Drugs affecting lipoprotein metabolism

Question 1

What is the primary target of therapy?

Answer 1

to decrease LDL cholesterol to an appropriate level

Question 2

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

Answer 2

Linear

Question 3

How do statins work chemically?

Answer 3

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

Question 4

How do statins lower LDL?

Answer 4

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

Question 5

What is the rule of 6%?

Answer 5

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

Question 6

At what dose do statins have greatest effect?

Answer 6

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

Question 7

Clinical use of statins

Answer 7

Strong clinical evidence, so use it for first line therapy

Question 8

Side effects of statins

Answer 8

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

Question 9

Name a cholesterol absorption inhibitor

Answer 9

Ezetimibe

Question 10

How does ezetimibe work mechanistically?

Answer 10

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

Question 11

How does ezetimibe produce its pharma effect?

Answer 11

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

Question 12

What is the clinical use of ezetimibe?

Answer 12

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

Question 13

Side effects of ezetimibe?

Answer 13

Well tolerated, can cause elevated transaminases

Question 14

What are bile acid sequestrates and how do they work?

Answer 14

• 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

Question 15

What are the side effects of BAS?

Answer 15

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

Question 16

How do we use BAS clinically?

Answer 16

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

Question 17

What is LDL apheresis?

Answer 17

Physically take out LDL from the blood

Question 18

What is Pcsk9?

Answer 18

Molecule synth in liver and secreted that targets LDLR for degredation

Question 19

How can we use Pcsk9 for pharma?

Answer 19

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

Question 20

What if your problem is VLDL? Will statins work?

Answer 20

No? Want to use other targets

Question 21

What treatments do we use for homozygous FH?

Answer 21

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

Question 22

What is the TG-HDL axis?

Answer 22

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

Question 23

Fibrates

Answer 23

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

Question 24

When do we use fibrates?

Answer 24

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

Question 25

Side effects of fibrates?

Answer 25

May inc liver transaminases or cause myalgia/myopathies

Question 26

Fatty acids

Answer 26

• reduce very high levels of TGs, but no clinical trials

- EPA and DHA have the effects

Question 27

Niacin

Answer 27

Raises HDL but doesn’t help with CV risk?