Lecture 8- Hyperlipidaemia Flashcards
most cholesterol is
synthesised in the body
25% contribution from diet
function of cholesterol
- Essential for membrane integrity
- Precursor in production of steroid hormones, bile acids and vitamin D
Atheromas and LDL
- LDL susceptible to oxidation at damaged endothelium, ROS contributes to endothelial dysfunction increasing adherence of lipid rich deposits and foam cells formed – precursor to atheromatous plaques
role of HDL
cholesterol transported to peirpehrla tissue which exceed catabolism needs returing to the liver
HDL absorbs cholesterol and carries it back to the liver.
HLD carries cholesterol to the liver where it is disposed of in
the bile
total cholesterol vs CHD
higher the cholesterol, higher risk of CHD
cholesterol as a target to reduce CVS events
- Modifiable (mostly) risk factor – like blood pressure
- Data shows 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
which cholesterol is primary target for CVD prevention
LDL
- every 1.0 mmol/L total cholesterol reduction there is ~ 22% relative risk ↓CVD
Why does high cholesterol result in increased CVD risk?
causes fatty streaks- precurosr to atheroma
fatty streaks are not just found in the old
- Fatty streaks starting forming in mid 20s
- Examination of intimal thickness of aorta of heart transplant donors suggest that:
drug classes which target high cholesterol/ primary CVD
First line treatment for high cholesterol/ risk of primary CVD
Statins
Treatment of hypercholesterolaemia
- Fibric acid derivatives (fibrates)
- Cholesterol absorption inhibitors
- PCSK9 inhibitors
Other options for treater hypercholestermia
- plant sterols
- fish oils
- vitamin C/E
- Alcohol (maybe
For primary prevention of CVD
statins
when should statins be prescribed
For primary prevention of CVD, GPs should offer atorvastatin 20mg to people who have a 10 per cent or greater 10-year risk of developing CVD.
QRISK SCORE of above 10%
name some statins
Atorvastatin (most widely used)
MOA of statins
- Competitive inhibition of HMG- CoA reductase- rate controlling enzyme in HMG-CoA to mevalonate pathway
- Reduce circulating cholesterol
- Contributes to upregulation of hepatic LDL receptors
- Increased clearance of circulating LDL
- lost in bile
adverse drug response: statins
- GI disruption, Nausea, Headache
- Myalgia - diffuse muscle pain
- Rhabdomyolysis (rare) - OAT differences and skeletal muscle ATP production
- Increased liver enzymes
contraindications: statins
- Renal or hepatic impairment
- Pregnancy and breast feeding
Drug-drug interaction: statins
- CYP 3A4 inhibitors which will increase [statin] plasma conc
- Amiodarone, diltiazem, macrolide
- Amlodipine (CCB) also increase [plasma] statin
- Maybe worth withholding statins short term whilst taking other agents
Additional benefits of statin therapy
- 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
- All contribute to reduction in CVD risk
difference between Atorvastatin and Simvastatin
- Simvastatin is a prodrug activated by first pass metabolism – t1/2 around 2h
- Atorvastatin is active- first pass metabolism- also active derivatives- t1/2 around 24h
although rosuvastatin is the most prescribed drug in the US, why is it used less in the UK
although it has the greatest efficacy
HUGE concerns about side effects e.g. diabtes
Are all statins equal- which should be used?
