Hyperlipidaemias Flashcards
How do we get most of our cholesterol and what is it used for?
Most is synthesised in the body
Essential for: membrane integrity, precursor in production of steroid hormones, bile acids, vitamin D
Explain why LDL is seen as ‘bad’ cholesterol and HDL is seen as ‘good’ cholesterol
LDL is susceptible to oxidation at damaged endothelium by necrotic tissue and ROS, adheres to proteoglycans -> atherosclerosis
Oxidised LDL uptaken by recruited monocytes via scavenger receptors -> foam cells form in intima -> proliferation of smooth muscle cells -> fatty streak
HDL carrier of cholesterol sway form circulation -> liver -> recycled
How much impact does reducing total cholesterol reduce CVD risk?
Every 1mmol/ L total cholesterol reduction = 20% reduction in CVD risk
Risk factors for CVD
- high systolic BP
- smoking
- diabetes
- echo left ventricular hypertrophy
- high serum cholesterol
- Male
Exaplain how statins work, give examples
- Statins are competitive inhibitors for HMG-CoA reductase (rate limiting step)
Mevalonate pathway: Acetate-> HMG CoA (HMG CoA reductase) -> mevalonic acid -> cholesterol - above causes: up-regulation of hepatic LDL receptors ->
- increase clearance of circulating LDL from blood
(- Also improve vascular endothelial function by increasing NO/ VEGF and decreasing endothelin.
- Stabilise atherosclerotic plaques (decrease SMC proliferation, increase collagen.
- Improve haemostasis (decrease plasma fibrinogen/ platelet aggregation, increase fibrinolysis)
- anti- inflammatory (decreased proliferation inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines
- antioxidant (decrease superoxide formation))
E.g. atorvastatin, simvastatin
How are the two main stains metabolised? What side effects and contraindications are there to stains?
Simvastatin - prodrug activated by first pass metabolism (t1/2 2hrs)
First line: Atorvastatin - first pass metabolism - active derivatives (t1/2 >30hrs)
❌ GI disruption, nausea, headache, myalgia (CPK 10X normal), rarely - rhabdomyolysis
Contraindications: renal impairment, pregnancy, breastfeeding, CYP 3A4 important (so if taking amiodarone, diltiazem, macrolides, amlodipine)
According to NICE guidelines how much should you increase the dose of atorvastatin if using it for secondary prevention as opposed to primary prevention? What should you do before prescribing? What should it be taken at night?
20mg -> 80mg (amend according to adverse reactions/ drug interactions (grapefruit (juice) / CKD patients)
Before prescribing: full lipid profile including HDL, non- HDL + TGs
Circadian rhythm of LDL receptor synthesis/ activity
How do fibric acid derivatives/ fibrates work? Give an example. Side effects and contraindication.
Activation of nuclear transcription factor - (PPARalpha) Which regulates expression of genes that control lipoprotein metabolism (⬆️production lipoprotein lipase)
E.g. fenofibrate
Also: increased triglycerides from lipoprotein in plasma, increase FA uptake by the liver, increase HDL, increase LDL affinity for receptor
Usually co-prescribed but can be used instead of statins if contraindicated
❌cholelithiasis (gall stones), myositis
Contraindications: warfarin
How do cholesterol absorption inhibitors work? Give an example. How is it metabolised? Side effects and contraindication
Inhibit NPC1L1 transporter, reduce absorption of cholesterol in gut by 50%, hepatic LDL receptor expression⬆️, ⬇️total cholesterol/ LDL
E.g. ezetimibe
Pro-drug - hepatic metabolism - enterohepatic circulation - limits systemic exposure - secreted by bile (good tolerability)
replaced most resins and sequestrants
As less side effects, often used adjunct to statin
❌abdo pain, GI upset
Contraindicated in hepatic failure
How do PCSK9 inhibitors work? Give an example. How are they administered?
PCSK9 is a protein that binds internalised LDL-R directing it for degradation (LDL receptor internalised and LDL catabolised, receptor degraded/ recycled)
So inhibition increased number of LDL receptors
E.g. alirocuMAB
Requires lifetime injections once a week (much more expensive than statins and long term effects lacks evidence) currently recommended for primary and secondary prevention in resistant familial hypercholesterolemia and some high risk secondary prevention patients
How do plant sterols work? What can they be found in?
Plant sterols provide LDL cholesterol lowering effects
Naturally occurring in grains, legumes etc. Structurally similar to cholesterol - competing for absorption
Work with statins but not with ezetimibe (same mechanism)
What foods are good for reducing cholesterol?
Grains Legumes Fish oils Fibre Whole grains Vitamin C/E
Alcohol increases HDL cholesterol but also increases triglycerides
How can you calculate someone’s CVD risk score?
QRISK - uses age, sex, ethnicity, smoking, diabetes, heart attack, angina, CKD, blood pressure, migraines, RA, lupus, mental illness, cholesterol/ HDL ratio, BMI
