L7 - Hyperlipidaemia Flashcards
Where is cholesterol synthesised
Liver
Sex organs
Adrenal glands
Dietary intake
What is cholesterol used for
Phospholipid membrane integrity
Precursor of steroid hormones
Vitamin D
Bile acids
Effects of high cholesterol
LDLs are susceptible to oxidation at damaged endothelium by ROS
Macrophages can engulf LDLs to form foam cells
Adhere to proteoglycans causing atherosclerosis
Increased risk of MI or stroke if the fibrous cap ruptures
Reduction in cholesterol
10% reduction - 15% reduced risk of CHD mortality and 11% reduced risk of total mortality
For every 1 mmol reduction , there is a 20% reduction reduced risk of CVD
Process of atherosclerosis
- Increased oxidative stress due to toxins, infection or fat
- Increased ROS damages the endothelium
- Platelets aggregate to site
- Macrophages uptake oxidised LDLs forming foam cells
- Foam cell aggregation causing fatty streaks to develop
- Proliferation of smooth muscle to form the fibrous cap which concludes the vessel and may rupture
Statin mechanism of action
- Competitive inhibition of HMG- CoA reductase therefore inhibiting the rate controlling enzyme in cholesterol production
- Upregulation of hepatic LDL receptors
- Increased clearance of circulating LDLs
Examples of statins
Atorvastatin - 1st line Simvastatin Fluvastatin Pravastatin Rosuvastatin Lovastatin
Additional benefits of statins
Antioxidant - decreases superoxide formation
Improves vascular endothelial function by:
- increasing nitric oxide
- increasing vascular endothelial growth factor
- decreasing endothelin ( vasoconstriction)
Stabilises atheromatous plaques by:
- decreasing the proliferation of smooth muscle
- increasing collagen
Decreased haemostasis by
- decreasing plasma fibrinogen
- decreasing platelet aggregation
- increasing fibrinolysis
Anti inflammatory by decreasing proliferation of inflammatory cells into plaque I.e.
- CRP
- cytokines
- adhesion molecules
Simvastatin
Prodrug activated in the liver by CYP 450
Short half life
Atorvastatin
Prodrug activated in the liver by CYP 450
Longer half life
Best efficacy
Lowest number needed to treat
Contraindications and interactions of statins
Contraindications:
- GI disruption
- Nausea
- Headache
- Myalgia - increased creatine phosphokinase
- Rhabdomyolysis
Interactions:
- renal impairment
- pregnancy
- breastfeeding
- CYP 3A4 - do not drink grapefruit juice
- amiodarone - anti-arrythmetic medication
- diltiazem - CCB
- macrolides - stop statin short term whilst on antibiotics
- amlodipine - give higher dose statin
Grapefruit juice effect on CYP 3A4
Inhibits CYP 3A4 which normally metabolises lovastatin
Therefore higher statin dose in plasma
Rosuvastatin
Greatest efficacy
But interacts with diabetes and can cause many side effects
Cerivastatin
Withdrawn as interacting with fibrates and can cause:
- death
- rhabdomyolysis
- renal failure
NICE guidelines with statin use
Primary prevention:
- 10+% QRISK
- low dose atorvastatin once daily
Secondary prevention:
- already had a CVD event e.g. MI
- high dose atorvastatin once daily
- CKD patients - lower dose
Check lipid profile and triglycerides before prescribing
Check LFTs for liver function before prescribing
- aim for more than 40% reduction in non HDLs at three months
- avoid grapefruits
When should atorvastatin and simvastatin be taken
Most cholesterol and LDL receptor synthesis occurs at night via circadian rhythm
- simvastatin has a short half life so should be taken at night
- atorvastatin has a longer half life so can be taken in the morning
Fibric acid derivatives aka fibrates mechanism of action
Activation of nuclear transcription factor - PPAR - alpha within the nucleus
- lowers triglycerides from lipoprotein in plasma
- decreases fatty acid uptake by the liver
- increased HDLs
- increases LDL affinity for the receptor
PPAR alpha
Peroxisome proliferation activated receptor
Regulates gene expression that controls lipoprotein metabolism
Increased lipoprotein lipase production
Fibrate use
Normally co-prescribed with statins when high dose statins are not tolerated
Rarely prescribed by itself
Contraindications and interactions with fibrates
Contraindications:
- choleliathiasis - gall stones
- myositis - inflammation of muscles
Interactions:
- warfarin - increased risk of bleeding
Example of fibrate
Fenofibrate
Cholesterol absorption inhibitors mechanism of action
Prodrug - activated by first pass metabolism by CYP 450 on the liver
Enters the enterohepatic circulation via bile
Inhibit NPC1L1 transporter on brush border of the intestines
Reduces cholesterol absorption from the gut
Increases hepatic LDL receptor expression
- decreases cholesterol by 15% and LDLs by 20%
Significance of enterohepatic circulation of cholesterol absorption inhibitors
Less systemic exposure
Less side effects and good tolerability
Replaced resins and sequestrants
When are cholesterol absorption inhibitors used
Adjunct with statin in familial hypercholesterolemia
No dose escalation with ezetimibe
Secondary prevention
Patients that cannot tolerate high dose statin
- benefits in CKD and secondary CVD prevention
