HY USMLE Q #1584 – Pharm / Biochem

Added: 2026-05-31

[00:00:00]How's it going, guys? So, we have 49-year-old woman, 2-week history progressive muscle soreness, hypertension, dyslipidemia. She's on a thiazide, a statin, and a fibrate. And we want to know the most likely explanation for this patient's acute presentation. So, look, obviously high yield, you know that statins cause myopathy, and it's worse especially when combined with fibrates.

[00:00:21]Now, my question to you for starters is what's the mechanism of action of statins? Literally, kindergarten question.

[00:00:29]Okay, so they inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, fine. So, my next question to you watching this is HMG-CoA reductase normally converts what to what?

[00:00:42]So, that's going to be HMG-CoA goes to mevalonate.

[00:00:46]So, choice C, wrong [ __ ] answer.

[00:00:48]Mevalonate is decreased with statin use, okay? Now, you say, "Well, it sounds a little bit nitpicky." Okay, I agree, but this is the thing.

[00:00:57]Mevalonate is normally not just used for cholesterol synthesis, but also for coenzyme Q10 synthesis in the electron transport chain and mitochondrial function. So, by giving a statin, by decreasing mevalonate, decrease coenzyme Q10 synthesis, and you disrupt mitochondrial function. This can lead to impaired muscle cell function and rhabdomyolysis myopathy, okay? So, that's the mechanism why statins alone cause myopathy. Now, my next question to you is, what's the mechanism of action of fibrates?

[00:01:37]So, fibrates activate PPAR alpha, which we don't even see that as an answer here.

[00:01:46]Choice A, wrong [ __ ] answer, okay?

[00:01:48]Fibrates activate the agonist PPAR alpha. So, what major effect will fibrates have on serum lipids?

[00:01:58]So, fibrates are notably effective for decreasing triglycerides, okay? So, they don't notably cause statins on their own.

[00:02:05]Now, decrease activation PPAR gamma, also nothing for you to assimilate. You would need to know that increase activation PPAR gamma increase activation. This can be thiazolidinediones.

[00:02:17]It's a type 2 diabetes uh class of drugs such as pioglitazone, etc. and these can cause cardio- and hepatotoxicity, peripheral edema, and weight gain, okay?

[00:02:30]But, students get hysterical about the alpha versus gamma, but I'll make a clip on it, all right? So, uh D wrong [ __ ] answer because thiazolidinediones aren't relating to this clip here. So, now, in terms of the combination, choice E is the correct answer. This is what NDME wants. So, fibrates in particular, gemfibrozil, there's other fibrates like fenofibrate, etc., but for whatever reason, gemfibrozil notably decreases hepatic metabolism {slash} clearance of statins.

[00:03:07]And, they'll have P450 interaction as an answer.

[00:03:10]Simple, okay? So, statins, they cause myopathy for the reasons we already discussed.

[00:03:16]Q uh coenzyme Q10, decrease synthesis, mitochondrial dysfunction, fine.

[00:03:21]Fibrates, especially gemfibrozil, decrease statin clearance by the liver, metabolism by the liver, so there's more statin around to cause myopathy. It's a P450 interaction.

[00:03:33]Choice E, correct answer.