Hyperlipidaemias Flashcards
(46 cards)
1
Q
How does cholesterol enter the body?
A
- Most synthesised in body
- ~25% contributed by diet
2
Q
Why is cholesterol essential in the body?
A
- Membrane integrity
- Precursor in production of steroid hormones
- Bile acids
- Vitamin D
3
Q
Why is LDL considered to be bad cholesterol?
A
- Susceptible to oxidation at damaged endothelium
- ROS contributes to endothelial dysfunction
- Increases adherence of lipid rich deposits
- Foam cells formed (precursor to atheromatous plaques)
4
Q
Which type of cholesterol is considered good?
A
- HDL
- Carries cholesterol away from circulation
- To tissues that require it
- To liver for disposal in bile
5
Q
What blood tests can be done to assess CHD?
A
- Total blood cholesterol
- Now non-HDL cholesterol is a more reliable measure
6
Q
Why is cholesterol targeted to reduce CVD risk?
A
- Modifiable risk factor, like BP (other than genetic predisposition)
- Data shows relationship between elevated cholesterol and morbidity and mortality from CHD
- Reducing cholesterol by 10% affords ~15% reduction in 10 year CHD mortality and ~11% reduction in total mortality
7
Q
How do we determine how aggressively to treat high cholesterol?
A
- Take total CVD risk into account
- Patient’s willingness to take medication and modify lifestyle
- Familial forms of hypercholesterolaemia have specific/focused targets
8
Q
Outline CVD risk
A
- Additive
- Multifactorial
9
Q
How does high cholesterol affect blood vessels?
A
- Causes fatty streaks
- First develop in adults aged 20-29
10
Q
What is the mechanism of action of statins?
A
- Competitive inhibition of HMG-CoA reductase
- Leads to decreased concentration of cholesterol within cells
- Stimulates synthesis of LDL receptors
- Increased number of LDL receptors promotes uptake of LDL from blood
- Low intracellular cholesterol decreases secretion of VLDL
11
Q
What are the additional benefits of statin therapy?
A
- Improved vascular endothelial function
- Stabilisation of atherosclerotic plaque
- Improved haemostasis
- Anti-inflammatory
- Antioxidant
12
Q
How does statin therapy improve vascular endothelial function?
A
- Increased NO
- Increased vascular endothelial growth factor
- Decreased endothelin
13
Q
How does statin therapy improve stabilisation of atherosclerotic plaques?
A
- Decreased smooth muscle cell proliferation
- Increased collagen
14
Q
How does statin therapy improve haemostasis?
A
- Decreased plasma fibrinogen
- Decreased platelet aggregation
- Increased fibrinolysis
15
Q
How does statin therapy act as an anti-inflammatory?
A
- Decreased proliferation of inflammatory cells into plaque
- Decreased plasma CRP
- Decreased adhesion molecules and cytokines
16
Q
How does statin therapy act as an antioxidant?
A
- Decreased superoxide formation
17
Q
Name some kinds of statin
A
- Simvastatin
- Atorvastatin
18
Q
What prescribing considerations need to be made with statins?
A
- Simvastatin is a prodrug activated by first pass metabolism - half life is 2h
- Atorvastatin - active derivatives obtained by first pass metabolism - half life is 24h
19
Q
What are the adverse effects of statins?
A
- GI disruption
- Nausea
- Headache
- Myalgia (dose related)
- Rarely - rhabdomyolysis
- Increased liver enzymes
20
Q
What are the contraindications for statins?
A
- Renal or hepatic impairment
- Pregnancy (cholesterol important for foetal development)
- Breastfeeding
21
Q
What are the DDIs of statins?
A
- Anything that is also metabolised by CYP 3A4
- Raises plasma statin concentration
- Because other compounds are metabolised by CYP 3A4 instead of statins
- E.g. amiodarone, diltiazem, macrolides, amlodipine, grapefruit juice
- May be appropriate to withhold statin short-term whilst taking other agents
22
Q
How do we decide which statins to use?
