Competitive Inhibition & Statins – Pharmacokinetics Lect 18

Published by Jan Heaney on

Competitive Inhibition & Statins – Pharmacokinetics Lect 18

So let’s continue our discussion of competitive talking about the statins. By the way, there’s a link underneath this YouTube video that should give you access to the slides if you care to take notes. So, the statins. Well the statins are probably the most commonly prescribed drug in the United States and their job is to lower the levels of lipids. They are lipid lowering drugs. Lipid lowering drugs. They decrease your cholesterol and every year, about 250 million prescriptions are written. So you’ve got to know the statins. And the first thing you should know is how would you recognize one of these statin drugs by name. How would you do it? Well, the answer to that is any drug that ends with the suffix -statin is obviously a statin drug. And so, examples here are Atorvastatin or Rosuvastatin. And because these statins are the most commonly prescribed drugs in the United States, they are the ideal candidate to discuss drug interactions and the reason we have these drug interactions and we somewhat discussed this in the last video which I recommend taking a quick peek at if you’re confused but the reason we have this drug interactions is because the statins are predominantly metabolized by the cytochrome p450 3A4. So, I’m going to write statins. They are metabolized by CYP 3A4 which is an enzyme, the name of it. And that forms the inactive metabolite. Remember, 3 was the name of the family. A was the name of the sub-family. 4 was the actual name of the enzyme. and this as we remember, this enzyme is the most common enzyme that metabolizes drugs in our body. And so, the reason we have these drug interactions is because things like grape fruit juice, antacid medications and the macrolides, they inhibit this enzyme and by inhibiting that enzyme, they are going to increase the amount of statins in our body. And so, these 3 examples are 3 examples that every clinician I feel should know but you know that I could’ve listed 30 examples and it’s really any drug that inhibits this enzyme will cause or has the potential to cause an increase in the statin concentration and possibly, side effects. So the first example we’re going to talk about is grape fruit juice and you will find a grape fruit juice warning on most bottles of prescription statin medications. Now, let me just say that one glass of grape fruit juice in the morning isn’t going to kill you but several glasses especially at night when most people are taking their statins, this actually might affect drug metabolism. And so, you’re bound to have a parent or family member ask you, why grape fruit juice isn’t allowed and what you know the point here is that you should be able to answer them. So what would your answer be? Well, underneath here, I wrote that CYP 3A4 is inhibited by something called Furanocoumarins. So, if I was going to respond to your parent or to my parent or family member, I would say, “There’s something in grape fruit juice called Furanocoumarins and the Furanocoumarins prevent the statins, the drugs that you’re taking from being metabolized in your body.” And if I wanted to provide more details, I would say, “And so these statins if you take them with grape fruit juice and you take let’s say more than 1 glass of grape fruit juice especialy at night, these Furanocoumarins are going to inhibit that super important metabolizing enyzme in your body called CYP 3A4 and as a result, the concentration of statins might build up. So because CYP 3A4 is inhibited by the Furanocoumarins in grape fruit juice, this might lead to an increase in our statin blood concentration, okay?” And that’s the gist of it. That’s how competitive inhibition is working and that’s why we’re getting these drug interactions. So, the next example that I’ve listed here are the antacid medications. Now, it’s not all antacids. Here, I’m specifically talking about the H2 Blockers. So, we should remember that the H2 blockers and if you haven’t learned it yet, here’s a great opportunity to learn They decrease acid secretion in the body by blocking a histamine receptor and it’s not the H1 receptor that we saw in a previous video which is for an anti-allergy medication, it’s the H2 receptor. So, this is actually a great opportunity to integrate a little bit. So, let’s draw a little picture here on the right and let’s cover the parietal cell and how this works. So, remember that the parietal cell is in the stomach and one side of it, the luminal side has a proton pump and that’s what I’ve drawn here in orange on the left hand side. And so, what this proton pump does is it takes protons as its name implies and it pumps them out into the stomach and helps create hydrochloric acid and it does that by pulling a – by replacing that proton with a potassium. Remember, that this uses ATP but we’re not interested in this part as of right now. What we’re interested on is on the other side where we have these receptors. And so, there are 3 receptors that you hopefully learned about in physiology. So, I’m just going to draw 3 receptors. One, two, and