Hyperlipidaemias Flashcards
What is cholestrol used for?
Cell membrane integrity and precursor in production of steroid hormones, bile acids and vitamin D production.
Why is LDL bad?
Susceptible to oxidation at damaged endothelium initiated by necrotic tissue and ROS, adhere to proteoglycans and cause atherosclerosis
Why is HDL good?
Carrier of cholestrol away from circulation to liver for recycling.
How is serum cholestrol related to CHD?
Higher serum cholestrol, higher incidence of CHD
But, link not as clear when look at world picture as other things have an effects too.
What things increase the risk of CVD?
High BP Low HDL-cholesterol Smoking Diabetes Echo LVH (heart failure)
How does LDL cause fatty streaks (atherosclerosis)?
Accumulation of LDL at the intima
Oxidation by local endothelial cell products
Modified LDL and additional oxidation - oxidised LDL
Recruited monocytes uptake oxidised 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 VSMC
When do fatty streaks develop?
The age in which they develop is variable and is influenced by lifestyle and congenital factors.
1/3 - 20-29yr olds
2/3 - 30-39yr olds
3/4 - 49yr olds
4/5 - 50 year olds
How do statins work?
Competitive inhibition of HMG-CoA reductase -rate controlling enzyme in mevalonate pathway.
Upregulation of hepatic LDL receptors
Increased clearance of circulating LDL and decrease secretion of VLDL
What are the most commonly prescribed statin?
Atorvastatin
Simvastatin
What are the additional benefits of statin therapy?
Deceased CVD risk
Improved vascular endothelial function
Stabilisation of atherosclerotic plaques (deceased SMC proliferation and increased collagen)
Improved haemostasis
Anti inflammatory
Antioxidant (decrease superoxide formation)
How does simvastatin work?
Prodrug activated by first pass metabolism -half life is 2hours
How does atorvastatin work?
First pass metabolism - active derivative
Half life is 30hours
Now prescribed more as cheap and long half life.
What are the ADRs of statins?
Transient serum transaminase elevation
Myalgia - diffuse muscle pain (dose related and more likely if taken in combination with other cholesterol lowering agents)
Rhabdomyoloysis (rare)
GI disruption, nausea, headache
Which statins are best?
All cause a dose dependant reduction in LDL cholestrol and specific side effect severity appears to drive choice.
In UK- atorvastatin and simvastatin
USA - Rauvostatin as it has he greatest efficacy (works at lower dose) but, concerns about side effects (diabetes?)
Cerivastatin was withdrawn from sale as drug interactions caused deaths (rhabdo, renal failure)
What are the NICE guidelines regarding statins?
Primary prevention 20mg Atorvostatin once daily. - if 10 yr CVS risk is over 10% (used to be 20%)
Secondary prevention (if already had MI stroke ect.) 80mg Atorvostatin once daily.
Full lipid profile inc. HDL, non-LDH and TGs
Should have over 40% reduction in non HDL-C at three months
How do fibrin acid derivates (fibrates) work?
Activation of nuclear transcription factor -PPARa (peroxisome proliferation-activated receptor)
PPARs regulate expression of genes that control lipoprotein metabolism - increase production of lipoprotein lipase.
The enhance the clearance of triglycerides from lipoprotein in plasma,
Increase fatty acid uptake by the liver,
Increase LDL affinity for its receptor (larger, more buoyant LDL, elevated levels of HDL)
They act at different sites to statins so, in very special circumstances they can be co-pescribed.
Examples of fibrates
Fenofibrate
Ciprofribrate
Genfibrozil
What are the indications of fibrates?
Adjunctive therapy to diet in hypertriglyceridaemia
Combined hyperlipidaemia with low HDL who do not respond to NA
Fenofibrate widely distributed and albumin bound.
What are the side effects of fibrates?
GI upset, cholelothiasis (gall stones), myositis, abnormal LFTs, Warfarin potentiation
When are fibrates contraindicated?
Hepatic or renal dysfunction
Pre-existing gall bladder disease
How do nicotinic acid work?
B vitamin has effects on lipids at pharmacological doses.
Antilopolytic - reduced fatty acid supply and decrease triglyceride synthesis.
It decreases VDL and LDL but increases HDL greatly. It is the best agent for increasing HDL.
Give an example of a nicotinic acid
Niacin
ADRs of niacin
Flushing (NIAC receptors in skin), headache, itching -reduced by immediate release preparations or low dose aspirin 30mins before (decrease prostaglandin release), hepatotoxicity, GI disturbance
Often poorly tolerated by can be overcome by slow dose increase.
When is Nicotinid acid prescribed?
Rarely
How doe cholestrol absorption inhibitors work?
Acts at the brush border of the SI mucosa inhibition NCPC1L1 transporter.
This reduces absorption of cholesterol into the gut by 50%.
It increases hepatic LDL receptor expression.
It decreases total cholestrol by 15% and LDL by 20%.
It is a prodrug - if is more efficacious once the liver turns it into ezetimibe glucuronide and then enters enterohepatic circulation.
Give an example of a cholestrol absorption inhibitor
Ezetimibe
When is multiple target therapy used?
Ezetimibe is used in combination with statins in CKD and CVD prevention.
Also used in those that can only tolerate a low statin.
Add fibrates or nicotinic acid when specialist advice in familial hypercholetrolaemia.
What cholestrol level do you aim for?
2mmol/L LDL cholestrol
4 mmol/L total cholesterol
What does it mean if a drug name ends in …Mab?
It is a monoclonal antibody
What are alirocumab and evolocumab?
PCSK9 inhibitor.
Monoclonal antibody
Will PCSK9 inhibitors replace statins eventually?
Maybe, but do not know long term effects.
Also, given as depot injection under skin every two weeks.
Cost is expensive as under patent.
Currently recommended for primary and secondary prevention in resistant familial hypercholesterolaemia and in some high risk secondary prevention patients.
What are thee non POM options to reduce cholestrol?
Plant sterols provide LDL cholestrol lowering effects.
Naturally occurring in grains, legumes ect. Structurally similar to cholestrol - competing for absorption.
Work with statin but not ezetimide (as ezetimide inhibit channels go through)
Fish oils
Fibre
Vitamins C and E
Alcohol - increases HDL cholestrol BUT increase triglycerides.
What is the cost effectiveness of treating hypercholestrolaemia?
Number needed to treat is relatively small (17-20)
Currently statins recommended in the UK are off patent so anybody can make it.
10 years age, the economical considerations with lowering the 10 year CVD risk to 10% but, now they are cheaper it can be done.
How do doctors assess CVD risk?
QRISK 3rd version
(used to be “Manchester” tables
