Flashcards in Drugs Affecting Lipid Metabolism Deck (34):
For every 30mg/dL lowered LDL, what's the decreased risk for coronary artery disease?
Every 30mg/dL -> 30% reduction in risk.
Which lipoproteins are considered "TG-rich"?
Chylomicrons (CMs), CM remnants, VLDL, IDL
Primary goal in cholesterol therapy?
Decreasing TGs and non-HDL, and increasing HDL are secondary goals.
Targets for LDL levels?
< 100, or even <70 is good if patient has existing CHD or lots of risk factors.
Normal TG levels?
< 150. In chylomicronemia, can be over 1000.
Definition of low HDL?
<40 mg/dL... but perhaps the cutoff for women should be higher, as estrogen pushes up HDL.
(anybody noticing a trend in these studies neglecting women?)
4 aspects of therapeutic life changes (TLC) for dyslipidemia? What does each affect?
Diet modification (lowers LDL, ...not sure about HDL)
Exercise (increases HDL)
Weight loss (increases HDL)
Avoiding alcohol (lowers LDL)
3 classes of drugs used to lower LDL?
Cholesterol absorption inhibitors
Bile acid sequestrants
Review: Mechanism of statins?
Problem with them?
HMG CoA reductase inhibition.
Problem: lots of important things are made from downstream metabolites, such as farnesyl-PP.
So statins reduce cholesterol synthesis. What does that have to do with lowering LDL?
If hepatocytes don't have enough cholesterol (and with a statin, they don't), they upregulate LDLR to recover the cholesterol from circulating LDL.
Statins have few side effects because they don't push cholesterol way down... they bring it back to "normal."
What does the rule of 6% with statins refer to?
What total reduction of LDL can be achieved with statins?
After the initial dose, each doubling of a dose of statins tends to reduce LDL by a further 6% (i.e. most of the effect is up front).
Statins can reduce LDL by 31-60%.
What have meta-analysis shown to be the reduction in risk of major coronary events for every 40mg/dL reduction in LDL?
22% (probs not important to memorize... but just know that it's a big effect)
2 main adverse effects of statins?
Elevated liver transaminases (usually transient).
Worst muscle problem caused by statins?
Rhabdomyolysis - muscle damage that leads to kidney damage.
What do risk factors for statin-induced myopathy have in common?
They increase statin levels.
(being old and frail, grapefruit juice, polypharmacy, etc.)
What's the MoA of the cholesterol absorption inhibitor Ezetimibe?
Binds to the cholesterol transport NPC1L1, inhibiting cholesterol absorption in the small intestine.
(can be used in combo with statins... but data showing decreased CV events has not yet been produced)
What do bile acid sequestrants do? Why does this lower cholesterol?
They cause bile acids to agglomerate, so they can't be absorbed by the transporter IBAT1 (note that they don't directly inhibit IBAT1).
If bile acids are excreted in feces, the liver has to shunt more cholesterol to bile acid production.
Are BASs effective at lowering LDL?
When are they used?
Yeah... they lower LDL 15-25% in mono or combination therapy.
They're used to augments statins, or when people are statin-intolerant.
3 bile acid sequestrants (BASs)?
Adverse effects of BASs? (3 things)
They're not absorbed, so don't cause systemic effects.
But they do cause GI side effects: flatulence, nausea, constipation, bloating, heartburn.
Can interfere with drug absorption.
Can raise TGs. (?)
If you don't have functioning LDLR, will statins, CAIs, or BASs lower LDL?
Nope. Their mechanisms rely on the liver upregulating LDLR as a response to their activity.
If drugs really aren't working, how can you get somebody's LDL down?
How can you target PCSK9? (recall PCSK9's function)
PCSK9 targets the LDLR for destruction.
It's hard to hit with a small molecule, but anti-PCSK9 antibodies can be given SubQ every 2 weeks.
How can apoB production be reduced?
Weekly subQ injection of a anti-sense oligonucleotide (mipomersen).
Why would you want to inhibit MTP?
This protein loads TGs onto VLDL. If you inhibit it, there will be less LDL secretion.
3 kinds of drugs that increase HDL / decrease TGs?
Omega 3 fatty acids (fish oils)
Does this affect CV outcomes?
Fibrates activate the transcription factor PPAR-alpha.
PPAR alpha leads to increased HDL, decreased VLDL production, increased VLDL clearance, and decreased LDL.
CV outcomes are mixed, but the best results are in people with high TGs.
When do we use fibrates today?
In patients with very high TGs (>500) to prevent pancreatitis.
As an adjunct to statins in pts with elevated TGs.
Fibrate adverse effects?
Generally well tolerated.
Some drug interactions...
What are the primary omega-3 fatty acids thought to be beneficial?
EPA and DHA
Utility of prescribing fish oils?
Outcome data for CV events isn't really there, but it does reduce TGs (useful to prevent pancreatitis?).
How does niacin lower cholesterol?
Reduces free fatty acid flux from adipose, and thus VLDL production.
What limits niacin's use for lowering cholesterol?
It works great at moving lipid levels in all the directions we want (including Lp(a)!)
Niacin causes a very uncomfortable flushing reaction in most of the patients taking it. (laropriprant helps prevent this..)
Hepatotoxicity is also a significant problem.
(making gout and diabetes worse are other concerns)