- Dose dependant reduction in LDL cholesterol for all cost and side effect severity appears to drive choice
- The higher the dose the higher the reduction in LDL cholesterol (in general)
- rosuvstatin most efficacious
- then atorvastatin- less side effects so used more
nocebo effect
pts perceive they will have side effects and therefore have them
One study found that when patients were given placebo they still reported these side effects- nocebo
NICE guidelines when prescribing statins
- Full lipid profile inc. HDL, and non-HDL and TAG before prescribing
-
Primary prevention (those who have high LDL but haven’t experienced CVS event - 10% QRISK score)
- 20 mg atorvastatin once daily (10 year CVD risk >10% using QRISK)
-
Secondary prevention (those who have CVS event)
- 80mg atorvastatin once daily (amended according to ADR/ interactions, CKD -20mg)
- Simvastatin relatively short half life
why is simvastatin taken at night
relatively short half life (so want to target a time e.g. night at which it will be most efficacious
- Take at night due to circadian rhythm of LDL receptor
- most cholesterol produced at night
- CYP3A4 is most active at night- therefore greatest reduction in cholesterol at night when taking statins
what can inhibits CYP3A4 interfering with statin metabolism
Amiodarone, diltiazem, macrolide
GRAPEFRUIT JUICE
Target of treatments with statins
>40% reduction in non HDL-C at three months is a target
name a fibric acid derivative (fibrate)
Fenofibrate
when is fibric acid derivative Fenofibrate indicated
- familial hypercholesterolaemia
- when statins are not tolerated or contraindicated
Mode of action: Fenofibrate (fibric acid dervivative)
Activation of nuclear TF such as PPARα (peroxisome proliferation-activated receptor)
- PPARα regulates expression of genes that control lipoprotein metabolism- increase production of lipoprotein lipase
- increase TAG from lipoprotein in plasma (lipolysis)
- increase fatty acid uptake by the liver
- increase HDL levels
- increase LDL affinity for receptor
Adverse drug response: fenofibrate
- GI disruption
- Cholelithiasis (gall stones)
- Myositis
Contraindications: Fenofibrate
- Photosensitivity
- Gall bladder disease
Drug-drug interaction: Fenofibrate
Warfarin- increase anticoagulation
Fenofibrate can increase the effects of warfarin and cause you to bleed more easily.
name a Cholesterol absorption inhibitor
Ezetimibe
where is Ezetimibe (Cholesterol absorption inhibitors) indicated
- familial hypercholesterolaemia
- adjunct to statins (if not tolerated)
mode of action of cholesterol absoprtion inhibitors (Ezetimibe)
- inhibits NPC1L1 transporter at brush border
- reducing absorption of cholesterol by gut by 50%
- hepatic LDL receptor expression increase
- decrease in total cholesterol
pharmacokinetics of `Ezetimibe
Adverse drug response:Cholesterol absorption inhibitors (ezetimibe)
- Abdominal pain
- GI upset
Contratindications: Cholesterol absorption inhibitors (ezetimibe)
hepatic failure
Drug-drug interaction: Cholesterol absorption inhibitors (Ezetimibe)
- Mindful if prescribed with statin- risk of rhabdomyolysis
- Ciclosporin increases ezetimibe in circulation
another form of treatment for hyperlipidaemia
PCSK9 inhibits
- monoclonal antibodies
name a PCSK9 inhibitor
Alirocumab and evolocumab (monoclonal antibodies)
when are PCSK9 indicated
familial hypercholesterolaemia
(esp if had CVS event)
PCSK9 inhibitors mode of action
- LDLR on the liver cell surface binds to LDL and the LDLR–LDL complex is then internalized, after which the LDLR is normally recycled back to the cell surface
- PCSK9 binds to the LDLR on the surface of the hepatocyte, leading to the internalization and degradation of the LDLR in the lysosomes, and reducing the number of LDLRs on the cell surface.
- Inhibition of secreted PCSK9 by PCSK9 inhibitors therefore increases the number of available LDLRs on the cell surface and increase uptake of LDL‐C into the cell.
- lowering LDL in plasma
how is PCSK9 inhibitors e.g. Alirocumab and evolocumab delivered
injected every few weeks- not as easy as pill
- cost x 100 statins
Plant sterol and hypercholesteremia
- provide some LDL cholesterol lowering effects
- E.g. found in special margarines
- Naturally occurring in grains and legumes
- MOAL structurally similar to cholesterol- compete for absorption
- Work with statins but not with ezetimibe
