[MUSIC] So this module continues the exploration of variable drug effects and the various kinds of mechanisms that can underlie variable drug effects. And I've entitled this module, A Patient with a Headache After Taking an Antidepressant. So this is a 36 year old woman with depression and she tells you, that she's tried lots of different medicines but they all give me side effects. And so after a long discussion she agrees to try venlafaxine a commonly used antidepressant. She comes back a week later with headaches that were really severe, new for her. She stopped the medicine and the headaches went away. So what are the potential explanations. So, one possibility is the headaches are unrelated, but the idea that they come on and then they resolve with drugs suggests, that they are somehow drug related. It's unlikely this is non compliance. She clearly is taking the medicine and is having an effect, not the effect she wanted or you wanted, but an effect. So are there other explanations, for variability in in response to this kind of drug and I'll walk you through a story, that we'll continue in subsequent modules, because it's an interesting one. This story starts in the 1970s, and it's actually one of the by now ancient stories in modern pharmacogenetics. The man on the left is named Robert Smith, and the man on the right is named Michel Eikelbaum, and they working in the United Kingdom and in Germany around the same time in the mid 70s, both made the same observation using different drugs. So, the observation that Dr. Smith made was he was studying a high blood pressure medicine, who's structure is shown in the upper left corner, and that medicine is called debrisoquine, and is metabolized to an inactive metabolite called 4-Hydroxy debrisoquine. You can see the hydroxy group on the debrisoquine molecule. The mythology in our community is that he was asked by the pharmaceutical sponsor to do a pharmacokinetics study of debrisoquine. What's its half life and how high are the drug concentrations? So he agreed, he, he recruited a bunch of post doctoral fellows and graduate students and research technicians in his lab and he made the critical mistake, of being a participant in the study himself. He took an ordinary dose of debrisoquine, that everyone else tolerated and he had severe profound, low blood pressure for a couple days afterwards. So what we say is that because it was him. He devoted the resources of his laboratory to try to understand, why this happened to him. Had it been a graduate student, he might have just said, well I'm not interested. So, that's one story and I'll tell you how that story turns out. The other story is, it took place in Germany with a drug that was used both in obstetrics and in cardiology, called spartane. Spartane undergoes in oxidation at the position shown with the arrow and patients who have high spartane levels, have side effects and there's a unusual small number of patients, who get a very high incidence of side effects with a relatively normal dose of spartane. So what Dr. Smith and Eikelbaum showed, is that the very ability in response, so starting with Dr. Smith and his debrisoquine, what he showed is he was unable to form the four hydroxy metabolite. So what happened, is that the parent drug the debrisoquine, accumulated very high concentrations in his blood and caused low blood pressure. The same thing happens to patients with spartane side effects, the parent drug accumulates to very high concentrations, because they're unable to get rid of it by metabolism. So, for a long time, we call it, talked about debrisoquine hydroxylation or spartane anoxidation, but it It turns out that's exactly the same enzyme. The enzyme is cytochrome P 450, or CYP2D6. CYP2D6 is responsible for the metabolism of about 25% of the commonly used drugs. So right after CYP3A, for and related members of the CYP3A family, CYP2D6 is the most important drug metabolizing enzyme in the liver. Interestingly, it makes up a tiny proportion by weight, but by importance, in terms of how many drugs it metabolizes, it's one of the most important drug metabolizing enzymes and one of the most polymorphic. So if you look at a large population and ask the question, how much activity does this person have of CYP2D6? And there's ways of measuring the activity, I won't go into the details, but you can see there's a funny x axis here. There's greater activity towards the left, lessor activity towards the right and it's a log scale, so it's like from 0.01 all the way to 100. So patients, who are on the right in black really have very, very little activity of the enzyme. Patients who are the rest of the population in blue, have a wide distribution of activities but they're all able to have some activity. So we now understand the genetic basis of this and it turns out that very very commonly, perhaps 25% of Caucasians carry one loss of function allele and that's shown in this genetic cartoon as the little black box. Patients who happen to have two loss of function alleles are about 7% of the population and they have no functional CYP2D6. So a common, the header is like it trait is quite common, even the homozygote, so the compound has it's zygote trait this quite common. Unlike CYP2DC19 where there is one predominant loss of functional deal, here, there are hundreds of loss of functional deals. Some of them quite common, some of them quite rare, many of them are not snips, many are larger insertions or deletion. Their difficult to assay and it's difficult to know whether somebody from a genetic test is a poor metabolizer or not