Pratique du Shadowing: Antimycobacterials | Anti-TB Drugs - Apprendre l'anglais à l'oral avec la vidéo
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What's up Ninja Nerds?
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In this video today we're going to be talking about anti -mycobacterial drugs.
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Very cool one.
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Very short one.
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Nice, right?
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Finally we're going to have a short video.
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But when we talk about these particular drugs, it's really important again to follow along with me.
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Grab the key, grab the actual illustrations, all the notes that we have at our website.
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We have a link down in the description box below.
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Go check that out
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so you guys can follow along with me i really think it'll aid in the learning process
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but when we talk about anti -microbacterial drugs there's a lot of different ones
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that we're going to talk about here
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but we should focus on how do they work what's their mechanism of action
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because if you're tested on that you should know what particular site
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and what kind of like function they interact or inhibit with
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and then after that we'll talk about what are they used for
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so we'll talk about obviously tb mac infections the super rare leprosy
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but if you get a question on the exam you'll know it
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and then we'll talk about the adverse effects
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that you got to watch out for all right so first thing
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when we talk about this actual mycobacterium you know in order
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for the actual mycobacterium to function it obviously needs to be able to replicate its dna
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and actually also transcribe its dna make particular proteins
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that allows for it to be able to control its structural
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and functional proteins we need that to occur well we have particular drugs
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that can inhibit this cute little pink enzyme you know what
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this cute little pink enzyme is called this enzyme here is called RNA polymerase.
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And what RNA polymerase does is, is it takes DNA, reads it, and from reading it, it makes a molecule called RNA.
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Particularly, this would be mRNA.
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Now, because it stimulates this particular step, mRNA then does what?
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It actually interacts with ribosomes.
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And those ribosomes will then synthesize particular types of proteins.
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And These proteins can obviously be structural proteins.
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They can be functional proteins, but either way, these bad boys are proteins and they're essential to the actual bacterial's function.
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Well, if I give this particular drug called rifamycins, you know, there's actually two particular ones that I want you to remember that treat mycobacterial infections.
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One is called rifampin.
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This is going to be the very commonly utilized one.
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And the other one is called rifabutin.
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And rifabutin is actually an interesting one we utilize a little bit more commonly in MAC infections, particularly if someone has HIV positive.
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Rifampin causes a lot of interactions with the CYP450 system, so rifabutin is a little bit more preferred.
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But either way, these drugs are going to inhibit the RNA polymerase.
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If you inhibit the RNA polymerase, can they take DNA and convert it into mRNA?
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No. So this type of reaction here will occur.
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There's less mRNA that's being formed.
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That means that less proteins will be formed.
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Proteins are integral to the actual structure and function of mycobacterium.
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You lose that, you lose their ability to be able to survive.
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They will then die.
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So that's a really cool function of this particular drug.
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Now, in the same way, focusing at the nucleic acid level, you know, nucleic acids are made up of nucleotides.
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And from nucleotides, we use very specific molecules that we can add into them, that we can use to make nucleotides to incorporate into the DNA or incorporate into RNA.
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There's this molecule here called para -aminobenzoic acid.
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And And para -aminobenzoic acid is actually converted into something called dihydrofolate and then tetrahydrofolate.
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And that's usually incorporated into particular types of like thiamine nucleotides.
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So it's important to incorporate into DNA and into RNA particularly is a nucleotide like thiamine.
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Now, if I give a particular drug,
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right, dapsone, what dapsone will do is dapsone will actually inhibit the particular enzymes involved in converting para -aminobenzoic acid into dihydrofolate.
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So it's involved in the metabolic pathway here.
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So it'll inhibit this particular step.
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When it inhibits the conversion of parametobenzoic acid into dihydrofolate, that means you get less of this, less of this, and less incorporation into DNA and RNA,
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less of the actual nucleotides to make DNA, to make RNA.
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And that is important because if we don't have that, we can't actually have the nucleic acids that we need to code for replication and transcription processes.
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Pretty straightforward.
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All right, so we got rifamycins, which is inhibiting the RNA polymerases, dapsone, which is inhibiting the metabolic pathway that makes nucleotides via the parametobenzoic acid pathway.
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The next one that I want you guys to remember is streptomycin.
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Now streptomycin is actually pretty cool.
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Streptomycin is a kind of a second line agent that we can use in like TB infections.
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But what streptomycin will do is it inhibits a very specific component here.
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So you know how we need mRNA to interact with the ribosome.
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Specifically, there's the two components, the 30S and the 50S ribosomal subunit.
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Streptomycin will bind to the 30S ribosomal subunit and inhibit it from being able to interact with the RNA and make proteins.
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So if you inhibit the 30S ribosomal subunit, what do you do to the actual protein synthesis?
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You decrease protein synthesis.
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So again, I want you to remember streptomycin inhibits the 30S ribosomal subunit, riflamycin inhibits the RNA polymerase enzyme, and dapsone inhibits the peraminobenzoic acid pathway,
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leading to less tetrahydrofolate, less nucleotides that are needed in DNA and RNA.
