Lipid lowering drugs Flashcards
Where does most of our cholesterol come from and where is it synthesised?
- Mostly synthesised in liver (80%)
- 20% comes from diet
What is the most imp. determinant of CVD risk?
- Fatty acids (more imp. than cholesterol)
- Comes in three forms - sataured, unsaturated, trans unsaturated
NB. Polyunsaturated has link with lower CVD
How are lipids transported?
- Esterified cholesterol and TAG in the centre
- Unesterified cholesterol on the outside
- Apoprotein on the outside - helps carry TAG anf fatty acids - there are receptors for these in order to help to internalise fats
What are chylomicrons?
- Transport cholesterol and TAGs from GI tract to muscle and adipose tissue
- TAGs released at end-organ by lipoprotein lipase
- Cholymicrons remnants transport cholesterol to liver (stored, bile acids, VLDL go to circulation)
What are VLDL?
- Newly synthesised TAGs and cholesterol transported as VLDL
- As TAGs are released become LDL
- LDL takes cholesterol to peripheral tissues via LDL receptors but also deposits on walls of blood vessels which can lead to plaques and blockade of coronary arteries
What is HDL?
- Collects cholesterol particles as they travel through blood vessels
- Deposits them into liver
- Transferred to bile acids and disposed of (and to steroidogenic organs such as ovaries and testes)
What is the main way fats are disposed of?
Bile in the gut
What is IDL?
Intermediate between VLDL and LDL
What are the risk factors for atherosclerosis in order from highest to lowest?
- Sensitivity to CPR
- BP
- LDL
What is the process of atherosclerosis?
- LDL ends up in vascular wall
- Endothelial layer can become dysfuncitonal due to certain risk factors such as high shear stress (where there are bifurcations of artery)
- LDL deposited becomes oxidised and causes inflammatory response
- Monocytes come into intima to phagocytose the fat which turns it into foam cells
- Foam cells die and leave lipid there
- Fibrous cap can develop over plaque - the cap can break and expose the lipid
- Induces thrombosis so can get stroke and MI
- Happens in any vascular bed such as kidneys and brain too
What are some secondary causes of hyperlipidaemia?
- Dietary
- Sedentary lifestyle
- Excess alcohol
- Uncontrolled diabetes
- Hypothrydoism
- Cushing’s
- Liver disease
- Nephrotic syndrome
- Medications
What is type I familial hyperlipidaemia?
- Elevated cholymicrons
- No cholesterol
- Raised TAG
Cause:
- Lipoprotein Lipase Deficiency
- Apolipoprotein C-II Deficiency
Control:
- Low fat diet
What is type II familial hyperlipidaemia?
- Raised LDL (more common)
- Raised cholesterol
- No TAGs
Cause:
- Familial hypercholesterolaemia
- Polygenic hypercholesterolaemia
- Usually due to lack of LDL receptor or dysfunction
- Homozygous people get atherosclerosis in childhood
What is the cause of familial hypercholesterolaemia?
- PCSK9 mutation
- Reduces hepatic LDL receptors (binds to LDL-R and then the complex is internalised)
- Gain of function mutation
- :. Reduced hepatic uptake of LDL
- Increased circulation LDL and atherosclerosis
What is type IIb hyperlipidaemia?
- Raised LDL and VLDL
- Raised cholesterol
- Raised TAGs
Cause:
- Familial combined hyperlipidaemia - v. common
What is type III hyperlipidaemia?
- Raised IDL
- Raised cholesterol
- Raised TAG
Cause:
-
Dysbetalipoproteinaemia
- Some IDL before converting to LDL is removed by liver by APO-E
- If have APO-E dysfunction :. more LDL aka remnant removal disease
What is type IV hyperlipidaemia?
- Raised VLDL
- Raised TAGs
- No cholesterol
Cause:
- Familial hypertriglyceridaemia
- Autosomal dominant
- Associated with metabolic syndrome
- More risk than type 1 :. why type 2 diabetics get more CVD than type 1
Who to treat with lipid lowering drugs?
Primary prevention
- Familial hyperlipidaemias
- Diabetes
- CKD
- 10 year CV risk > 10%
- Take into account: lipid levels, BP, BMI, Age, smoking status
Secondary prevention
- MI
- Angina
- PVD
- Non-haemorrghagic stroke
- TIAs
- Aim to have 40% reduction in non-HDL cholesterol
What is the mechanism of statins?
- Competively inhibit HMG CoA reductase
- Enzyme which catalyses rate limiting step in cholesterol synthesis within liver
What are first line drugs for primary and secondary prevention of CVD?
- Statins
What are the side effects of statins?
Usually pretty well tolerated
- Myopathy
- Myositis (inflammation of muscles)
- Rhabomyolysis (death and release of muscle fibres) into blood stream
Common: headache, dizziness, nauseau, drowziness, difficulty sleeping
The above SE are very rare and more likely with higher doses and high risk patients such as those with renal impairmnet, high alcohol intake, elderly
Rare: Hepatitis, Jaudince
V. rare: Hepatic failure, interstitial lung disease, pancreatitis, lupus like reactions
What is the mechanism of action of ezetimibe?
- Inhibits intestinal absorption of cholesterol
- Used as adjunct to statin therapy to lower LDL levels (can be used instead of statins if not well tolerated)
- No clinical benefits - but lowers cholesterol so benefits inferred
How do fibrates work?
- Most powerful after statins
- PPARa agonist:
- Increases fatty acid oxidation in muscle and liver
- Activation of lipoprotein lipase
- Decrease serum TAGs (more effective than statin)
- Used mainly as adjunct to treat high levels of serum TAG
- :. useful in familial hypertriglyceridaemia and mixed hyperlipidaemias
- Often with statins (but muscle effects incr)
- SE: nausea, diarrhoea
How do bile acid sequestrants (colysteramie, colestipol) work?
- Bind to and inhibit intestinal reabsorption of BA
- Promotes hepatic conversion of cholesterol into BA :. increased hepatic uptake of LDL
- Used mainly as an adjunct in hypercholesterolaemia (primary and familial)
- SE: interference with fat soluble vitamins (ADK). GI disturbanc, can induce hypertriglyceridaemia
