5.1 Hyperlipidemias Flashcards
What vitamin is cholesterol important in the production of ?
Vitamin D, steroid hormone, bile acids
How do you get a fatty streak?what is the pathology?
- Accumulation of LDL at the intima
- Oxidation by local endothelial cell products
- Modified LDL and additional oxidation gives you an oxidized LDL
- Recruited monocyte uptake oxidized LDL via scavenger receptors (SR-A)
- Foam cells formed building up in intima/endothelial space
- Proliferation of smooth muscle cells
- Fatty streaks develop
- Chronic inflammation and accumulation of disrupted vascular smooth muscle cells
When do you get fatty streaks?
Dependant in cholesterol levels, doesn’t really link to age
What are statins?
Competitive inhibition of HMG-CoA reductase – (rate controlling step) enzyme in mevalonate pathway
This up-regulates hepatic LDL receptors
So, get increased clearance of circulating LDLs = helps prevent against cardiovascular disease
Name some statins
Atorvastatin
Simvastatin
What are the additional benefits of statins?
CVD reduction
Improved vascular endothelial function (increased NO and VEGF, decreased endothelin)
stabilisation of atherosclerotic place (decreased SMC proliferation and increased collagen)
improved haemostasis (decreased plasma fibrinogen, platelet aggregation and increased fibrinolysis)
anti-inflammatory (decreased proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines)
antioxidant (decreased superoxide formation)
how are statins activated?
simvastatin
- activated by first pass metabolism
- half life 2 hrs
atorvastatin
- first pass metabolism
- half life of 30hrs
what are the ADR of statins?
- raised ALT and AST
- myalgia
- rarely get rhabdomuoloysis
- GI disruption, nausea and headache
what are the NICE guidelines for statin prescription?
primary prevention
- 20 mg of atorvastatin once daily to all those who have CVD risk of over 10%
secondary prevention
- 80 mg atorvastatin once daily
check lipid profile including HDL, non HDL and TG before prescribing
what are fibrates?
fibric acid derivatives e.g fenofibrate and ciprofribrate
activate nuclear transcription factor (PPARa) which regulates expression of genes that control lipoprotein metabolism (increase production of lipoprotein lipase)
they enhance the clearance of triglycerides from lipoprotein plasma and increase fatty acid uptake by the liver
they also increase LDL affinity for its receptor
name two fibrates
fenofibrate
ciprofribrate
what are the ADRs of fibrates?
GI upset
cholelithiasis (gall stones)
myositis
what are nicotinic acids?
an antilipolytic = reduces fatty acid supply = reduced triglyceride synthesis
e.g niacin
what are the ADRs of nicotinic acids?
flushing heachache itching (reduced by low dose of aspirin 30mins prior) hepatoxicity GI disturbance
give an example of a nicotinic acid
niacin
what are cholesterol absorption inhibitors?
act at the brush border of the small intestine of the mucosa and reduce cholesterol absorption = hepatic LDL receptor expression increases = decreases total cholesterol and LDLs
A pro drug that stays in the enterohepatic circulation (= less systemic exposure)
e.g ezetimibe
what are the ADRs of cholesterol absorption inhibitors?
headache
abdominal pain
diarrhoea
give an example of a cholesterol absorption inhibitor
ezetimibe
what combination of drugs can be used against CVD?
statins e.g atorvostatin and a cholesterol absorption inhibitor e.g ezetimbine
what can you use if statins aren’t working at reducing LDL levels, and how do they work?
Alirocumab
Evolocumab
when LDL attaches to LDL receptor, it is internalised and receptor is degraded and I recycled in the cell
PCSK9 is a protein that directs the degradation of internalised LDL receptors
these drugs are PCSK9 inhibitors, so prevent internal LDL receptor degredation = more receptors = more LDLs can be taken into cells
what other suggestions can be made to a patient to reduce risk of CVD?
eat more
- fish oils
- fibre
- vit C/E
- alcohol = increases HDL cholesterol but increase triglycerides
effective, especially in low risk patients maintaining low risk