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All right.
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The next thing here is isoniazid.
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Now this one is a little bit kind of a complicated pathway.
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I'm going to try to dumb it down a little bit, but what happens is isoniazid gets taken up into this actual mycobacterial cell.
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When it gets taken up into the mycobacterial cell, it's converted into like a metabolite, kind of an active metabolite.
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We're just going to kind of draw like little asterisks on this because now it's activated.
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In order for it to be activated, there's a very specific enzyme that performs
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that function to activate it once it's brought into the mycobacterium
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and this is called catalase peroxidase also known as cat g enzyme
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and what this does is it activates the isoniazid into this
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active metabolite all right once it's in this active metabolite form
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it then binds with another molecule that's present inside of the actual mycobacterium
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and this molecule is called nad so it'll bind with nad
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So then we get kind of this active metabolite of isoniazid plus we have bound to it the NAD molecule.
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Once you have this, this molecule is very interesting because of what it can do is it finds a little enzyme here.
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You see this enzyme right here?
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This enzyme is called enoyl reductase.
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And what enol reductase does is it helps to be able to stimulate the production of particular molecules
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that are integral into the cell wall.
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And obviously the cell wall is important for resisting osmotic forces.
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If you don't have the integral component of it, you aren't able to resist osmotic forces and the actual bacterial cell will die.
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What is that particular component that it makes?
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Well, let's actually say that we take a slice of the cell wall out and zoom in on it.
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There's different types of molecules that are integral to the actual cell wall.
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And this would be from the outer portion all the way to the inner portion.
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So outer to inner.
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That inner layer here is going to be the inner cell membrane.
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So this would be your cell membrane as the innermost layer.
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So your phospholipid bilayer.
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Then after that, in this pink layer, this is your peptidoglycan layer.
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So this is your peptidoglycan layer.
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Then after that, in this maroon color here, we have something called arabinogalactin.
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Arabinogalactin.
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So kind of like a sugar molecule, kind of like a polysaccharide molecule.
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Then you have this fatty acid layer called mycolic acid.
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So mycolic acid, very important component.
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And on the outermost layer here in red, you have your glycolipid layer.
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Now, what's really, really important is enol reductase helps to be able to synthesize the mycolic acid molecules, which are integral to the cell wall.
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Whenever you give them isoniazid, it gets converted into this metabolite, binds with NAD, and now when it binds with NAD and it's in the activated form,
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it can then inhibit the enol reductase.
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If we inhibit the enol reductase, we then reduce the synthesis of mycolic acid.
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If we reduce the synthesis of mycolic acid, we lose an integral component of the cell wall in the bacteria and then subsequently die.
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So that's isoniazid.
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I know it's a little bit complicated, but I hope that pathway makes it a little bit more simplified.
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All right, to go along with mycolic acid, there's another particular drug.
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We didn't completely know how this enzyme, this drug actually worked.
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It's still questionable, but what we know is that this drug here called pyrazinamide works to inhibit mycolic acid formation.
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And so there was questions of how exactly it does it.
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Some of the most recent literature says that it inhibits a very specific enzyme.
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And this enzyme is called fatty acid synthase.
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And mycolic acid is kind of like a fatty acid.
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So if you don't have this enzyme, guess what this enzyme actually does?
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It helps to be able to synthesize the very important molecule that we incorporate into the cell wall.
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What do you think it is?
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Mycolic acid.
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So if we inhibit this enzyme, we use pyrazinamide, we inhibit the actual fatty acid synthase.
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Can we make the mycolic acid molecules that are integral to the actual cell wall?
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No. So we'll decrease the actual synthesis of mycolic acid molecules.
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So two drugs will inhibit mycolic acid.
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One is isoniazid through this kind of complex pathway.
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And the other one is pyrazinamide, which inhibits the fatty acid synthase.
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So fatty acid synthase, pyrazinamide, enoreductase inhibition, isoniazid.
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Okay, we're almost done.
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Last one here.
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Ethambutol is another interesting one.
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So remember I told you that there was two important components here to the actual cell wall.
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Mycolic acid is a big one that I want you to remember.
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And then this maroon color one here is the arabinoglactin.
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This is another important layer that I want you to remember.
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This enzyme here is called arabinosoil transferase.
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So you're like, what the heck?
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This enzyme here is called arabinosoil transferase.
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And what this enzyme does is, is it takes particularly like sugar molecules that are present inside of the bacteria.
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The two sugar molecules that you actually would need to remember, one is called arabinose and the other one is called galactose.
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What it'll do is it'll take a combination of these molecules, utilize them, and then convert them into arabinogalactin, okay?
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Which is integral into making this particular molecule here that's incorporated into the cell wall.
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So it'll use these molecules and make this thing called arabinogalactin.
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That's what the job of this enzyme is.
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If I give this drug called ethambutol, ethambutol will inhibit the arabinosyltransferase.
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If I inhibit arabinosyltransferase, I can't take arabinose and galactose and make arabinogalactin.
