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Flashcards in Drugs affecting lipoprotein metabolism Deck (27):
1

What is the primary target of therapy?

to decrease LDL cholesterol to an appropriate level

2

What is the relationship between LDL-C levels and relative risk for CHD?

Linear

3

How do statins work chemically?

Competitively inhibit the liver's HMG CoA reductase, which is the rate limiting step of cholesterol synthesis, has higher affinity for the enzyme than HMG CoA

4

How do statins lower LDL?

They cause a decrease in cholesterol synthesis in the liver so that there is less cholesterol stored there. The liver then up regulates its LDLR in order to replenish its cholesterol stores. This takes more LDL up from the blood. Also up regulates HMG CoA reductase

5

What is the rule of 6%?

Each double of statin dose produces about a 6% decrease in LDL-C
-->effect of statins is dose related

6

At what dose do statins have greatest effect?

Biggest bang for your buck is achieved with the starting dose. Increasing dose thereafter has relatively smaller effect. So we use more potent statins at higher doses first

7

Clinical use of statins

Strong clinical evidence, so use it for first line therapy

8

Side effects of statins

-Muscle related adverse events (myalgia, myopathy, rhabdomyolysis)
-Elevated hepatic transaminases (rare)

9

Name a cholesterol absorption inhibitor

Ezetimibe

10

How does ezetimibe work mechanistically?

It binds and inhibits NPC1L1, which is found on the surface of enterocytes and is the primary regulator of cholesterol uptake. Ezetimibe thus prevents the absorption of cholesterol

11

How does ezetimibe produce its pharma effect?

By inhibiting cholesterol intake, you are decreasing your hepatic cholesterol stores, inc LDLR etc

12

What is the clinical use of ezetimibe?

Used in combo with statins or in the statin intolerant. Clinical trials down show a clear reduction in CV risk

13

Side effects of ezetimibe?

Well tolerated, can cause elevated transaminases

14

What are bile acid sequestrates and how do they work?

-BAS, resins
-large molecules that bind bile salts in the gut lumen and prevent their reabsorption
-Because the liver relies on reabsorption of bile salts, it is forced to make more, using up cholesterol in the process and leading to an upreg in LDLR

15

What are the side effects of BAS?

They are so big, they can't be absorbed by the body so their side effects don't include toxicity, but rather flatulence, constipation, bloating etc

16

How do we use BAS clinically?

Combo w/statins, not proven to reduce CV risk alone

17

What is LDL apheresis?

Physically take out LDL from the blood

18

What is Pcsk9?

Molecule synth in liver and secreted that targets LDLR for degredation

19

How can we use Pcsk9 for pharma?

We want to inhibit it (say with an antibody) to stop it from degrading LDLR. Clinical data is promising, not yet in use

20

What if your problem is VLDL? Will statins work?

No? Want to use other targets

21

What treatments do we use for homozygous FH?

-Disease with LDL receptor mutation
-Target ApoB in liver to stop VLDL production
-Target MTP which loads TG onto apoB allowing for VLDL secretion

22

What is the TG-HDL axis?

There is a link between TGs and HDL
-CETP enzyme transfers cholesterol esters from HDL in exchange for TGs from VLDL causing a decrease in HDL numbers.
-Some drugs target this system, but haven't been proven to reduce CV disease

23

Fibrates

Activate PPAR-alpha to increase the activity of LPL (which hydrolyzes TGs)
-->leads to increase in HDL production

24

When do we use fibrates?

When someone has REALLY high TGs (>500mg/dL) to prevent pancreatitis

25

Side effects of fibrates?

May inc liver transaminases or cause myalgia/myopathies

26

Fatty acids

-reduce very high levels of TGs, but no clinical trials
-EPA and DHA have the effects

27

Niacin

Raises HDL but doesn't help with CV risk?