S3) Lipid and Cholesterol Metabolism Flashcards
Describe the four pro-atherogenic effects of oxidised LDL
- Inhibits macrophage motility
- Induces T-cell activation and VSMC division / differentiation
- Toxic to endothelial cells
- Enhances platelet aggregation
What are the indications for statins?
- CV risk prevention (CVD + DM)
- Familial Hypercholesterolaemia
Describe the three ways in which statins act as a lipid-lowering drug
- Inhibit cholesterol synthesis in hepatocytes
- Increase clearance of IDL and LDL
- Decrease production of VLDL and LDL
→ Inhibit HMG - coA reductase so reduced conc of cholesterol in cell → low intracellular cholesterol stimulates synthesis of LDL receptor → more LDL uptake from blood
What are the possible adverse reactions of statin drug treatment?
- Increased transaminase levels – rapidly reversible, no evidence of chronic liver disease
- Myopathy – seen when higher doses of statins are used in combination with other drugs, rarely rhabdomyolysis
- Miscellaneous – GI complaints, arthralgias, and headaches
Identify four secondary benefits of statin treatment
- Anti-inflammatory
- Plaque reduction
- Improved endothelial cell function
- Reduced thrombotic risk
Describe the structure and function of fibric acid derivatives
- Structure: ampipathic carboxylic acids
- Function:
I. PPARα agonist – increases production of lipoprotein lipase
II. Reduces triglyceride production
what are two common fabric aid derivatives
fenofibrate and gemfibrozil
What are the indications for fibric acid derivatives?
- Adjunctive therapy to diet
- Hypertriglyceridemia
- Combined hyperlipidemia with low HDL (do not respond to NA)
What are the contraindications for fibric acid derivatives?
- Hepatic or renal dysfunction
- Pre-existing gallbladder disease
What are the possible adverse effects of fibric acid derivatives?
- GI upset
- Cholelithiasis
- Myositis
- Abnormal LFTs
Describe the three ways in which nicotinic acid acts as a lipid-lowering drug
- Reduces VLDL and increases HDL at high doses
- Lipid lowering effect by inhibition of lipoprotein synthesis
– inhibits adipose tissue to release fatty acids
- Reduces coronary events
What are the possible adverse effects of nicotinic acid?
- Flushing, itching, headache
- Hepatotoxicity
- Activation of peptic ulcer
- Hyperglycemia and reduced insulin sensitivity
What are the contraindications of nicotinic acid?
- Active liver disease
- Unexplained LFT elevations
- Peptic ulcer disease
Describe the three ways in which ezetimibe acts as a lipid-lowering drug
Ezetimibe selectively inhibits intestinal cholesterol absorption:
- ↓ intestinal delivery of cholesterol to the liver
- ↑ expression of hepatic LDL receptors
- ↓ cholesterol content of atherogenic particles
What are the possible adverse effects of ezetimibe
- Headache
- Abdominal pain
- Diarrhoea
Describe how lipid lowering drugs can be used in combination therapy
Statin plus:
- Fibrate (not gemfibrozil)
- Nicotinic acid
- Ezetimibe
- Omega-3 fatty acids
- Resins
What should one consider when assessing the use combination therapy of lipid lowering drugs
- Benefit (CV risk reduction)
- Cost
- ADRs
In three steps, explain why gemfibrozil is not the fibrate of choice in combination fibrate + statin therapy
⇒ Fibrate + statin therapy may significantly improve triglyceride, LDL-C, and HDL-C levels
⇒ However, fibrates + statins are associated with increased risk for myopathy and rhabdomyolysis
⇒ Gemfibrozil may impair glucuronidation of statins
Complete the table by indicating whether the drug increases/decreases or does not affect the listed lipid parameter
Provide two examples of a lipid-lowering drug
- Simvastatin: prodrug that is activated by first pass metabolism
- Atorvastatin
which factors increase levels of statins in the body
→ CYP3A4 breaks down statin
→ amiodarone, macrolides, grapefruit all inhibit CYP3A4 so reduction in the breakdown of statin
Cholesterol break down
- mainly synthesised in body (25% from diet)
- important for membrane integrity, involved in steroid hormones, bile acids and vitamin D
- LDL susceptible to oxidative reactions → atheroma plaques
- HDL carries cholesterol from blood → tissues (good cholesterol) to liver
- triglycerides transport cholesterol from HDL→VLDL
when can fatty acid streaks start to occur
- at any age
*
how can statins cause an antinflammatory effect
- reduced proliferation of anti-inflammatory cells into plaque, plasma, CRP, adhesion molecules and cytokines
how can statins cause improved plaque conc
increases collagen and increases SMC
how do statins improve vascular endothelial function?
- increase NO and vascular endothelium growth factor (VEGF)
- decrease in endothelin so reduced vasoconstriction
how do statins improve haemostasis
- reduced plasma fibrinogen and platelet aggregation
- increase in fibrinolysis
how do statins act as an antioxidant
reduce superoxide formation
who should you avoid giving statins to?
- people with renal/hepatic impairments
- pregnant/breastfeeding → cholesterol is important in development of a baby
what is a big side effect of statins you should be aware of
rhabdomyolysis:
if they complain of muscle aches and pains in arms check for CK levels
so if this is the case can prescribe them some ezetimibe
Ezetimibe few ADR
prodrug that undergoes hepatic metabolism so undergoes significant enterohepatic circulation so most ADRS are related to the GI tract
statin doses for primary prevention
CVD risk > 10%
20mg atorvastatin
if someone has had a stroke or heart attack how much statin do you prescribe
80mg atorvastatin to prevent another stroke
when is simvastatin taken
- Most cholesterol production occurs during night, So it has a greater effect at reducing levels at night
- It has a short half life, during night there is less interference with elimination and metabolism so might have a longer lasting effect
PCSK9 inhibitors
→ PCSK9 binds to LDL receptors on liver cells, leading to the destruction of the receptors and a reduction in the liver’s ability to clear LDL cholesterol from the bloodstream.
→ inhibitors will increase the number of LDL receptors and so increase elimination of LDL receptors
→ effective in patients already taking statins and very effective in reducing LDL
what are some examples of PCSK9 Inhibitors
‘mab’
→ Alirocumab
→ evolocumab
how does Inclisiran work
SiRNA that reduces the synthesis of PCSK9
what are some common side effects of statins
Asthenia: abnormal physical weakness or lack of energy
Gastrointestinal disturbance and headache are very common, particularly on starting treatment.
Myositis is rare, and reversible but significant a rare group of diseases characterized by inflamed muscles, which can cause prolonged muscle fatigue and weakness
what are some secondary causes of hypercholesterolaemia