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If I can't make arabinogalactin, do I have the integrity of the actual cell wall?
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No, I lose my integrity.
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Therefore, the actual bacteria cell is susceptible to death.
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So to quickly recap these, rifamycin inhibits RNA polymerases.
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Shreptomycin inhibits the 30S ribosomal subunit.
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Dapsone inhibits the pava pathway, which inhibits nucleotide formation.
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Isoniazid inhibits fatty acid synthesis, particularly of mycolic acid by inhibiting enoyl reductase.
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Pyrazinamide inhibits mycolic acid formation by inhibiting fatty acid synthase.
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And ethambutol inhibits arabinoglactin formation by inhibiting arabinocyl transferase.
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I know it was a lot, slightly complicated.
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I apologize, but I hope this makes sense.
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Now let's move on to the actual indications of these drugs.
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We're going to talk about what are the actual clinical usages.
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It's actually straightforward.
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So mycobacterium tuberculosis.
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We're not going to go through the entire pathophys and all the the clinical features of TB, we'll talk about that when we dedicate an actual lecture to tuberculosis and all these other ones.
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But when we talk about tuberculosis, obviously we know it's due to the bacterium, mycobacterium tuberculosis.
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Now, obviously that area, that bacterium loves the lungs.
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So it loves to kind of stay, interact with macrophages and cause these types of nasty lesions that you can see within the lungs.
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And then the problem is once it actually causes these lesions typically within the upper lobes of the lungs, what happens is it has the ability of, so actually if someone's severely immunosuppressed for some reason,
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it can disseminate and spread to other organs of the body, where it can spread to the actual brain, causing like meningitis or encephalitis, spread to the actual bones, where it can cause osteomyelitis,
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spread to the adrenals, where it can cause adrenal failure, spread to the liver, cause liver failure, spread to the actual lymph nodes, causing like lymphadenopathy or scrofula.
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So a lot of things that can happen when you have this infection.
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But the question is, sometimes people can be infected with TB, never know it, not have any idea, but when we do like the tubercular skin test,
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the PPD test, and we see that the bump is maybe a particular size, but they don't have any active infection going on, but they have maybe the latent infection of TB, we can treat them for that.
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Now, if they have the full -blown active infection where it's involving their lungs or it's disseminating, then we have an active TB treatment.
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We should know what are the agents that we utilize in the latent
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and what are the ones that we utilize in the active infection.
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So in the latent TB, where they're not actually having active pneumonia infection.
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They're not disseminating into the actual systemic vasculature and other parts of the body.
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We utilize two particular drugs that we can use here, one or the other.
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So one is you can use isoniazid, commonly abbreviated INH.
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Just get used to that one.
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I might use that sometimes.
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So INH, we can do this for about six to nine months.
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Some literature will say six months, some will say nine months.
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It depends upon how frequently you take it.
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The other one we can utilize is rifampin.
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So rifampin would be the other option we could utilize here and we could use that one for four months.
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So if a patient has latent TB, they test positive or they have a particular size of the tuberculin skin test, we can put them on one of these two drugs for that time duration.
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Now, if they have active TB, they actually have active like caseating granulomas with inside of the lungs, or they have gone complexes, or they have ranky complexes, or they have dissemination to other areas of the body,
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they have active TB, we treat them a little bit differently.
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We utilize what's called a ripe regimen.
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That sounds crazy, But you start off first with what's called the RIPE regimen.
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So this is rifampin, isoniazid, pyrocinamide, and ethambutol.
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So you utilize these four drugs first for at least two months.
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Okay?
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After the two months are up, you then move into the second part of the regimen, which you utilize rifampin and isoniazid for four months.
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so it always works in this particular fashion for the first two months you use the ripe drugs
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rifampin isoniazid pyrazinamide
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and ethambutol for the second part of the regimen for the next four months you use rifampin
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and isoniazid when you have a patient on isoniazid one of the common adverse effects is b6 deficiency
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which can cause neuropathy it can cause anemia it can even increase the risk of seizures
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so because of that we want to be able to give the patient b6
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so we give them B6 supplements to be able to augment that and prevent them from developing B6 deficiency because of isoniazid.
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Now, if a patient has active tuberculosis and it's actually seeding, it's spreading, so they have like miliary tibia, they have TB meningitis.
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oftentimes we may add on streptomycin as a second line agent
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but generally when you're at this point you're going to seek the id consult
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because they're going to be way too sick for you to
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be able to have to figure this out you'll see got an actual infectious disease specialist
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and they'll be able to kind of figure out what is best in this situation
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so what i think is the most important remember is what are the two drugs
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that we can utilize in latent tb what are the length of the duration.
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Then active TB, what are the actual regimen, RIPE and then rifampin and INH, two months for the RIPE, four months for the rifampin and INH, add B6.
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It's very important.
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Sometimes you can add streptomycin or other particular drugs into this regimen if they have more systemic or refractory TB.
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All right, so the next one here is Mycobacterium leprase, so leprosy.