cuz you have to, you're always left, with the lingering concern that they might have some rare variant that you didn't assay. There is also this striking variability of variant alleles by ethnicities. So for example, the poor metabolizer trait is really quite unusual in Asian populations, but again, five to 10% of Caucasian and African populations. Most antidepressants are metabolized by CYP2D6, and, or CYP2C19. You can see the list here, and so it turns out that if you have an antidepressant that's metabolized by both, and you're a poor metabolizer for one of those traits, it doesn't make much of a difference, cuz you can always get rid of the drug, by the other pathway. But it does modulate the amount of drug that you have around. So this is an example of variability, in response to a widely used antidepressant called citalopram by CYP2C19 genotype and you can see, the poor metabolizers have a greater response. That's because they have higher drug concentrations and greater drug effect, they also run the risk of having more side effects. The rest of the population metabolized the drug and have roughly the same effects, you'll notice the differences are not large [COUGH], but they're, they are there. And, you can then make a cascade of how much you should adjust the dose of the drug, if you know somebody is a poor metabolizer. An intermediate metabolizer or a normal metabolizer for CYP2C19 for a variety of antidepressant drugs, as shown in this slide. So coming back to venlafaxine for a second [COUGH], here's a very small study from the Mayo Clinic, 38 subjects treated with venlafaxine, out of the five poor metabolizers in this study. So that's actually a pretty high incidence of poor metabolizers, it's about 13% or so, a little bit higher than you might expect. Nobody could tolerate even a low dose, they all got headaches, headaches go away after the drug was stopped. The remainder of the subjects all did pretty well. In fact, two thirds of them had a were able to tolerate therapeutic doses and had an effect. So with the background that I've given you, I want you to think about three questions, relating this genotype and this genetic effect to variability and response. So, the first question is, do you believe this? And that's an important question, because this is in a very, very small study, you know, zero out of five patients. Well, maybe there's something funny about those five patients. Maybe there's something funny about this particular practice. So it's a very small study and basing sweeping recommendations on a very small study is always dangerous. The second rhetorical question is, would you genotype your patients before starting venlafaxine? So I've already told you that the effect is small, there are many other antidepressants that are available. And in fact, no one's ever died of a headache, you can always argue that it would be nice to get people on effective antidepressant therapy, and that is important. But there are many alternatives, and genotyping is complicated. It's complicated to get this, this is not assaying one snip, this is assaying many, many, many kinds of variants. In a highly sophisticated way and then figuring out from the variants what the actual genotype, or what we call the diplotype is, the genotype on one [INAUDIBLE] and the genotype on the other, and the combination and the predicted effect on drug metabolism. So it gets complicated, just to avoid a headache. And the third question is, if you knew, if you had a patient who had previously undergone genotyping for some reason and the information was there. Would you use this? Would you look down the chart of that 36 year old woman and say, well, I see that you're a poor metabolizer for CYP2D6, so we won't try venlafaxine in you. There's soft data, but there's data never the less that you were unlikely to tolerate it. Let's try something else. So I think the answer to the third question, the way I phrased it at least, is perhaps yes. How do you get to the point where you have those readily available. That's an interesting question that we'll discuss in subsequent modules. So, it is important to have a list of these drugs in your head, there are lists that are available on the web. And the reading material will provide more comprehensive lists, but there's long lists of drugs, starting with debrisoquine and sparteine, two drugs by the way that no one ever uses and in fact never got to the market in this country. One reason that they never got to the market, is because they had this variability in effect and one of the spin offs in understanding CYP2D6 pharmacokinetics and pharmacogenetics is that a drug that is metabolized solely by that pathway. Is now unlikely to get developed by a big pharmaceutical company because they will say well, we're dooming five to 10% of our population to some variant response. So if we're gonna do that, let's find another drug that at least has a second pathway that it could be eliminated by or doesn't use CYP2D6. So that's an important learning lesson for drug developers and then there's a long lists of other kinds of drugs and other drugs classes. Antidepressants, beta blockers and other drugs that are active drugs that are substrates for CYP2D6. And then there are a couple important inhibitors that clinicians should be aware of. Two SSRIs, fluoxetine and puroxetine, the antiretroviral drug, ritonavir is an extraordinarily potent 2D6 inhibitor. It's not a very great antiretroviral drug I am told, but people use it in combinations nevertheless in order to boost the concentrations of other drugs. And then