfarin dosing is due to variation in VKORC1 and therefore it has been hypothesized that identification of the VKORC1 variants could conceivably help us lead to more accurate prediction of the warfarin dose for individual patients. So how can this be applied in clinical practice? So if VKORC1 testing were available, how would this help us improve treatment for patients? Well, one of the area’s that’s been suggested, is for patients who are being newly started on warfarin. Depending on the VKORC1 status for these patients, the warfarin doses could be adjusted and this strategy could be tested against the standard warfarin dosing regimens that we would otherwise be using.
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There are already a number of randomised trials carried out that are based on this VKORC1 testing strategy. Unfortunately, meta-analysis of these randomised trials does not demonstrate significant benefit on reducing thromboembolic events, or preventing hemorrhaging events in patients being started on warfarin.
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So, although we are aware that genetic variation can influence drug action in the body at a wide range of diverse sites and through a variety of mechanisms, the cost-effectiveness of a genetically guided strategy has not been fully established for many drugs. Future studies are still needed to demonstrate effectiveness of procedures involving genetic testing and guiding drug treatment.
This tutorial by Professor Yoon Loke will explain how genetic variation can affect the individual’s response to drugs.
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Using Personalized Medicine and Pharmacogenetics

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