DIP Episode 70 - Oncology Pharm For The USMLEs Part 1

Okay, okay, welcome. My name is Devine. I'm a first-year president going into radiology. This is the 70th episode of the Divine Intervention Podcasts and today we're specifically going to be talking about onc pharmacology. This will be a two-part podcast again because many of these onc drugs, they can get very frustrating very quick. So I'll try to split up the information into two podcasts and you should be good to go after this. And the thing is please for onc pharmacology I will not recommend saying like, oh for pancreatic countries, all these drugs. For this use all these drugs. Step one essentially does not test those pieces of information. There are some exceptions to those but if you pay attention as we go along I would mention those exceptions. Those are the only ones you need to come into memory. In fact, to be perfectly honest, if you know what I'm going to discuss with these two podcasts for onc farm, you should be good for step one. So let's begin. Now, the thing is as a class side effect many cancer drugs cause boomer suppression, they cause allupicia. So the first drug group will talk about at the anti metabolites, right? And basically these drugs inhibit DNA synthesis. And remember that DNA synthesis occurs in the S phase of the cell cycle. In fact, I talked about this during the cell biology podcasts. So you'll prevent DNA and RNA synthesis if you're an anti metabolite.

Now, remember let's just do some quick DNA review and then jump to the pharmacology so it's more easy to understand, right? So remember we have pure ins, those have two rings, right? Pure ins have two rings. Those are things like adenine and guanine, right? And then the pyrimidines have one ring, right? So like cytosine, uracil and thymine. Now, one other thing you want to know is that when you deaminate cytosine, right? So you lose an amino group, you form uracil. And when you add a methyl group to uracil, you actually form thymine. So just remember, caught, CUT. To go from the C to the U, you perform a deamination, to go from the U to the T, you perform a methylation. And remember that if you take nitrogen base, okay? Plus a sugar you have on your clear side, I talked about this in the bio-cam video review. If you take a nucleoside and adenin phosphate, you have a nucleotide, okay? Now, your anti-metabolized first class I'll talk about are the folid antagonists, right? And the poster child here is methyl trexate. Remember methyl trexate is an inhibitor of dihydrofolid reductase, okay? And the key thing to understand here is that methionine is the major carry of methyl groups in the body. Now, the thing is if you want to go from deoxyurid monofosphate to deoxythymid monofosphate, right? In the process of DNA synthesis, you need an enzyme known as dimelolate synthase for that to happen, okay?

And the thing is, that dimelolate synthase actually requires folate as a cofactor, right? It requires reduced folates, that's THF as a cofactor, to proceed in adding that methyl group I talked about earlier to uracil, to convert it to thymine. So from deoxyurid monofosphate to deoxythymid monofosphate, but the thing is after thymidolitsin, this uses THF as a cofactor, it forms something known as DHF. If you want to keep that cycle going, you want to keep making that sweet sweet DNA, you need to regenerate THF from DHF. And to regenerate that THF from DHF, we use an enzyme known as dihydrofolid reductase. So this is where methyl trexate comes into play, methyl trexate, inhibits dihydrofolid reductase. So you have no ability to regenerate THF from DHF. And if you don't have that ability, then you cannot provide a cofactor to convert uracil to thymine, and then you get into trouble. Another drug that also works at that part of the cycle, but for the purposes, right? A drug like trimethyl-prim, right? Trimethyl-prim is a DHF R inhibitor, so it's a dihydrofolid reductase inhibitor. Remember that I use it for PCP-prim-flaxis, right? And you can also use it to prophyl-ax against a toxoplasma-gondii. And then also don't forget pyramethamine, pyramethamine is also an inhibitor of dihydrofolid reductase. It's actually used to treat toxop. So there's something that's actually very high you to know for your exams.

