9 - Hyperlipidaemias Flashcards
breifly outline the role of choleserol in the body - meh revison
and explain why we should act to reduce it with drugs
Most cholesterol synthesised in body with contribution from diet
• Essential for membrane integrity, precursor in production of steroid hormones, bile acids and vitamin D
• LDL susceptible to oxidation at damaged endothelium
by necrotic tissue and ROS, adhere to proteoglycans – causevatherosclerosis
• HDL carrier of cholesterol away from circulation to liver for recycling - “good cholesterol”
Cholesterol – target to reduce CVD risk
Modifiable risk factor
• Data shows relationship between elevated cholesterol and morbidity and mortality from CHD
• LDL cholesterol lowering is the target for CVD prevention
how to high LDL levels lead to atherosclerosis ?
- Accumulation of LDL
- Oxidation by local endothelial cells
- Modified LDL and oxidation – oxidized LDL
- Recruited monocyte uptake oxidized LDL
- Foam cells formed building up in intima/endothelial space
- Proliferation of smooth muscle cells
- Fatty streaks develop
- Chronic inflammation and accumulation of disrupted VSMC
this results in a fatty streak - can for plaques or rupture - both can then go onto emoblise - MI, stroke ect
what are the key statin drugs
1 atorvastatin 2 simvastatin fluvastatin pravastatin rosuvastatin lovastatin
1 and 2 are the key to remember
statins - mechanism of action
Competitive inhibition of HMG-CoA reductase – rate controlling enzyme in mevalonate pathway - decreases cholesterol conc. within cell - cell will synth LDL recptors in response - leads to more LDL uptake from blood - reducing LDL blood conc and hence rate of fatty streak forming
- Upregulation of hepatic LDL receptors
- Increased clearance of circulating LDL
look at image lec 9 slide 10
what are the other benefits of statin therapy ?
you do not need all of these, however one or two / general idea would be good
a lowering of CVD risk
Improved vascular endothelial function - ↑NO, VEGF, ↓endothelin
- Stabilisation of atherosclerotic plaque
- Improved haemostasis - ↓plasma fibrinogen, platelet aggregation, ↑fibrinolysis
- Anti-inflammatory - ↓proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines
- Antioxidant - ↓superoxide formation
prescrbing statins - DDI’s and ADRS
Simvastatin is a prodrug activated by first pass metabolism – t1/2 ~2h
• Atorvastatin - first pass metabolism – active derivatives – t1/2 >30h
• X GI disruption, nausea and headache
myalgia – diffuse muscle pain (↑CPK >10 X normal limit)
dose related
Rarely – rhabdomyolysis – OAT differences?
• Δ renal impairment, pregnancy! and breastfeeding - think twice before giving - will fuck them up
CYP 3A4 important – amiodarone, diltiazem, macrolides
amlodipine
? withhold statin short term
before prescribing do a full lipid profile - LDL, TG’s, HDL
monitor and look for reducitons in lipid levels
take it at night for greater efficacy
what is the key fibric acid derivative ?
fenofibrate
mechanism of fenofibrate
side effects
DDI’s and Contras
Activation of nuclear transcription factor – PPARα
(peroxisome proliferation-activated receptor)
PPARα regulate expression of genes that control lipoprotein
metabolism – increase production of lipoprotein lipase - so more lipoprotien breakdown
leads to ↑triglycerides from lipoprotein in plasma ↑fatty acid uptake by the liver ↑levels of HDL ↑LDL affinity for receptor
• Different mechanism to statins – rarely alone, co-prescribed
- X cholelithiasis (gall stones), myositis
- Δ warfarin - increase bleedng risk
Cholesterol absorption inhibitors - key drug
ezetimibe
Cholesterol absorption inhibitors - mechanism
side effects
DDI’s and Contras
Inhibit NPC1L1 transporter
• Reduces absorption of cholesterol by the gut ~50%
• Hepatic LDL receptor expression increases
• ↓total cholesterol ~ 15%, LDL ~ 20%
• Pro-drug - hepatic metabolism - enterohepatic circulation
Limits systemic exposure
secreted by bile – good tolerability
- Adjunct to statin
- X abdominal pain, GI upset
- Δ hepatic failure
why and when may we use multiple target therapy on hyperlipidemias
- Combination of etezimibe and statin benefit in CKD and secondary CVD prevention
- Those that can only tolerate a low dose statin – addition of ezetimibe - more effective than monotherapy
• Addition of fibrates or nicotinic acid - specialist advice in familial hypercholesterolemia – not primary or secondary prevention
PCSK9 inhibitors
Names
Mechanism
DDI and contra
When LDL attaches to LDL-R , receptor is internalised,
LDL catabolised and receptor degraded or recycled in cell
• PCSK9 – protein that binds internalised LDL-R – directing for degradation
• PCSK9 inhibitors demonstrating highly significant reduction in LDL cholesterol over placebo (statin +/- ezetimibe)
BUT more expensive and injection only - not ideal at all
