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
Why is it recommended to take statins at night?
Due to the circadian rhythm of LDL receptor synthesis being greatest at night
More relevant for simvastastin due to short t 1/2
What is the mechanism of action of fibrates?
- Activate nuclear transcription factor PPARalpha
- PPAR a regulations expression of genes that control lipoprotein metabolism
- Net effect= increased production of lipoprotein lipase
What is the main fibrate drug?
Fenofibrate
What are the effects on the body of fibrates?
- Increase TAG breakdown from lipoprotein in plasma
- Increased fatty acid uptake by the liver
- Increased levels of HDL
- Increased LDL affinity for receptor
In which patients would you use fibrates with cauution/ not prescribe them to?
Do not presribe to: patients with cholelithiasis (gall stones), myositis (muscle inflammation)
Prescribe with caution: patients on warfarin due to increased risk of bleeding
Name a cholesterol absorption inhibitor
Ezetimibe
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%

When would you prescribe ezetimibe with caution/ not prescribe?
Do not prescribe if: abdominal pain, GI upset
Prescribe with caution if: hepatic failure (as it’s a pro-drug)
Describe the pharmacokinetics of ezetimibe
- Ezetimibe is a pro-drug needs activating by hepatic metabolism
- Enters into enterohepatic circulation → limits systemic exposure
- Secreted by bile - good tolerability