You prophyl-ax against toxoplasma-gondii when the CD4 count is less than 100, with TNPSMX, right? So we try methyl-prim-sopharmethoxysl. However, if a patient has confirmed toxoplasmosis, you treat it with pyramethamine and sulfur diazine, okay? I know it's kind of like, you're like, you have the same mechanism of action, that doesn't make any sense. I know, but that's what you want to pick on your USM Ls. Now, the thing is, if a patient is taking methyl-trek-sate, right? Obviously, we'll suppress the bone marrow because you're not making DNA. If you have like, profound bone marrow suppression and it's causing like significant symptoms, you can actually give them a THF analogue to basically keep the cycle going in the presence of methyl-trek-sate. That THF analogue is known as lukovorin, okay? That's the basis of the lukovorin rescue. And actually, I know, the usual question you may get on your USM Ls is for them to give you something relating to a person suffering bone marrow suppression from thinking trimethoprimsophanethoxysol, a bone marrow suppression from thinking pyramethamine, you can also rescue those people from those bone marrow suppression associated with those agents by given lukovorin. Now, remember that methyl-trek-sate, right? It can actually cause pulmonary fibrosis, right? So, it can cause like a restrictive pattern of lung disease. So, hopefully, you remember that your FEV1 to every serious show will be normal or slightly elevated, right?

And because it causes like a pulmonary fibrosis, right? Your DLC or your diffusion capacity for carbon monoxide will actually decrease, okay? And I mean, you want to know the other drugs that can cause a pulmonary fibrosis, right? So, like we've already said methyl-trek-sate does that amyote-erone. Remember, that's a class three. I'm telling you, it's a potassium channel blocker. Remember, Bliomisin. Bliomisin is the only G2-specific agent. I've mentioned this in the prior podcast, mega high U2-MF1. Bliomisin, G2-agent is a... It's also... It can also cause pulmonary fibrosis via sulfen, it can also cause pulmonary fibrosis, and also in mitrofiorin toin. Many ladies who know this drug as macrobid that's used to treat UT Is in females, like cystitis in females, it does cause pulmonary fibrosis, so that's super, what it does happen. Now, methyl-trek-sate can also actually be used for the treatment of molar pregnancy, right? So, the classic example question will be like a lady that's super young, it's a first pregnancy, and she's having preeclampsia-like symptoms in the first trimester. That's kind of weird, it is like before 20 years, it's kind of off-kilter, right? If you ever see that, think about molar pregnancy, right? Classically, you don't have an ultrasound that you see like the snowstorm appearance on imaging. So, again, for hydratideformal molar pregnancy, basically that any gestation ultra-phoblastic disease, even Choreocarsinoma, right?

Ectopic pregnancies, all those things are susceptible to methyl-trek-sate, okay? And if you're liver-int, if your liver doesn't work, don't give methyl-trek-sate, it's not a great idea. Okay, now, the next set of drugs will jump to that end time metabolites at the Pyramidine Analogs, right? So, the big one we'll talk about is a five FU, I mean, there's others, but this is the big one you probably want to know, so five-flurry or cell, right? The thing is, five-flurry or cell is actually converted in the body to five DUMP, but it is not just like deoxyriide monophosphate, it's like five FDOMP, okay? So, five-flural deoxyriide monophosphate, right? Because if you remember from cell biology reviews, right? So, in DNA, you have a three-prime, actually I also talked about this in the biochemistry reviews. So, in DNA, you have a three-prime hydroxy group, right? And the thing is, that three-prime hydroxy group is part of what you use to form the FUSFODYSTRA bond. So, let's assume that hydroxy group is not there, right? You can then cause something known as chain tramination, because if, for example, you're a nifty pharmacologist and you put off that hydroxy group and slap on like a fluorine, therefore example, then DNA is like, wait, this is my three-prime hydroxy group. Can for many FUSFODYSTRA bond, and then you cause something called chain tramination and boom, your cancer are dropped, okay? So, this is essentially how many of these permitting analogs work, right?

