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