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So in this one, I can't say that you'll often see this very often, but it's a Mycobacterium, so we should know the particular agents
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that we utilize for this in the same way
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that we know tuberculosis so typically it loves to involve the skin
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so it likes to cause like these hypopigmented skin lesions that's one particular thing
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so you may see particular skin lesions
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and then the other thing is you actually may see nerve palsies
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so it typically likes to cause like thickening of the nerves and
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when it thickens up the nerves it actually may get compression
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in particular areas one of the common areas is like the ulnar nerve
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so you may see like an ulnar nerve palsy that might be one and then the other one is the peroneal nerve.
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So you actually may see a peroneal nerve palsy in these situations as well.
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So that would be the particular thing to think about.
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Now, if somebody does have leprosy, what are the particular agents that we utilize in this?
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It's often two particular drugs, dapsone and rifampin.
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So I want you guys to remember dapsone and rifampin.
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Sometimes we may add another drug in called clofazamine, but generally that's if they have like what's called the tuberculoid form of leprosy
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so i don't want to go too far down
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that road remember dapsone rifampin for leprae remember these isonized for
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69 months for latent tb rifampin for four months for latent
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tb active is ripe for two months rifampin high in age for four months
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and then add on your b6 the last mycobacterium infection
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that i want to talk about it's called a mac
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so it's called mycobacterium avium intracellular complex infections let's talk about
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that so with mycobacterium avium intracellular complex infections generally these love to cause like these like fibrocavitary like pneumonia
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so we're obviously going to see like some type of pneumonia
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like generally some type of like nodular fibrocavitary lesion what can
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happen is in certain situations this can actually disseminate especially in
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immunosuppressed individuals spread to the liver spread to the actual bone marrow
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and even spread to the spleen in situations where a patient
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tests positive for mycobacterium avium intracellular complex what do you treat
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them with it's usually particularly like a three -part combination
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so we you're going to utilize one drug is called fmbutol you guys remember
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that one and then we'll add on another drug to that
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and we usually utilize what's called rifampin so we'll add rifampin as another one
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that we can utilize
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and then the last one here is we add something called
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a macrolide we talked about this in the antibiotic section
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but this would be particularly like your clarithromycin your azithromycin the next thing to potentially consider is the plus
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or minuses when will we add other particular agents on.
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So these are the primary agents that we're going to utilize in the MAC infection.
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But we may add on things like aminoglycosides.
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You may add on things like fluoroquinolones, particularly in those severe or refractory cases.
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Severe slash refractory cases.
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But that would be the particular thing
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that I want to want you guys to remember for the mycobacterium avium intracellular complex infections.
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You always start with ethambutol, rifampin and a macrolide plus or minus an aminoglycoside or fluoroquinolone in the severe refractory cases.
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One thing to add to these actual things here is that anytime you're actually giving somebody rifampin, so I would add this as an extra little side note in case they ask you this on the exam.
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If a patient is HIV positive and they are going to be on rifampin, if you put them on rifampin, whether that be for mycobacterium leprae,
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whether that be for tuberculosis or whether that be for mycobacterium avium intracellular complex
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because rifampin can interact with the cyp 450 system you might want to switch to rifabutin
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so this may be a question that they ask on the exam
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because there is less interaction with the nrti's and
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that is extremely important because remember when we treat hiv we use nrti's
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or nrti's or protease inhibitors all those different drugs Well, if you give someone rifampin, rifampin may actually decrease the concentration of these NRTIs, but if you give them rifabutin,
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there is no actual cytochrome P450 inhibition with this one.
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So less effect on the NRTIs, NNRTIs, protease inhibitors, all those things.
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So that's really, really important to remember.
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So HIV positive patient that you're putting on rifampin, switch them to rifabutin because there's less kind of like drug interactions there.
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All right, now that we've talked about that, let's hit the adverse reactions.
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All right, so let's talk about the adverse effects of these antimicrobacterial drugs.
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So first thing, rifampin.
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What do we need to know about this one?
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First thing is that they will ask you this on the exam.
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Patient comes in, they're freaking out because they have red -orange urine.
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That's a completely normal, harmless adverse effect of rifampin, but just be aware it is an adverse effect.
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And I would probably let the patient know that before they go home.
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Okay.
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So watch out for any kind of like red, orange urine.
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It's completely harmless, but just let them know that so they don't have like a heart attack.
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Okay.
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Then the other thing here is that it can actually cause false positive urine opiate tests.
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I just thought that was an interesting thing to potentially no. So false positive urine opiates.
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But I think the other big thing to remember here is the effect on the CYP450 system.
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Remember I told you it acts as an inducer.
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So because of that, if you give this, it's going to decrease the concentration of a particular drug that you're taking it with.
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That's why if a patient is HIV positive and they're taking NRTIs or NNRTIs or produce inhibitors, if you give that with rifampin,
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it can actually decrease the concentration of that drug because it is a CYP450 inducer.
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So it's important to be able to remember that when you put them on rifampin.