A
- Dose dependant reduction in LDL-cholesterol for all
- Cost and side effect severity has driven prescribing choices
- Atorvastatin and simvastatin are relatively cheap and easily accessible
23
Q
What is the recommended dose for primary prevention of CVD?
A
- 20 mg atorvastatin once daily
- Given to patients with 10 year risk of CVD greater tan 10%
- Incorporate individual patient and risk/benefit discussions
24
Q
What is the recommended dose for secondary prevention of CVD?
A
- 80 mg atorvastatin once daily
25
What other steps need to be taken before prescribing statins?
- Full lipid profile
- Includes HDL and non-HDL and triglycerides
26
What is the target when prescribing statins?
- Broadly >40% reduction in non-HDL cholesterol at 3 months
27
Why is simvastatin taken at night?
- Has a relatively short half life
- LDL receptor synthesis and activity are much greater at night
- Drug is most effective at night when plenty of receptors are active
28
What nocebo effect is associated with taking statins?
- Muscle pain
- Big challenge to adherence
- Leads patients to decrease or stop use of statins
- Makes patients reluctant to even begin taking statins as they are aware of the potential side effects
29
What is the mechanism of action of fibrates?
- Activate PPARa
- Nuclear transcription factor that regulates expression of genes controlling lipoprotein metabolism
- Increase production of lipoprotein lipase
- Increases triglyceride removal from lipoproteins in plasma
- Increase fatty acid uptake by liver
- Increase levels of HDL
- Increase LDL affinity for receptor
30
How are fibrates prescribed?
- Co-prescribed with statins
- In mixed hyperlipidaemias
31
What are the adverse side effects of fibrates?
- GI upset
- Myositis
- Gall stones
32
What are the contraindications of fibrates?
- Photosensitivity
- Gall bladder disease
33
What are the DDIs of fibrates?
- Warfarin
- Causes increased anticoagulation
34
Give an example of a fibrate
- Fenofibrate
35
What is the mechanism of action of cholesterol absorption inhibitors?
- Inhibit NPC1l1 transporter at brush border in small intestines
- Reduces absorption of cholesterol by gut
- Hepatic LDL receptor expression increases
- Decreases total cholesterol by ~15%
- Decreases LDL cholesterol by ~20%
36
How are cholesterol absorption inhibitors metabolised by the body?
- Pro-drug
- Hepatic metabolism
- Enter enterohepatic circulation for recycling
- Limits systemic exposure
- Secreted by bile
37
How are cholesterol absorption inhibitors prescribed?
- Adjunct to statins
- Beneficial in CKD and for secondary CVD prevention
- Cannot escalate dose of ezetimibe
- Useful in patients who can only tolerate a low dose of statins
38
What are the adverse side effects of cholesterol absorption inhibitors?
- Abdominal pain
- GI upset
- Angioedema
39
What are the contraindications of cholesterol absorption inhibitors?
- Hepatic failure
40
What are the DDIs of cholesterol absorption inhibitors?
- Need to be mindful if prescribed with a statin
- Theoretical increased risk of rhabdomyolysis
41
In which patients might we consider adding fibrates or nicotinic acids alongside statins?
- Patients with familial hypercholesterolaemia
- Not given to patients for primary/secondary prevention of CVD
42
What is the mechanism of action of monoclonal antibodies designed to treat high cholesterol?
- Inhibits PCSK9
- PCSK9 signals that LDL receptors should be internalised for degradation
- Inhibition increases uptake of LDL cholesterol into cells
43
Why are monoclonal antibodies not commonly prescribed?
- Very expensive
- Long term effects yet to be determined
- Requires lifelong injections every 3-6 months
44
Give some examples of monoclonal antibodies that treat high cholesterol?
- Alirocumab
- Evolocumab
45
What is the mechanism of action of inclisiran?
- Inhibits hepatic translation of PCSK9
- Very newly available to some in primary care e.g. patients with genetic causes of hypercholesterolaemia
46
What non-medicinal options can help lower cholesterol?
- Plant sterols (occur naturally in grains, legumes etc)
- Fish oils/oily fish
- Fibre, whole grains
- Vitamin C and E
