Hypelipidaemiais Flashcards
Gove an overview of cholesterol
- Majority of cholesterol synthesised in the body with contribution from diet
- Essential for cell membrane integrity and precursor in production of steroid hormones, bile acids and vitamin D production
- LDL susceptible to oxidation at damaged endothelium initiated by necrotic tissue and ROS, adhere to proteoglycans - atherosclerosis
- HDL carrier of cholesterol away from circulation to liver for recycling so called “good cholesterol”
- Quantity of cholesterol transported to the peripheral tissues exceeds its catabolism and needs to be returned to the liver
- High triglycerides not particularly good but limited data to suggest it should be targeted as a modifiable risk factor
Give a overview of total cholesterol vs chd risk
Ss
Describe cholesterol as a target to reduce cvs risk
• Modifiable risk factor
• Extensive data shows the relationship between elevated cholesterol
and morbidity and mortality from CHD
• Reduction in total cholesterol of 10% affords 15% reduction in CHD mortality and 11% in total mortality
• LDL cholesterol lowering is the target for CVD prevention
• ~ for every 1.0 mmol/L total cholesterol reduction there is a 20% CVD
risk
• How aggressive treatment should be depends on total CVD risk
Describe ldlatheroma and atherosclerosis
- Accumulation of LDL at the intima
- Oxidation by local endothelial cell products
- Modified LDL and additional oxidation – 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 VSMC
When d oofatty streaks form
• When does it begin • Examination of intimal thickness of heart transplant donors suggests: • 1/3 20 - 29 year olds • 2/3 30 - 39 year olds • 3⁄4 40 - 49 year olds • 8/10 > 50 years old • And the descending aorta of the male on the RHS →
What are statins
• Competitive inhibition of HMG-CoA reductase – rate controlling enzyme in mevalonate pathway
• Upregulation of hepatic LDL receptors
• Increased clearance of circulating LDL
atorvastatin simvastatin
What are additional benefits of statin therapy
Lowers cvs risk
• Improved vascular endothelial function - ↑NO, VEGF, ↓endothelin
• Stabilisation of atherosclerotic plaque - ↓SMC proliferation ↑collagen
• Improved haemostasis - ↓ plasma fibrinogen, platelet aggregation, ↑ fibrinolysis
• Anti-inflammatory - ↓ proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines
• Antioxidant - ↓ superoxide formation
Describe statin pk
- Simvastatin is a prodrug activated by first pass metabolism – t1/2 ~2h
- Atorvastatin - first pass metabolism – active derivatives – t1/2 >30h
- CYP 3A4 important – (drug interactions)
What ar adrs associated with statins
- Transient serum transaminase elevation ~ 1% - reversible – liver function test – drug accumulation
- Myalgia – diffuse muscle pain (↑CPK >10 X normal limit) – typically dose related and more likely in combination with other cholesterol lowering agents, amiodarone, cilclosporin, some antibiotics
- Rarely – rhabdomyoloysis - PG effect of OAT at greater risk?
- GI disruption, nausea and headache
Which statin should ve used?
• All cause a dose dependant reduction in LDL cholesterol cost and specific side effect severity appears to drive choice
• Rosuvastatin – was most prescribed drug in USA – greatest efficacy – concerns about side effects (diabetes?)
• Cerivastatin withdrawn for DDI (gemfibrozil) which caused some deaths – rhabdomyolysis and renal failure
Ss or table
Describe the nice guidelines or statins
- Primary prevention 20 mg Atorvastatin once daily (10 year CVD risk of >10% using QRISK) inc. patient considerations and risk/benefit
- Secondary prevention 80 mg Atorvastatin once daily (amended according to adverse reactions/drug interactions, CKD - 20 mg)
- Full lipid profile inc. HDL, and non-HDL + TGs before prescribing
- > 40% reduction in non HDL-C at three months
- Grapefruit juice or (whole grapefruit)!
- q.h.s - circadian rhythm of LDL receptor synthesis (low t1/2’s – simvastatin) - highest at ight - take before bed
Descrive fibrates
• Activation of nuclear transcription factor – PPARα (peroxisome proliferation-activated receptor)
• PPARα regulate expression of genes that control lipoprotein metabolism – increase production lipoprotein lipase
Enhances the clearance of triglycerides from lipoprotein in plasma Increase fatty acid uptake by the liver
Increases LDL affinity for its receptor (larger more buoyant LDL) (Elevated levels of HDL)
• Act at different site to statins – very specific circumstances – co- prescribed
fenofibrate ciprofribrate
Describe the indicationn f fbrates
• Indications:
- Adjunctive therapy to diet in Hypertriglyceridaemia
- Combined hyperlipidaemia with low HDL who do not respond to NA - Fenofibrate widely distributed and albumin bound
• Efficacy: Decreases TG 25-50%
LDL decreases, but variable ~ 20%
Increases HDL 15-25% in hypertriglyceridemia
Describe teh side effects and adrs iffibrtes
Side Effects: GI upset (8%), cholelithiasis (gall stones), myositis Abnormal LFTs
Warfarin potentiation
• Contraindications: Hepatic or renal dysfunction Pre-existing gallbladder disease
• Predominant effect is lowering of triglycerides – long term effects on CVD risk to be elucidated
Descrive bicotinic acid
Eg niacin. • B vitamin has effects on lipids at pharmacological doses
• Antilipolytic → reduced fatty acid supply ↓tryglyceride synthesis
• ↓ VDL and LDL (~15%) but increases HDL cholesterol greatly (25%) – best agent for this (similar effects to exercise)
• ADRs
Flushing (NIAC receptors in skin), headache, itching – reduced by immediate
release preparations or low dose aspirin 30 min before (↓prostaglandin release)
Hepatotoxicity, GI disturbance
• Often poorly tolerated but can be overcome by slow dose increase
• Hepatic metabolism – resulting metabolites thought to contribute to ADRs
• When limited options – not primary CVD risk reduction