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Watch out for any other drugs that they're taking it with.
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All right, pyraxenamide.
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What's the important thing to remember for this one?
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Monitor those LFTs.
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Some people will say rifampin is hepatotoxic.
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It is a very minor, minor, minor hepatotoxicity.
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It's important to train the LFTs, but it's significantly less hepatotoxic in comparison to all these other ones.
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So pyraxenamide is the big one that I would remember is hepatotoxic.
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This one is an isoniazid.
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So hepatotoxicity, watch for the bump in the LFTs.
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So watch for any kinds of hepatotoxicity.
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Next thing here, with pyraxenamide, it plays a particular role within the uric acid.
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So it may actually reduce the uric acid in the actual urine and increase the uric acid inside of the blood.
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And so this is called hyperuricemia.
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So it may increase the uric acid in the blood, causing hyperuricemia.
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So if the patient is actually in the vignette and they say, okay, putting them on pyrazinamide, but they have a history of gout, what should you potentially watch out for?
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Worse exacerbations of their gout because you're gonna increase their uric acid levels, increase your uric acid crystal formation, and they can deposit into that big toe and then they come in, my toe's all jacked up.
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So important to remember that with the pyrazinamide.
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Ethambutyl, what is the important thing to remember for this one? affects the eye particularly the optic nerve
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so this can actually cause optic neuritis important to remember
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that they may have visual disturbances and decreased visual acuity
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so optic neuritis whenever you put this medication on somebody watch
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out for any types of visual dysfunction maybe follow up with the optometrist
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or ophthalmologist all right so rifampin red orange urine false positive urine screens this is the big one cyp450 inducer perazinamide apatotoxic, hyperuricemia, watch out in gout.
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Ethambutol, optic neuritis, consider doing like follow -up with the actual ophthalmologist or particularly optometry.
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Dapsone, if you put somebody on dapsone, what should you potentially watch out for?
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One of the big things is it can actually oxidize the hemoglobin and convert it into the ferric form.
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Whenever that does that, you can't bind oxygen.
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So oxygen won't be able to bind with this ferric form, this oxidized form.
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And because of that, they can cause hypoxia, more of like a cytotoxic or histotoxic hypoxia
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and this is actually called methemoglobinemia
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so watch out for this one the other thing is
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if a patient has a g6 pdh deficiency
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and you give them dapsone it can increase their hemolytic events
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and so it may cause an acute hemolysis event
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and that's an important thing to remember along with like nitrofrantoin
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and forloquinolones and and bactrim and things like
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that the other thing is it can actually suppress the production of particular white blood cells such as neutrophil
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so it may actually cause a neutropenia all right
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so big thing to watch out for again methemoglobinemia g6 pdh deficiency
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if they have that and you give them this drug it can cause an acute hemolytic crisis
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and neutropenia ethambutol optic neuritis parazinamide hyperircemia hepatotoxicity rifampin watch out
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for the cyp450 induction all right let's come down isoniazid and streptomycin all right isoniazid.
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What do we got to remember about this bad boy?
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This one actually will cause some injury to the liver.
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So watch out for the bump in the LFTs.
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You should monitor that when you have the patient on isoniazid or what else?
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Pyrazenomide.
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Not so much with the rifampin though.
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Remember that.
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The other thing, here's what's really interesting.
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It can actually cause an anion gap metabolic acidosis through two ways.
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So it can cause an anion gap metabolic acidosis by bumping your beta -hydroxybutyrate.
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Do you remember what that is?
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That's a ketone body.
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So it may cause a keto acidosis
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because of it causing an increased acetyl -CoA metabolism or increase through the acetyl -CoA pathway.
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And it also can increase your lactate.
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So it may cause a lactic acidosis and a ketoacidosis as a particular cause of their anion gap metabolic acidosis.
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The other thing is it can cause a drug -induced lupus.
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You're like, what the heck?
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It's important to actually remember this because especially in your exams, especially in the step one,
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they may ask you what are the particular drugs to remember that can cause drug -induced lupus.
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And this is one of them, but you can remember this by the ship mnemonic.
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sulfa drugs, hydralazine, isoniazid, procainamide, and phenytoin, just remember these because they can come up on your exam.
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The next thing is it can cause a B6 deficiency.
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Now, B6 deficiency can do two things.
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One of the things with the B6 deficiency is it may alter the myelination of particular neurons and lead to neuropathy.
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So watch out for any types of peripheral neuropathy.
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The other thing is it can also alter the activity of particular enzymes inside of the actual red blood cell
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or alter the ability to make red blood cells.
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And this can lead to anemia, whether this is like a aplastic anemia or a sideroblastic anemia, it can drop your red blood cells.
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The other thing is it can actually cause seizures.
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So it may actually reduce your seizure threshold and these can actually be refractory.
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So you can actually give a patient like multiple benzos if they're in status epilepticus and it'll not work.
377
So watch out for any refractory to benzos in patients who have a B6 deficiency.
