Curbing Cholesterol Flashcards
Some cholesterol is obtained from diet, but where does the majority come from?
Synthesised in the LIVER
What roles does cholesterol play in the body?
Plasma membrane component
Precursor for steroid hormones
Precursor of bile acids
In what form is cholesterol transported around the body?
Cholesterol ester (Cholesterol linked to fatty acid)
Within lipoproteins
What are the 5 distinct classes of lipoproteins? (MEH 4.2)
Chylomicrons
VLDL
IDL
LDL
HDL
98% of lipids are carried as what? Are these molecules or particles?
Lipoprotein particles
Particles
Lipoprotein particles are made up of what components?
Peripheral apolipoproteins (ApoC, ApoE)
Integral apolipoproteins (ApoA, ApoB)
Phospholipid monolayer
Cargo- TAG, cholesterol ester, fat soluble vitamins
Particle diameter of lipoproteins is inversely proportional to what?
Density
The larger the diameter of lipoprotein, the ________ its density
Lower
Apolipoproteins have two roles in lipid transport, what are they?
Structural: packaging water insoluble molecules
Functional: co-factor for enzymes +ligands for cell surface receptors
How is dietary fat transported once it reaches the small intestine?
In chylomicrons + ApoB
Via lymphatics to thoracic duct which drains into the LEFT SUBCLAVIAN VEIN
Then acquires ApoC and ApoE once in blood
ApoC binds LPL- released fatty acids enter cells
Chylomicron remnants return to the liver, taken up after recognition of ApoE
Where are very low density lipoproteins formed, for what purpose?
Formed in the liver
To transport TAG to other tissues
Muscle: fatty acids used for energy
Adipose: fatty acids coverted back to TAG and stored
As the TAG content of VLDL decreases at the tissues, what happens to the VLDL particles?
Some of them dissociate from the LPL enzyme and return to the liver
(Depleted to 30%:) Some of them become intermediate density lipoproteins (IDLs)
(Depleted to 10%:) Some of them become LOW density lipoproteins (LDLs)
What is a key difference between HDLs and LDLs that prevent them from being efficienty cleared by the liver?
Lack ApoC and ApoE which liver LDL receptors have a high affinity for
This means they have a much longer half life making them more susceptible to oxidative damage
Oxidised LDL is taken up by macrophages and transform to foam cells
Contribute to atherosclerotic plaques
How does LDL enter cells?
Receptor mediated endocytosis
What is the main role of HDLs and how does this have a protective effect on individuals?
Remove excess cholesterol from cells with high levels of cholesterol and return it back to the liver
Disposes as bile salts and to cells requiring additional cholesterol
Reduce likelihood of foam cell and atherosclerotic plaque formation
Describe the anatomy of an atherosclerotic plaque
Fibrous cap surrounds a lipid core filled with foamy macrophages
What is the mechanism of action of statins?
Inhibit HMG-CoA reductase:
Increases LDL receptor synthesis
Decrease serum LDL and VLDL cholesterol
Reduced VLDL cholesterol
List some adverse drug reactions of statins
Increased transaminase levels- rapidly reversible
Myopathy- muscle pain
GI complaints
Headaches
List some secondary benefits of statins
Anti-inflammatory
Ploaque reduction
Improve endothelial cell function
Reduced thrombotic risk
According to NICE:
“Statin therapy is recommended as part of the management strategy of CVD for adults who have a _____ or greater ___ year risk of developing CVD”
20%
10 year risk
What is the mechanism of action of fibric acid derivatives in the reduction of LDL?
Increases the production of lipoprotein lipase
Reduces triglyceride production
Increases fatty acid uptake and oxidation
Increases LDL particle size
Increases HDL
What is the mechanism of action of nicotinic acid for use against hyperlipidaemia?
Inhibition of lipoprotein a synthesis
Reduces VLDL and increases HDL
Redduces coronary events (Coronary Drug Project)
List some adverse effects of nicotinic acid.
Flushing, itching, headache
Hepatotoxicity
Activation of peptic ulcer
Hyperhlycemia
Nicotinic acid is contraindicated in which diseases?
Peptic ulcer disease
Active liver disease/uneplained LFT elevation
What is the drug of choice in patients that cannot tolerate statin therapy?
Ezetimibe
What is the mechanism of action of ezetimibe?
Selectively inhibits intestinal cholesterol absoprtion
Reduced intestinal delivery of cholesterol to the liver
Increased expression of hepatic LDl receptors
Reduced cholesterol content of atherogenic particles
List some ADRs of Ezetimibe
Headache, abdominal pain, diarrohoea
What is combination therapy, in relation to curbing cholesterol?
Statin +
- Fibrate
- Nicotinic acid,
- Ezetimibe,
- Omega-3 FAs
Combination of stain + fibrate may significantly improve _______ levels
BUT
This combination is associated with increased risk for __________ and _________.
Triglyceride, LDL and HDL
Myopathy
Rhabdomyolysis
Which dietary factors can have a positive effect on cholesterol levels?
Fish oils
Fibre Vitamin C/E
Alcohol
Which dietary factors have a negative effect on cholesterol?
Dietary cholesterol/fat
Alcohol
Which patients are started on statins irrespective of their cholesterol levels?
Acute MI patients
What do we use to calculate cardiovascular disease risk?
QRISK2
New NICE guidelines:
“Offer _______ ___mg for the primary prevention of CVD to people who have a 10% or greater 10 year risk of developing CVD”
Atorvastatin 20mg
NICE:
“Start statin treatment in people with CVD with __________ ____mg”
“Use a lower dose if any of the following apply….. _______”
Atotvastatin 80mg
potential drug interactions, high risk of adverse events, patient preference
