Drugs affecting lipoprotein metabolism Flashcards
What is the primary target of therapy?
to decrease LDL cholesterol to an appropriate level
What is the relationship between LDL-C levels and relative risk for CHD?
Linear
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
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
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
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
Clinical use of statins
Strong clinical evidence, so use it for first line therapy
Side effects of statins
- Muscle related adverse events (myalgia, myopathy, rhabdomyolysis)
- Elevated hepatic transaminases (rare)
Name a cholesterol absorption inhibitor
Ezetimibe
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
How does ezetimibe produce its pharma effect?
By inhibiting cholesterol intake, you are decreasing your hepatic cholesterol stores, inc LDLR etc
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
Side effects of ezetimibe?
Well tolerated, can cause elevated transaminases
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
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
How do we use BAS clinically?
Combo w/statins, not proven to reduce CV risk alone
What is LDL apheresis?
Physically take out LDL from the blood
What is Pcsk9?
Molecule synth in liver and secreted that targets LDLR for degredation
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
What if your problem is VLDL? Will statins work?
No? Want to use other targets
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
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
Fibrates
Activate PPAR-alpha to increase the activity of LPL (which hydrolyzes TGs)
–>leads to increase in HDL production
When do we use fibrates?
When someone has REALLY high TGs (>500mg/dL) to prevent pancreatitis