378
You give them some B6, they actually might start responding to some of the benzos okay
379
so isoniazid watch for hepatotoxicity watch the anion gap for any
380
metabolic acidosis watch for drug -induced lupus remember the mnemonic
381
and then seizures refractory to benzos and then with b6 deficiency you can particularly see anemia and neuropathy
382
last one here is your streptomycin remember that's
383
that second line in your mycobacterium tuberculosis we don't it's not
384
a part of the ripe regimen it's not a part of the second part for the four months afterwards.
385
It's more of the add -on for like miliary TB or more of your TB meningitis.
386
And these ones, it's important to remember it's an aminoglycoside.
387
Aminoglycosides are nephrotoxic.
388
They will jack those kidneys up.
389
So watch for any signs of nephrotoxicity.
390
So monitor their creatinine, monitor their BUN, their urine output.
391
The other thing is it can actually really hurt their inner ear, causing ototoxicity.
392
Particularly, it can actually hit the eighth cranial nerve right
393
so particularly watch out for the vestibular cochlear nerves watch out for any ototoxicity
394
and it also can affect the growth of the baby
395
so it's important to remember that is teratogenic teratogenic is a big one here
396
so avoid this in patients who are pregnant
397
and then the last thing is you want to be careful
398
if you give this to a patient who has a history
399
of myasthenia gravis it should be contraindicated in what's called myasthenia
400
gravis i'm gonna put mg the reason why is it alters with the actual uh response of the antibodies
401
that actually bind at the particularly at the nicotinic receptor on the muscle cells
402
and so this may alter that in a particular way
403
so it's important to remember do not give this in patients
404
who have myasthenia gravis do not give this in patients who are pregnant
405
and watch the actual renal function
406
and again watch for any kind of changes in their hearing
407
when you put a patient on streptomycin all right my friends you think we're done
408
but we got to review this we got to we got to anchor this stuff into our cerebral cortex.
409
So let's do some cases and see if we can actually anchor this stuff into our cerebral.
410
All right, Nationals, let's do some practice problems or kind of like really understand what we talked about here on the whiteboard.
411
So you're performing rounds, you're with your infectious disease and they say, okay, I'm going to ask you some questions about their mechanism of action.
412
Let's see if you guys can pick out which drug it is based upon what I'm kind of prefacing you with.
413
So first one is which drug inhibits the RNA polymerase?
414
So this cute little enzyme here that takes DNA, makes RNA
415
and helps to be able to synthesize particular types of bacterial proteins this would be your rifamycins right
416
so your rifampin rifabutin things of that nature next one is
417
which one of the drugs actually inhibits the 30s ribosomal subunit inhibiting protein synthesis
418
that are needed in the bacteria this would be streptomycin great
419
which one of these drugs actually works to inhibit the arabinosyl transferase
420
which takes arabinose and galactose and makes arabinol arabinoglactin which is an important component of the actual cell wall.
421
You guys know this would be which particular structures?
422
Come on, let's see if you guys remember this one.
423
Come on.
424
This is the ethambutol. So ethambutol.
425
Which drugs actually inhibit the fatty acid synthase that takes particular fatty acids
426
and helps to be able to make what's called mycolic acid, which is an important component of the actual cell wall?
427
This would be pyrazenamide.
428
Which of the particular drugs helps to be able to inhibit the enzyme
429
that actually helps to convert what's called the paramina benzoic acid into dihydrofolate and then subsequently tetrahydrofolate,
430
which is needed to be able to make nucleotides to incorporate into the DNA.
431
This would be, which particular drug do you guys remember?
432
Dapsone.
433
Right, okay, good.
434
Next one is which one of the drugs is actually going to be taken into the fungal cell, acted on by the catalase peroxidase, and whenever that happens, it turns it into an inactive,
435
I mean, it turns from an inactive into a very active type of molecule.
436
There, it binds with NAD.
437
And when it binds with NAD, this molecule here actually can inhibit enol reductase.
438
And what that does is it decreases the synthesis of mycolic acid in the cell wall.
439
This is going to be isoniazid.
440
All right, great.
441
So we covered all of these particular drugs, okay?
442
Next question is, this patient has latent tuberculosis.
443
What are the particular treatment options for those with latent TB.
444
You guys remember that we always can consider two options.
445
One is we can do isoniazid for about six to nine months, right? or rifampin for about four months.
446
The next question is you have a patient with active tuberculosis.
447
If they have active tuberculosis, you always do the ripe regimen.
448
So rifampin, isoniazid, parazenamide, and fambutal for two months.
449
Then you subsequently follow after that with rifampin and isoniazid for four months
450
and add on B6 because B6 is important because if you're taking isoniazid, that can actually cause a B6 deficiency and lead to neuropathy and seizures, et cetera.
451
So it's important to remember that.
452
The other thing is if a patient is HIV positive and also has an active TB or a latent TB, you should consider switching rifampin to rifabutin.
453
And the reason why is rifampin can actually act at that cytochrome P450 system.