quinidine, the other antiarrhythmic, even at very, very low doses, does that are so low that no cardiac electrophysiologist, whatever they think they would do anything. Five milligrams, ten milligrams, 15 milligrams, those really low doses are very potent inhibitors of CYP2D6. So that's an interesting observation. So let me just tell you a story, that has to do with interactions in an unusual and unexpected way. This is a case report in the annals of internal medicine in 1985. That reported bradycardia in a patient receiving quinidine and timolol eye drops. So, timolol is a CYP2D6 substrate, quinidine is a CYP2D6 inhibitor. Group of my colleagues Vanderbilt, then went on to study this potential reaction in a very systematic way and the reason I show it to you is because there is an interaction and more importantly, or more interestingly, it involves Timolol eye drops. And people don't think about eye drops as a source of adverse drug effects, there just things you drop in your eye, but of course. The drug actually gets into the body and the amount of drug that gets into the body and hangs around, depends on metabolizer genotype and it depends on the presence of inhibiting drugs. So they took a group of extensive metabolizers and poor metabolizers. Gave them Timolol eye drops, low and behold there was no effect with placebo but heart rate lowering with the eye drops, more so, in the poor metabolizers than in the extensive metabolizers. If you then gave timolol or timolol plus quintadena you will see there is a greater effect with quintadena in combination with timolol. Timolol alone on heart rate and yet quinidine alone did nothing to heart rate just like placebo. And then when you look at plasma concentrations, plasma concentrations, not eyeball concentrations. Concentrations are highest among patients who are poor metabolizers, next highest among patients who are extensive metabolizers receiving quinidine, the inhibitor drug. And then lowest among patients who are extensive metabolizers and who don't get the inhibiting drug. So there's a drug interaction that is genetically based and that involves a drug, that is given by a root that we ordinarily don't even think about. Here's another example. Again, a little bit of a cardiac flavor, this is a very unusual case of flecainide intoxication. This is a 36 year old woman who presents with palpitations and near syncope. You can see her electrocardiogram shows these bizarre, very, very wide QRS complexes. It's a miracle that she has any blood pressure at all, she'd been on chronic therapy with flecainide for supraventricular tachycardia and chronic therapy with fluoxetine. She had developed acute renal failure with a Cr 4.5, but her potassium was normal. So one thing you would think of when you look at this electrocardiogram is whether this patient is hypovolemic. This patient was not hyperkalemic, this is flecainide intoxication, very rare syndrome and actually easily fatal. So how is flecainide eliminated. Flecainide, it turns out, is eliminated by hepatic biotransformation and by renal elimination. So she's sitting there taking fluoxetine, the inhibitor of CYP2D6 and CYP2D6 mediated metabolism. So the only way in which she can get rid of flecainide is through the renal route. Of course her plasma concentrations and her drug effects are all normal because she has normal elimination, but when the kidneys fail acutely, then she has no way of getting rid of the drug. So this is a double hit causing a severe adverse drug reaction. And a patient who is taking a drug that ordinarily isn't subject to these kinds of adverse effects because it's not a high risk situation in the sense that there are multiple pathways for drug elimination. So, I talk before about this idea of prodrugs being high risk situations, high risk pharmacokinetics is what I've called this. And poor metabolizers or people taking inhibiting drugs run into particular problems when they're taking prodrugs like clopidogrel. This is a separate example. This is an example with flecainide or timolaw of patients taking a parent drug and that parent drug is eliminated generally by a single pathway. Flekanide is the exception. And when that single pathway is perturbed, either because the patient's a poor metabolizer, or because the inhibiting drug is present. You actually get not less pharmacologic effect, you get exaggerated pharmacologic effect cause the parent drug accumulates and the parent drug is active. Accumulates in plasma and produces excess effects. There's some drugs where accumulation doesn't make much difference. If you double the plasmic concentration of a beta blocker most patients don't notice it, they might have slower heart rates. But of course if you double the concentration of a drug like flecainide or an anticoagulant drug, where a little bit too much can produce catastrophic side effects, then you'll certainly be aware of it. So this is another example of the phenomenon that I've called high risk pharmacokinetics. So in summary, again, we can always think about the mechanisms underlying variable drug effects and accumulations of a parent drug by genetics or by drug interaction can have large effects on drug action, especially in the setting of this problem of high risk pharmacokinetics. And this story again emphasizes, just like the last module with clopidogrel, this idea of how much evidence do you need to order a genetic test. How much evidence do you need to be able to. Able to act on a genetic test whose are already available to you. We'll be talking about that some more in later modules. >> [APPLAUSE]
