Session 5 Hyperlipidaemias Flashcards
Why is cholesterol important?
Essential for membrane integrity
It is a precursor in production fo steroid hormones, bile acids and vitamin D
Cholesterol is a modifiable risk factor for CVD. Describe the relationship between cholesterol and morbidity/mortality from coronary heart disease
For every 1 mmol/L total cholesterol reduction, what happens to CVD risk?
Relationship between elevated cholesterol and CHD mortality and morbidity
Reduction in total cholesterol of 10% affords 15% reduction in CHF mortality and 11% in total mortality
LDL cholesterol lowering is the target for CVD prevention
For every 1 mmol/L reduction of total cholesterol there is around 20% decrease of CVD risk
Statins
Drug names?
Atorvastatin
Simvastatin
Statins
MoA
Competitive inhibition of HMG-CoA reductive (which is a rate controlling enzyme in mevalonate pathway)
Leads to up-regulation of hepatic LDL receptors
Increased clearance of circulating LDL
Other than increased clearance of circulating LDL’s, what are the additional benefits of Statins?
- improved vascular endothelial function
(Increase NO and decrease endothelin) - stabilisation of atherosclerotic plaque
(Decrease smooth muscle cell proliferation and increase collagen) - improved haemostasis
( decrease plasma fibrinogen and platelet aggregation but increase fibrinolysis) - anti-inflammatory
( decrease proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines - all decrease!) - antioxidant
(Decrease superoxide formation)
Prescribing considerations for
Simvastatin
Atorvastatin
Half life?
Simvastatin = prodrug that is activated by first pass metabolism PLUS short half life (2 hours) Atorvastatin = first pass metabolism active derivatives PLUS long half life (over 30 hours)
Warnings/side effects of statins
GI disruption
Nausea and headache
Myalgia (normally dose related)
Rhabdomyolysis (rare)
Contraindications - Statins
Renal impairment
Pregnancy and breastfeeding
CYP 34A important
Primary prevention (10 year CV risk of >10%)? Secondary prevention?
20 mg atorvastatin once daily
80 mg atorvastatin once daily
Need to do a full lipid profile before prescribing!
- avoid grapefruit juice
- take at night
What do fabric acid derivatives do?
Name?
They activate a nuclear transcription factor = PPAR alpha which regulates the expression of genes that control lipoprotein metabolism so increase the production of lipoprotein lipase
Name = fenofibrate
What is the effect of increased production of lipoprotein lipase have?
Increased triglycerides from lipoprotein in plasma
Increased fatty acid uptake by the liver
Increased levels of HDL
Increased LDL affinity for receptor
Side effects of fibrates?
Contradictions?
Side effects = cholelithiasis (gall stones) and myositis (inflammation of muscles)
Contradictions = warfarin
What do cholesterol absorption inhibitors do / how do they act?
Inhibit NPC1L1 transporter
Reduces absorption of cholesterol by the gut by around 50%
Hepatic LDL receptor expression increases
Decrease in total cholesterol by about 15%
Decrease in LDL cholesterol by about 20%
Name of a cholesterol absorption inhibitor?
Ezetimibe
Metabolism of cholesterol absorption inhibitors? E.g. ezetimibe
Pro-drug
Hepatic metabolism —> enterohepatic circulation
Limits systemic exposure
Sequestered by bile so good tolerability and replaced most resins and sequestrants
Side effects and contradictions of cholesterol absorption inhibitors?
Side effects
- abdominal pain
- GI upset
Contradictions
* hepatic failure
How do PCSK9 inhibitors work?
PCSK9 is a protein that binds internalised LDL-R, directing it for degradation
So PCSK9 inhibitors significantly reduce LDL cholesterol
Name of PCSK9 inhibitors?
Alirocumab
Evolocumab
Why might it be appropriate to prescribe statin an ezetimibe (cholesterol absorption inhibitor) together?
There is no dose escalation with ezetimibe
Combination with statin has a benefit in CKD and secondary CVD prevention
Good to combine these two in people that can only tolerate a low dose of statin
What are the non-pharmaceutical methods of trying to reduce cholesterol?
Diet!
- plant sterols provide LDL cholesterol lowering effects
- plant sterols are naturally occurring in grains, legumes etc
- plant sterols have a similar structure to cholesterol so compete with it for absorption
Good things to include in diet
- fish oils and oily fish
- fibre and whole grains
- vitamin C and vitamin E
Alcohol = increases HDL cholesterol BUT also increases triglycerides
What is the cost-effectiveness of treating high cholesterol?
Numbers needed to treat are relatively small
Economic considerations significant in decision to lower 10 year CVD risk to >10%
Cost increases as baseline risk of patient falls