454
And when you give rifabutin, it doesn't actually have to have as much interaction with the CYP450 system because what can happen is rifampin is a CYP450,
455
what's called inducer.
456
And because it's actually acting as an inducer, it decreases the concentration of the particular the drug that's being metabolized by the CYP450 system.
457
And patients who are taking HIV medications like NRTIs, it would decrease the efficacy of those drugs or the concentration of those drugs.
458
So that's why you switch to rifabutin because it's not an inducer.
459
And if they have TB meningitis or miliary meningitis, you should really seek infectious disease expertise, but you can consider adding on streptomycin.
460
All right, another patient has what's called the MAC infection, so mycobacterium avium intracellular infection.
461
What are the particular treatment options?
462
Because this is another type of mycobacteria.
463
So we can actually consider treating these patients with what?
464
We can do rifampin or also known as rifabutin if they have HIV.
465
We can also consider ethambutol.
466
And then lastly, we can add on a macrolide like azithromycin.
467
Okay.
468
Now, if they have severe refractory cases, you can add on something like a fluoroquinolone or an amino glycoside.
469
So again, ethambutol, rifampin, and a macrolide for a MAC infection.
470
And the big ones to remember here is
471
that fmbutol is a part of that triad
472
and rifampin is a part of that
473
so again for latent tb isoniazid 69 months or rifampin for four months
474
if it's active it's going to be the ripe for two months
475
and then after rifampin isoniazid for four months add b6 could switch to rifabutin
476
if they have hiv okay add streptomycin refractory or miliary types of tb or what's called tuberculosis meningitis.
477
If it's a MAC, ethambutol, rifampin, and macrolide, add -on, aminoglycosides, and fluoroquinolones in refractory cases.
478
All right, you have another person who has another mycobacterial infection called mycobacterium leprae, which is leprosy.
479
If they have leprosy, this obviously causes these hypopigmented and nasty skin lesions, and this can also lead to nerve palsies.
480
It thickens the nerve, which can actually cause compression of the ulnar nerve, the peroneal nerve, and this can cause a lot of problems there as well.
481
So we treat these patients with dapsone and rifampin.
482
Dapsone and rifampin, you can add on clofazamine and tuberculoid leprosy.
483
So rifampin, dapsone, mycobacterium leprae, ethambutol, rifampin, macrolide, and mycobacterium avium intracellular.
484
Rifampin for four months, isoniazid for six to nine months, and latent.
485
Ripe for two, rifampin, isoniazid for four if it's active TB.
486
Switch rifampin to rifabutin if any patient has HIV, because it can reduce the efficacy of the NRTIs.
487
All right, boom.
488
Now, the next thing that we have to think about is what are the adverse drug reactions?
489
So a big thing to think about here is we talked about all of these already and what they're treating.
490
But let's start off with the rifamycins first.
491
What I want you guys to remember, especially with rifamibin, cause red -orange urine.
492
And this is actually completely harmless.
493
This is something to think about if a patient starts getting really scared.
494
The other thing is it can actually cause a false positive urine opiate.
495
So if someone's actually getting drug screened, remember it can potentially cause a false positive.
496
The other thing, it's what's called rifampin.
497
It's a CYP450 inducer, meaning that it can actually work to actually increase the activity of the cytochrome P450 metabolism,
498
which will decrease the concentration of the drug.
499
All right, so those are big things to remember.
500
The next one that we should talk about here is going to be isoniazid.
501
This is the big one.
502
It's really, it actually hepatotoxic.
503
You should be monitoring patients' LFTs, and it can also produce what's called a metabolic acidosis.
504
It can actually increase the production of ketone bodies and it can actually increase the production of lactate.
505
So watch out for any metabolic acidosis that have an anion gap that's elevated.
506
The other thing is it can actually suppress the bone marrow and potentially lead to anemia.
507
One of the ways that we think this is actually maybe sideroblastic anemia due to the B6 deficiency.
508
And then the other thing is it can actually cause drug -induced lupus.
509
Remember the mnemonic SHIP, right?
510
So we said sulfa drugs, hydralazine, isoniazid, and then we also have phenytoin and procainamide.
511
And then remember it can also cause seizures.
512
It can lower the seizure threshold whenever patients have B6 deficiency, having them become refractory to benzodiazepines, and it can also cause neuropathy.
513
All right.
514
Pyrazenamide, we said that this is also hepatotoxic.
515
So watch those LFTs and it can also increase the uric acid.
516
So watch out for this in patients who have gout.
517
And then butol can cause optic neuritis, so it can cause changes in their vision, so make sure that they're getting annual eye exams if they're on this drug.
518
And then we have a patient who's on dapsone for, again, what was that for?
519
Leprosy.
520
We can actually watch out for any methemoglobinemia, G6PDH deficiency that can actually, if they take this and they have that underlying disease, it can actually cause an acute hemolytic crisis,
521
what it causes severe anemia.
522
And then watch out for neutropenia, okay?
523
Okay.