So, for example, in five FDOMP, that three-prime hydroxy group is substituted for three-prime fluorine, okay? And then that causes chain tramination. And remember, I said that you can use LECOVORING to rescue a person that has a toxicity from a methyl trixate. Well, actually, LECOVORING increases the toxicity of five FUSFODYSTRA bond. Here's why. When you give five FUSFODYSTRA it's converted to five FDOMP, right? The thing is, that DOMP is converted to DTMP in DNA synthesis. And I already said that THF is used as a co-factor in that reaction under the action of finidilates and things. Well, if THF is a co-factor for that reaction that involves DUMP, right? Imagine if you're giving like an FDUMP analog and you're giving more LECOVORING, which is a THF analog, that reaction will go even better so you can get even more toxicity from five FUSFODYSTRA. So, again, very high you to know this. LECOVORING can be used to rescue the bond marrow in methyl trixate toxicity, that's boom, myar suppression. However, LECOVORING actually increases the toxicity of five fluorideersil. And I mean, I've talked about this other point many times in many prior podcasts, but remember there are five flu cytosine, right? The drug that we used to treat what's this bug called, Cryptococcus Neiformins, right? That five flu cytosine is actually converted by cytosine diamines in the body to five FU and then it destroys the Cryptococcus that way.

Remember Cryptococcus is the thing that has the India-ingsden and causes meningitis in HIV patients. And then there's some other Pyramidine analogs like cytarebine, just remember cytarebine is a Pyramidine analog, that's what I'm going to say about that. Now let's jump to the Pyramidine analogs, right? So the Pyramid analogs, they work under the purview of the Pyramid salvage pathway. I've talked about the Pyramid salvage pathway in previous podcasts, but I'll just give you a quick Cliffs Notes version here. So the thing is, say for example, you have GTP, right? So Guanosine try phosphate, right? If you remove a phosphate, let's say two phosphates, you form GMP. And then that GMP, right, that's still a nucleotide because it has a phosphate group. You remove, you remove the last phosphate and then you form Guanosine. Guanosine is a nucleoside because it's just a nitrogen base and the sugar. And then let's assume you then remove the sugar, you're then left with a nitrogenous base guani. Okay? Now the thing is, if you want to go back and reverse all you've just done, to go back from like Guanosine to like GMP for example, you need to add a phosphate and a sugar. And the end time that makes that happen is HGPRT, right? So, and I mean the name is actually very helpful. HGPRT, which is a hypoxanthine guanine phosphoribosol transferase, right? So hypoxanthine guanine, right? Phosphoribosol, so phosphol, you're adding the phosphate, right?

Bosphol, you're adding the sugar transferase, right? So transfer enzyme. So HGPRT, okay? HGPRT helps you reverse that reaction in the process of the appearance of each pathway. And please don't forget, right? If a patient has a HGPRT deficiency, that's the pathophys behind the Leschnihan syndrome. Basically they will describe a boy with like self-mutilitina behavior. Remember it's an ex-linked recessive disease. Now, I mean this is more theoretical thing. I don't think it makes much in the way of a clinical use, but it's something that I could see them potentially introducing on step one. But basically if a patient has Leschnihan syndrome, you probably would not want to give them the drug is a thioprin. Because the thing is, if you want to activate is a thioprin to six-megaphalopurin, you actually need HGPRT for that process to work. And I will talk about that actually, like in a few seconds. And then, yeah, so I guess I'll just go ahead and jump to the next drug. So this is, again, also a period analog six-megaphalopurin. The thing is the pro drug here is a thioprin. The thing is, is a thioprin is converted to six-megaphalopurin, and then HGPRT converts that six-megaphalopurin to something called six-thioinocenic acid. Okay? That's like the activated form of six-megaphalopurin. This activated purine can then basically inhibit many steps in purine synthesis. Now, why is six... Yeah, six-megaphalopurin is an anti-cancer drug, but what are some things you want to know about?

