Lecture 8- Hyperlipidaemia Flashcards
most cholesterol is
synthesised in the body
25% contribution from diet
function of cholesterol
- Essential for membrane integrity
- Precursor in production of steroid hormones, bile acids and vitamin D
Atheromas and LDL
- LDL susceptible to oxidation at damaged endothelium, ROS contributes to endothelial dysfunction increasing adherence of lipid rich deposits and foam cells formed – precursor to atheromatous plaques
role of HDL
cholesterol transported to peirpehrla tissue which exceed catabolism needs returing to the liver
HDL absorbs cholesterol and carries it back to the liver.
HLD carries cholesterol to the liver where it is disposed of in
the bile
total cholesterol vs CHD
higher the cholesterol, higher risk of CHD
cholesterol as a target to reduce CVS events
- Modifiable (mostly) risk factor – like blood pressure
- Data shows relationship between elevated cholesterol and morbidity and mortality from CHD
- Reduction in total cholesterol of 10% affords ~15% reduction in CHD mortality and ~11% in total mortality
which cholesterol is primary target for CVD prevention
LDL
- every 1.0 mmol/L total cholesterol reduction there is ~ 22% relative risk ↓CVD
Why does high cholesterol result in increased CVD risk?
causes fatty streaks- precurosr to atheroma
fatty streaks are not just found in the old
- Fatty streaks starting forming in mid 20s
- Examination of intimal thickness of aorta of heart transplant donors suggest that:
drug classes which target high cholesterol/ primary CVD
First line treatment for high cholesterol/ risk of primary CVD
Statins
Treatment of hypercholesterolaemia
- Fibric acid derivatives (fibrates)
- Cholesterol absorption inhibitors
- PCSK9 inhibitors
Other options for treater hypercholestermia
- plant sterols
- fish oils
- vitamin C/E
- Alcohol (maybe
For primary prevention of CVD
statins
when should statins be prescribed
For primary prevention of CVD, GPs should offer atorvastatin 20mg to people who have a 10 per cent or greater 10-year risk of developing CVD.
QRISK SCORE of above 10%
name some statins
Atorvastatin (most widely used)
MOA of statins
- Competitive inhibition of HMG- CoA reductase- rate controlling enzyme in HMG-CoA to mevalonate pathway
- Reduce circulating cholesterol
- Contributes to upregulation of hepatic LDL receptors
- Increased clearance of circulating LDL
- lost in bile
adverse drug response: statins
- GI disruption, Nausea, Headache
- Myalgia - diffuse muscle pain
- Rhabdomyolysis (rare) - OAT differences and skeletal muscle ATP production
- Increased liver enzymes
contraindications: statins
- Renal or hepatic impairment
- Pregnancy and breast feeding
Drug-drug interaction: statins
- CYP 3A4 inhibitors which will increase [statin] plasma conc
- Amiodarone, diltiazem, macrolide
- Amlodipine (CCB) also increase [plasma] statin
- Maybe worth withholding statins short term whilst taking other agents
Are all statins equal- which should be used?
- Dose dependant reduction in LDL cholesterol for all cost and side effect severity appears to drive choice
- The higher the dose the higher the reduction in LDL cholesterol (in general)
- rosuvstatin most efficacious
- then atorvastatin- less side effects so used more
PCSK9 inhibitors mode of action
- LDLR on the liver cell surface binds to LDL and the LDLR–LDL complex is then internalized, after which the LDLR is normally recycled back to the cell surface
- PCSK9 binds to the LDLR on the surface of the hepatocyte, leading to the internalization and degradation of the LDLR in the lysosomes, and reducing the number of LDLRs on the cell surface.
- Inhibition of secreted PCSK9 by PCSK9 inhibitors therefore increases the number of available LDLRs on the cell surface and increase uptake of LDL‐C into the cell.
- lowering LDL in plasma