524
And then we also have streptomycin, which any aminoglycoside within this category is nephrotoxic, ototoxic, teratogenic as well.
525
And then again, can be contraindicated to myasthenia gravis because it can worsen the myasthenia gravis.
526
All right, engineers, that covers the antimicrobacterials.
527
I hope it made sense.
528
I hope that you guys enjoyed it.
529
As always, until next time.
530
Thank you.
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Vocabulaire et conseils d’expression pour cette leçon
Cette vidéo contient 530 phrases et 6759 mots à répéter en shadowing. La partie parlée dure 35:55. Le locuteur parle vite, environ 188 mots par minute : attendez-vous à des liaisons et à des sons réduits. Seuls 77 % des mots font partie des 3 000 mots les plus courants en anglais, le vocabulaire est donc exigeant.
Vocabulaire clé de cette vidéo
15 mots de la vidéo à retenir, avec leur prononciation et leur sens :
| Mot | Prononciation | Sens |
|---|---|---|
| acid nom | /ˈæsɪd/ | acide |
| enzyme nom | /ˈɛn.zaɪm/ | enzyme |
| molecule nom | /ˈmɑ.lɪ.kjul/ | molécule |
| infection nom | /ɪnˈfɛkʃən/ | infection |
| nerve nom | /nɝv/ | nerf |
| deficiency nom | /dɪˈfɪʃənsi/ | déficience |
| tuberculosis nom | /tʃuːˌbɜː(ɹ)kjʊˈləʊsɪs/ | tuberculose |
| decrease verbe | /dɪˈkɹiːs/ | diminuer |
| urine nom | /ˈjʊɹɪn/ | urine |
| ripe adjectif | /ɹaɪp/ | mûr, mûre |
| layer nom | /ˈleɪ̯ɚ/ | couche |
| component nom | /kəmˈpoʊ.nənt/ | composant |
| pathway nom | /ˈpæθˌweɪ/ | voie |
| convert verbe | /kənˈvɝt/ | convertir |
| integral adjectif | /ˈɪntəɡɹəl/ | entier |
Les verbes à particule que vous entendrez
| Mot | Sens |
|---|---|
| come down verbe | descendre, tomber |
| figure out verbe | cerner |
| go through verbe | traverser |
| pick out verbe | distinguer, faire la distinction |
| watch out | attention |
Prononciation à surveiller
Le locuteur utilise 75 contractions et formes réduites, comme you're, they're, we're. Prononcez-les sous leur forme courte, telles que vous les entendez.
- Les sons « th »: pathway /ˈpæθˌweɪ/, synthesis /ˈsɪnθəsɪs/, threshold /ˈθɹɛʃ(h)oʊld/, eighth /eɪtθ/, ethambutol /ɛˈθæm.bjəˌtɔl/
- Les sons « sh » et « zh »: infection /ɪnˈfɛkʃən/, deficiency /dɪˈfɪʃənsi/, seizure /ˈsi.ʒɚ/, potentially /pəˈtɛnʃ(ə)li/, concentration /ˌkɑn.sənˈtɹeɪ.ʃən/
- Mots longs — placez bien l’accent: deficiency /dɪˈfɪʃənsi/, tuberculosis /tʃuːˌbɜː(ɹ)kjʊˈləʊsɪs/, metabolic /mɛtəˈbɒlɪk/, incorporate /ɪŋˈkɔɹ.pɚ.eɪt/, potentially /pəˈtɛnʃ(ə)li/
Comment s’entraîner avec cette vidéo
- Écoutez la vidéo en entier une fois sans parler et notez les mots que vous ne connaissez pas.
- Commencez à la vitesse 0,75×, répétez phrase par phrase, puis revenez à la vitesse normale quand cela devient facile.
- Enregistrez-vous et comparez avec l’original, en faisant attention à des mots comme acid, enzyme, molecule.
La grammaire de cette vidéo
Les structures que le locuteur utilise le plus, avec les mots exacts de la vidéo :
| Structure | Dans la vidéo |
|---|---|
| Phrases conditionnelles if + proposition, will/would + verbe — une condition et son résultat | if they're in status epilepticus and it'll not |
| Voix passive be + participe passé — l’accent est mis sur ce qui arrive, pas sur qui le fait | is called · being formed · will be formed |
| Propositions relatives who / which + proposition — une précision sur une personne ou une chose | rifamycins, which is · molecules, which are · arabinoglactin which is |
| Present perfect have/has + participe passé — une action passée qui compte encore maintenant | have bound · have gone · we've talked |
Qu'est-ce que la technique du Shadowing ?
Le Shadowing est une technique d'apprentissage des langues fondée sur la science, développée à l'origine pour la formation des interprètes professionnels. Le principe est simple mais puissant : vous écoutez de l'anglais natif et le répétez immédiatement à voix haute — comme une ombre suivant le locuteur avec un décalage de 1 à 2 secondes. Les recherches montrent une amélioration significative de la précision de la prononciation, de l'intonation, du rythme, des liaisons, de la compréhension orale et de la fluidité.