Other things you want to know about six-megaphalopurin. The thing is, six-megaphalopurin, you break it down into an active metabolite via many mechanisms. But the key one you want to know for step one is xanthin oxidase. So the thing is, if, for example, you take a xanthin oxidase inhibitor, like alopurin all of the buxostat, you inhibit xanthin oxidase, you cut down on the breakdown of six-megaphalopurin. And if that happens, you actually can boost your six-megaphalopurin to like very toxic levels. Alternatively, some oncology physicians actually take advantage of this. They actually give people that are being treated for cancer. A zanthin oxidase inhibitor, like alopurin all of the buxostat, to actually decrease the dose of is a thioprate that they need to give their patients. It's kind of useful in that regard. And then another purine analog you want to know about is six-thioguani, it's a purine analog, that's all you need to know. Hydroxyuria is another cancer drug I'll talk about. Basically, use this for sickle cell disease, because it actually by some unknown mechanism increases the production of hemoglobin F. Remember that if you want to go from RNA to DNA, right? So like going from a ribonucleic acid to a deoxyribonucleic acid, it's a reduction reaction. And because it's a reduction reaction, it should make sense that the enzyme that makes that happen is ribonucleotide reductase. Ribonucleotide reductase is inhibited by hydroxyuria. Okay?

So that's how ribonucleotide reductase can act as an anti-can, I mean, sorry, that's how hydroxyuria can act as an anti-cancer agent. But I will be stunned if you ever saw anything beyond anything beyond the use of hydroxyuria in sickle cell disease tested on an exam. Okay. Now, cladry beam is another purine analog, it's used to treat hair cell leukemia, that's all I'm going to say about that. Okay. So now let's talk about the anti-cancer antibiotics and we're on top for today. Basically, there are two general mechanisms of anti-cancer antibiotics. Okay? Actually, some of them come from astriptomycin species, but anyway, but the big thing you want to just remember is that these, so these anti-cancer antibiotics, right? So they have to general mechanisms, right? So one is that they can cause DNA intercollection. Okay? Please don't confuse DNA intercollection with DNA cross-linking. DNA cross-linking is something totally different. I'll talk about that in the next podcast, but DNA intercollection is basically you getting in the way of DNA. DNA cross-linking is not you getting in the way of DNA. It's totally different, okay? It's totally different. Now, so again, first mechanism of action, they can cause DNA intercollection. Second thing is that they can generate free radicals. Now, the thing is to understand these anti-cancer antibiotics, just sort of group them into three categories.

There are those that do both, they generate free radicals, they intercollect, there are those that don't lead intercollating, and there are those that do only free radical generation, right? So in terms of doing both, think about your own for cyclans, right? So drugs like doxorobsin and donor-rebicin, the high yield things you want to know about these drugs, they generate free radicals through the fentanyl reaction. Okay? Remember, iron is a key player in that fentanyl reaction. I know you've probably heard this many times from Pothoma. The thing is this free radical generation underlies these drugs causing an irreversible diluted cardiomyopathy because of like free radical injury to the cardiac myocytes. And you can actually prevent this by giving a drug known as dexrosoxin. Dexrosoxin is an ion key later that is used in the treatment of, that is used to prevent the diluted cardiomyopathy that accompanies a doxorobsin use. And again, remember that the diluted cardiomyopathy is a type of systolic heart failure, right? So basically like heifereth, heart failure would reduce the ejection fraction. In fact, this is going ahead and talk this out real quick because it's actually kind of high yield to notice for example. In systolic heart failure, you have a reduced ejection fraction, right? This is what's associated with eccentric hypertrophy, where you're essentially at saccomere in series, okay?

