Hyperlipidaemias Flashcards
Where does most of the cholesterol in the body come from?
Most developed in the body
Some contribution from diet
Why is cholesterol essential for the body?
- Membrane integrity
- Precursor of steroid hormones
- Bile Acids
- Vitamin D
What is the problem with high cholesterol?
High cholesterol leads to an increase in incidence of cardiovascular heart disease
What are the target cholesterol levels in the UK?
- Total cholesterol 5 or below
- HDL (good cholesterol) 1 or above
- LDL (bad cholesterol) 3 or below
- Non-HDL (bad cholesterol) 4 or below
- Triglycerides 2.3 or below
Which type of cholesterol is the primary target for cholesterol lowering drugs?
LDL cholesterol
How much does a 1.0 mmol/L reduction in cholesterole reduce CVD risk by?
Each 1.0mmol/L drop reduces CVD risk by 20%
Describe the process by which LDL cholesterol causes atherosclerosis
- Accumulation of LDL cells (long t 1/2)
- Oxidation by local endothelial cells
- Oxidised LDL taken up by macrophages
- Recruited monocytes uptake oxidised LDLs via scavenger receptors (SR-A)
- Foam cells build up in intima/ endotherlial space
- Proliferation of smooth muscle cells
- Fatty streaks develop
- Chronic inflammation and accumulation in vascular smooth muscle
At what age do fatty streaks develop?
Not confined to old age
- 1/3 20-29 year olds have fatty streaks
- 2/3 of 30-39 y/olds
- 3/4 of 40 y/olds
- 8/10 >50 y/olds
What is the mechanism of action of statins?
Competitive inhibition of HMG-CoA reductase
(The rate controlling enzyme in mevalonate pathway)
- low intracellular cholesterol stimulated LDL receptor synthesis
- Increased LDL uptake from blood
Name the 2 most commonly used statins in the UK?
Atorvastatin
Simvastatin
Aside from lowering CVD risk, what are the additional benefits of statin therapy?
- Improved vascular endothelial function - increased NO, VEGF and decreased endothelin
- Stabilisation of atherosclerotic plaque - decreased smooth muscle cell proliferation, increased collagen
- Improved haemostasis - decreased fibrinogen and platelet aggregation, increased fibrinolysis
- Anti-inflammatory effect - decreased inflammatory cells in plaques, decreased CRP and cytokines
- Antioxidant effect - decreased superoxide formation
What are the most common side effect of statins?
- GI disruption
- Nausea
- Headache
- Myalgia- diffuse muscle pain seen if CPK increases >10x normal limit
- Rarely - rhadbomyolysis
What are the half lives of simvastatin and atorvastatin respectively?
Simvastatin - a pro-drug activated by 1st pass metabolism. t1/2 2 hours
Atorvastatin - t1/2 >30 hours
Which patients would you prescribe statins to with caution?
- Those with renal impairment
- Pregnancy - the fetus needs cholesterol
- Breastfeeding
- Other drugs metabolised by CYP3A4 - amiodarone, diltiazem, macrolides
- Amlodipine - may need higher doses statins of co-administered
What are the NICE guidelines for prescribing statins for primary and secondary prevention?
- Primary prevention - 20mg atorvastatin once daily
- Secondary prevention (anyone most MI/ ACS) - 80mg atorvastatin once daily
Explain the mechanism of action of ezetimibe
- Inhibits NPC1L1 transporter (in brush border of intenstines)
- Reduces cholesterol absorption from gut by ~50%
- Increases expression of hepatic LDL receptors
- Reduces total cholesterol ~15%
What is the best way to prescribe ezetimibe?
Co prescribe with simvastatin
What is the mechanism of action of alirocumab?
- Alirocumab binds to protein PCSK9 that normally causes LDL receptor internalisation
- Binding PCKS9 prevents receptor internalisation therefore more receptor available for LDL to bind to remove from plasma
- Highly significant reduction of LDL vs placebo
