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Skip to 0 minutes and 1 second Welcome. In this session, we will be looking at the concept of genetic testing and how it helps us choose the right drug for the right patient. The key objectives that we hope to cover in the next few minutes include a description of the factors that help us determine the benefit/harm balance of treatment. We will also look at how prognostic markers can guide treatment decisions in individual patients. The particular areas where genetic variation can influence the benefit harm balance for the patient include the area of pharmacodynamics pharmacokinetics and adverse drug reactions.

Skip to 0 minutes and 39 seconds Now, one of the fundamental principles of clinical pharmacology, is that we try to use the right drug at the right dose and at the right time for the right patient. Most of the evidence for drug therapy comes from clinical trials which give us some estimate of the average effect of the drug in a particular patient group. However, it is unclear for individual patients, who will benefit and who will be harmed. We have some idea that some patients benefit some of the time but we don’t know exactly who. Similarly, we know that some patients will suffer harm but the severity of the harm varies amongst patients.

Skip to 1 minute and 28 seconds Now it would be great if, at the time the drug is prescribed, we could choose the drug for those who are most likely to derive the greatest benefit and we could avoid using the drug in those that we’ve identified to be at high risk of adverse effects.

Skip to 1 minute and 55 seconds This is where the role of prognostic markers comes in. Current practice is that there is no guarantee that any particular individual will benefit from the drug treatment and obviously there’s no foolproof way of predicting whether someone will be harmed or not. Hence markers have been developed for predicting response to drugs. And how do these markers work? Well, if there was some sort of clue as to who will develop harm and who has a greater likelihood benefit, then we could hopefully stratify the treatment, or personalise the treatment to fit best with an individual patient. Now, actually individualised treatment is not new.

Skip to 2 minutes and 48 seconds Most, if not all clinicians, are already perhaps are consciously tailoring the treatment according to the patient in front of them. For instance, there are national guidelines that suggest that patients of afro-caribbean ethnicity should be offered different types of blood pressure lowering drugs, as compared to those of different ethnicities. And most clinicians are actually already very familiar with looking at blood tests and deciding what the most appropriate dose for the patient should be. However, most of us would consider treatment decisions by ethnicity to be a rather imprecise method. New technical advances now allow us to focus therapy better according to the genetic makeup of the patient, rather than just the broad brush of ethnicity.

Skip to 3 minutes and 51 seconds Let’s look at how genetics may play a part. Genetic information, if used properly ,can help us refine the benefit versus harm ratio in drug therapy. One of the areas is in pharmacodynamics. This is what the drug does to the body. The second area is in pharmacokinetics. This relates to how the body handles drugs. And finally, there are patients who experience hypersensitivity or allergy adverse reactions and genetic variation may play a role in this area. So let’s take pharmacodynamics first of all. This relates to the study of drug action and man and we know that drugs can act on multiple different sites in the body. This includes receptors, or other physiological mechanisms.

Skip to 4 minutes and 42 seconds This may include an enzyme or ion channel, or even transporter mechanism. Now the drug exerts a measurable change in the body process. Genetic variation means that the drug exerts different responses in different patients. This variation in response may arise because of differences in receptor configuration, or how the drug binds to receptors, as well as the number and distribution of receptors in that particular individual. Now moving on to pharmacokinetics. This is a study of what the body does to the drug. In simple terms, we need to look at what happens to the drug after administration. The drug enters the body and travels to the site of action.

Skip to 5 minutes and 37 seconds Here genetic variations can affect the drug concentrations because of a number of factors, which include bioavailability, for instance, the amount that is absorbed from the stomach and makes it into the bloodstream. Now, when the drug enters the body, metabolism can take place. Some of this is known as first pass metabolism, where the drug may be activated or broken down by enzymes within the body. Finally, the drug concentration can be affected by clearance. Now, clearance can be due to enzyme metabolism that breaks the drug down, or by excretion in the urine as an example. One of the most well recognised areas of metabolism and clearance is with regard to the enzyme activity in the human liver.

Skip to 6 minutes and 38 seconds Most people are already familiar with the cytochrome p450 family of enzymes. There’s huge genetic variation in this family of enzymes that affects the activity of the enzyme in handling the drug. We can imagine that there is an effect on drug concentration which depends on whether the enzyme actually activates or breaks the drug down, whether the enzyme activity is fast, or slow, whether there are alternative metabolic pathways that affect a drug in the body, and finally, whether there’s variation in a process by which the drug is removed from the body. Now this leads us on to genetics and serious adverse drug reactions. Some adverse reactions may be predicted through our knowledge of the pharmacodynamic orpharmacokinetic mechanisms that we’ve already discussed.

Skip to 7 minutes and 41 seconds For instance, we know that poor metabolisers can’t break the drug down very quickly, and because of this, toxic concentrations and adverse reactions may occur. However, some adverse drug reactions are allergic reactions, or due to hypersensitivity. It is much more difficult to predict these adverse reactions. It may well be that individuals have specific genetic susceptibility to the drug in these cases, and identifying this marker of adverse reactions may help us avoid giving a harmful drug to the patient. So just to recap what we’ve covered in the past few slides. We’ve discussed a diverse range of ways that the drug and body can interact.

Skip to 8 minutes and 36 seconds In assessing our treatment response, we’ve also seen that there numerous mechanisms by which genetic variation can affect this drug response. Now, pharmacodynamics and pharmacokinetics are two key areas where genetic variation may play an important part in drug therapy. And finally, we’ve also discussed whether the benefit/ harm balance may be optimised or improved if we have information on markers of benefit, or markers of serious harm.

Principles of pharmacology

This 10 minute tutorial by Professor Yoon Loke will explain some principles of pharmacology that are applied in pharmacogenetics.

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This video is from the free online course:

Using Personalized Medicine and Pharmacogenetics

UEA (University of East Anglia)