Contraries that would have stolic heart failure, where you have a preserved ejection fraction, basically you have problems filling the ventricles, okay? And that's associated with a concentric hypertrophy of cardiac myocytes. So you're essentially adding saccomere in parallel. I remember that cardiac cells at least for purposes of the USML Es can only undergo hypertrophy and increase in size. They can also undergo hyperplegia. It cannot like just like make new cardiac myocytes, okay? It's kind of important to know that that's why M Is are bad in the first place, right? And your docs don't know Ruby saying just don't forget that they cause red urine also like rifampine. Now the drugs that cause only that only work by causing DNA intercollation, those are drugs like actinomycin D, okay? People also call it ductinomycin. One of the thing I guess ductinomycin does is that it can actually inhibit RNA polymerase, right? So it can inhibit DNA dependent RNA polymerase. Remember that actinomycin D is used to treat childhood cancers, right? So like e-wings or like worms, tumors, right? So this is an example of where oh a drug being used to treat a specific cancer is something you want to know about, okay? This is one example of that situation. Now just I guess one on the business of discussing DNA dependent RNA polymerase inhibitors like actinomycin D, don't forget that alpha amannetin, right? So like that death cap mushroom also works through that mechanism.

Remember that can cause liver failure, kidney failure and then you ultimately die. And then rifampine, rifampine also works through inhibiting RNA polymerase and it also causes red urine. But remember I said red urine is for your your doxodono-robicin, actinomycin D for the most part works primarily by causing DNA intercollection. And then the anti-tumorant antibiotics that work by generating free radicals include drugs like bleomysin. Bleomysin just know that it causes pulmonary fibrosis and it's like this is like it's so ridiculously high-oated, unbelievable. You need to know that bleomysin works in the G2 phase of the cell cycle. In fact it is probably the only drug you need to know on step one that works specifically in the G2 phase of the cell cycle. It's a very very high yield point to know for your exams. And again I remember causes pulmonary fibrosis and actually this drug does not cause bone marrow suppression. So I know talked about a lot of drugs today. So in the next podcast I'll pick up with the alkalinity agents. I'll talk about some other anti-cancer drugs and you should be a master of onc pharmacology. So have a wonderful rest of the day. I just want to point out that I offer tutoring for the USMLE Step 1, 2 CK, 2 CS and Step 3 exams. I've tutored hundreds and hundreds and hundreds of people for those tests. I also tutor to the medicine and training exams and also the medicine board exams and also the application prep.

Basically I can prepare your ERAS application for residency, also help your mock interviews and also the AMCA's application for med school. I have done this with again, tons of people. I have a lot of experience both helping people in this purpose and also some other like nice experience like with regards to admissions committees that also make me pretty useful in this regard. So if you know anyone that needs any of those services and feel free to pass them along to me, the email is divine intervention, podcasts, podcasts with an SAD end at gmail.com alternatively. They can just email me through the website and yeah and then I should be able to point you in the right direction. So have a wonderful rest of the day. I hope the Lakers win their game against the pistons. Tonight I'll see you in the next podcast. God bless. Thank you.

They inhibit DNA synthesis by interfering with nucleotide precursors (e.g., folic acid antagonists, pyrimidine analogs).

Pyrimethamine (or Trimethoprim/Pyrimethamine combination).

Dihydrofolate reductase.

Bleomycin.

By administering Leucovorin (a THF analogue), which bypasses the need for dihydrofolate reductase.

Intercalation means getting physically in the way of the DNA helix; cross-linking involves forming chemical bonds between strands.

Folate antagonists (e.g., Methotrexate, Pyrimethamine).

Leucovorin (a THF analogue).

Doxorubicin/Daunorubicin.

Xanthine oxidase.

Lesch-Nyhan syndrome.

Leucovorin, because it provides excess THF needed for the metabolic pathway supporting 5-FU's action.

Pre-eclampsia-like symptoms in a young woman during her first trimester of gestation.

Folate antagonists (e.g., Methotrexate, Pyrimethamine).

Leucovorin (a THF analogue).

Doxorubicin/Daunorubicin.

Xanthine oxidase.

Lesch-Nyhan syndrome.

Leucovorin, because it provides excess THF needed for the metabolic pathway supporting 5-FU's action.

Pre-eclampsia-like symptoms in a young woman during her first trimester of gestation.