16: Atherosclerosis+ Lipid lowering drugs Flashcards
Explain the role of endothelial dysfunction in the formation of atherosclerotic plaques
- Increased endothelial permeability
- Upregulation of endothelial adhesion molecules
- Leukocyte adhesion
- Migration of leukocytes into the artery wall
Initiation of Fatty Streak formation
Explain the formation of fatty streaks in Atherosclerosis
- Foam cells formation and accumulation in the intima
- Causing drivin of inflammation and triggers the initiation of other effects
- Adherence and entry of leukocytes
- migration of SM cells
- Platelet aggregation
- T-cell activation

Explain the development from a fatty streak to an atherosclerotic plaque
- Foam cells die and dissolve –> bulit up of necrotic core
- Causes an macrophage accumulation
- Formation of a protective fibrous cap by Vascular smooth muscles cell

What is the role of Remnant lipids and Atherosclerosis
Remnant lipids are associated with the inflammatory compound of Atherosclerosis
What are remnant lipids?
Remanants are break down products of cyclomicrons , composed of VLDL and IDL (very high in cholesterole)
Explain the role of LDL in the formation of Atherosclerosis
Formation of Atherosclerosis is highly associated with LDL levels but LDL levels do not cause the inflammatory component of Atherogenesis
What are the diffferences between a stable and an unstable atherosclerotic plaque?
- Unstable plaque have a thin fibrous cap and can easily rupture –>
- Rupture can be triggured by increased BP or inflammation
What does a 10% increase in LDL levels mean in regards to the risk of developing CHD?
•10% increase results in a 20% increase
in CHD risk
Which factors can influence the negative effects of LDL on CHD and atherosclerosis?
Risk factors like:
- low HDL cholesterol
- smoking
- hypertension
- diabetes
Can make the risk for CHD (with high LDL) a lot worse
Explain the role of HDL in CHD and atherosclerosis
- HDL cholesterol has a protective effect for risk of atherosclerosis and CHD
- The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
- HDL cholesterol tends to be low when triglycerides are high
- HDL cholesterol is lowered by smoking, obesity and physical inactivity
What are statins?
What is their drug target?
inhibitors of HMG CoA reductase (enzyme involved in the rate-limiting step of cholesterole synthesis)

Explain the MOA of statins
Statins competitevely inhibit the HMG-CoA reductase (enzyme in the rate limiting step of cholesterole synthesis)
–> reduce cholesterole synthesis in the liver leading to
- Hepatic upregulation of LDL receptors
- increasing binding and removal of LDL cholesterol and LDL precursors from the plasma
Resulting in:
- Decreased LDL
- Increased HDL

What are the main side effect in the use of statins?
General (common): headache and gastrointestinal symptoms (e.g., constipation, diarrhea, flatulence)
Rarer:
- increase in Liver-function test
- myopathy
Explain the effects of the use of Statins on the lipid profile
Generally: Statins lower LDL and triglycerides, increase HDL
- different statins are differently effective
- But in all statins : Rule of 6: double the dose but only 6% reduction in LDL

Explain the effects of statins on CHD and aterostclerosis
They overall: decrease the risks of CHD and atherosclerosis via
- lipid-lowering effects
- Plyothropic effects (not related to lipid profile)
What are the pylotrophic effects of statins?
The effects they get which are not related to improvement of the lipid profile
- Decrease platelet aggregation
- have a thrombolytic effect
- increase plaque stability
- decrease inflammation
- decrease vasoconstriction

What are fibrates?
When would you use them?
A type of lipid lowering drugs
–> used as second line-treatment in dyslipidaemia
Explain the MOA of fibrates
Activatethe peroxisome proliferator-activated receptor alpha (PPAR–α) →
↑ lipoprotein lipase activity →
↓ LDL, ↑ HDL, ↓↓↓ triglyceride

Explain the clinical use of Nicotinic acid (Nicatin, VIt B3)
As an additional treatment with statins
(thought it has lipid lowering effects, no clinical significant effects could be proven yet)
Explain the MOA of Nocotinic Acid (Niactin, VIt B3)
inhibits lipolysis and fatty acid release in adipose tissue, decreases hepatic VLDL synthesis → ↓ triglyceride and LDL synthesis, ↑ HDL

What are the effects of Niactine on clinical outcome
Though it does increase lipid profile, it is not does not decrease the risk of vascular events
- –> use needs to be reconsidered
What is Ezetimibe?
What is its clinical use?
It is a lipid-lowering agent
- used as an addition to statins
- outcomes are there but not too significant
Explain the MOA of Ezetimibe
selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol transporter NPC1L1) → ↓ LDL

What is Proprotein convertase subtilisin/ kexin type 9? (PCSK9)
What happens to it in the treatment of statins?
It is an inhibitor of LDL receptor
- In the treatment of statins: though receptors are upregulated: PCSK9 is also upregulated and limits the effects of statins
Explain the use of PCSK9 inhibitors and its limitations
Normally as an add on to statins to get a more effective reduction in dyslipidaemia
- but: Expensive (4000ppy)
- Maybe: use in familiar hypercholesteraemia
- Might be available as drug
Explain the MOA of PCSK9 inhibitors
Inhibits the LDL receptor degradation by PCSK9

What type of lipid-lowering drugs are there?
What is the MOA?
- Bile acid sequestians
- low adherence due to side effects like bloating
- Cholesterole absorbance inhibitors (Ezetimibe)
- HMG-reductase inhibitors (Statins)
- Fibrates
- Nicotinic acid (Niactin)
- PCSK9-inhibitors

Summarise lipoprotein metabolism
Uptake of fats by cyclomycrons and transported to the liver
- Synthesis of LIVer–> LDL, IDL and VLDL by heptic lipase
- VLDL are sent out to the blood stream and lipoprotein lipase removes triglycerides from the core and replaces them with Cholesterol
- VLDL is converted into
- LDL (majoity)
- IDL (directly removed from circulation, very atherogenic)
- LDL in circulation or excreted in bile