let’s make this one kind of curved. So these 3 receptors. By the way this is the parietal cell. Let’s label that. Parietal cell. So, my question to you is if you remember physiology here, what are the 3 molecules that can bind to the receptors on a parietal and increase acid secretion? And hopefully, you’re saying those 3 molecules. One of them we just talked about is histamine. So that’s what I’m going to draw here in blue as a triangle. The other is kind of neurally controlled. I believe it’s through the vagus nerve. That’s acetylcholine. Let’s just write here histamine. So, the other one is acetylcholine. And the last one’s kind of tricky. This last one here is actually gastrin. You might remember gastrin if you learned about it in physiology possibly pathology where some patients have a gastrin secreting tumor in the pancreas. And so because that we are secreting gastrin, that activates our parietal cells to release lots of protons and the person as a result gets tons of you know stomach ulcers or duodenal ulcers. And that was called a gastrinoma. And we saw that with something called Zollinger-Ellison syndrome. Just a quick little integrative fact here. But getting back to this histamine receptor, this is the H2 receptor and we have the drug and so, that drug – this actually blocks histamine from having its effect on the parietal cell and those are the H2 blockers. Now you want to know at least one of the names of these H2 blockers and one of those names is cimetidine. So going back to this image on the left here, cimetidine, one of the things it does is it acts as an antacid and by blocking that you know H2 receptor or having an opposite effect of histamine but the other thing that it does is it also inhibits the cytochrome p450 3A4 that we talked about and again, as a result, we’re going to get an increase in that statin concentration. Same story. Now there’s actually another drug here that is not just called cimetidine that you might be more familiar with and that’s an over the counter medication. Actually, cimetidine is over the counter too. If you want a little historical fact, cimetidine was one of the first blockbuster drugs. That is a drug that generates over $1 billion of annual revenue but many people haven’t heard of cimetidine, they might’ve heard of something called Zantac and Zantac is a brother of cimetidine. It’s just another drug called Ranitidine. So, let’s move on to the last example and that is the statin drugs with macrolide antibiotics. Really quick, what are 2 statins that we covered? Atorvastatin, Rosuvastatin. Very nice! So, the macrolide antibiotics. Well you’ll learn here shortly when we cover antibiotics that the macrolides, what they’re typically known for is that their only use but they’re known for upper respiratory tract infections and because they’re antibiotics, these are bacterial upper respiratory tract infections and I’m just going to write URI. And the way that you would recognize these drugs is that the macrolides, they all end with the word -mycin. And so, we’ll see a couple of examples. And the way I remember all the macrolides is with this little term here, MACE. The macrolides – the M are Azithromycin, Clarithromycin and Erythromycin. Notice that we have this -mycin at the end of it. We also have a thro here as well but the way I remember this is all the -mycins. So, I actually had an attending recently ask me a question which I want to share with you. And that question was, which macrolide antibiotics is it okay to give to patients who are taking the statins? And while you probably won’t get that exact question on a board exam, it’s important clinically and you know, you might get it on a future board when you’re passed basic pharmacology. And the answer to that question really depends on out of these 3 macrolide antibiotics, 1 of them does not inhibit cytochrome p450 3A4 and that one is the one I’m kind of pointing to right now that is Azithromycin. So, Azithromycin – let’s just write right here. This one has no CYP 3A4 inhibition. but the other ones, Clarithromycin and Erythromycin, do. So real quick, I just gave you 3 examples, you know grape fruit juice more than 1 glass, antacid medications specifically the H2 blockers and the macrolide antibiotics with the exception of Azithromycin. Subtitles by the community


Kathleen Jackson · November 2, 2012 at 6:12 am

Just starting revising pharmacology for the first time since medical school, and your pictorial explanations are a great start.Have just watched the whole series. Looking forward to future videos. Thanks!

Simon Munro · March 8, 2013 at 5:47 pm

Hi Areo, thank you for a very clear and informative video. I have a potentially silly question! I'm wondering if patients could take Statins and still drink grapefruit juice if the dose of Statin was lower. A lower dose could mean they suffer less side effects from the Statin. Of course, if the serum concentration of Statin become too high, this could lead to toxicity but could a lower dose of Statin be used so patients can freely drink grapefruit juice and still be in a therapeutic range?

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