S3) Lipid and Cholesterol Metabolism

Question 1

Describe the four pro-atherogenic effects of oxidised LDL

Answer 1

• Inhibits macrophage motility
• Induces T-cell activation and VSMC division / differentiation
• Toxic to endothelial cells
• Enhances platelet aggregation

Question 2

What are the indications for statins?

Answer 2

• CV risk prevention (CVD + DM)
• Familial Hypercholesterolaemia

Question 3

Describe the three ways in which statins act as a lipid-lowering drug

Answer 3

• Inhibit cholesterol synthesis in hepatocytes
• Increase clearance of IDL and LDL
• Decrease production of VLDL and LDL

Question 4

What are the possible adverse reactions of statin drug treatment?

Answer 4

• 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
• Miscellaneous – GI complaints, arthralgias, and headaches

Question 5

Identify four secondary benefits of statin treatment

Answer 5

• Anti-inflammatory
• Plaque reduction
• Improved endothelial cell function
• Reduced thrombotic risk

Question 6

Describe the structure and function of fibric acid derivatives

Answer 6

• Structure: ampipathic carboxylic acids
• Function:

I. PPARα agonist – increases production of lipoprotein lipase

II. Reduces triglyceride production

Question 7

What are the indications for fibric acid derivatives?

Answer 7

• Adjunctive therapy to diet
• Hypertriglyceridemia
• Combined hyperlipidemia with low HDL (do not respond to NA)

Question 8

What are the contraindications for fibric acid derivatives?

Answer 8

• Hepatic or renal dysfunction
• Pre-existing gallbladder disease

Question 9

What are the possible adverse effects of fibric acid derivatives?

Answer 9

• GI upset
• Cholelithiasis
• Myositis
• Abnormal LFTs

Question 10

Describe the three ways in which nicotinic acid acts as a lipid-lowering drug

Answer 10

• Reduces VLDL and increases HDL at high doses
• Lipid lowering effect by inhibition of lipoprotein synthesis
• Reduces coronary events

Question 11

What are the possible adverse effects of nicotinic acid?

Answer 11

• Flushing, itching, headache
• Hepatotoxicity
• Activation of peptic ulcer
• Hyperglycemia and reduced insulin sensitivity

Question 12

What are the contraindications of nicotinic acid?

Answer 12

• Active liver disease
• Unexplained LFT elevations
• Peptic ulcer disease

Question 13

Describe the three ways in which ezetimibe acts as a lipid-lowering drug

Answer 13

Ezetimibe selectively inhibits intestinal cholesterol absorption:

• ↓ intestinal delivery of cholesterol to the liver
• ↑ expression of hepatic LDL receptors
• ↓ cholesterol content of atherogenic particles

Question 14

What are the possible adverse effects of ezetimibe

Answer 14

• Headache
• Abdominal pain
• Diarrhoea

Question 15

Describe how lipid lowering drugs can be used in combination therapy

Answer 15

Statin plus:

• Fibrate (not gemfibrozil)
• Nicotinic acid
• Ezetimibe
• Omega-3 fatty acids
• Resins

Question 16

What should one consider when assessing the use combination therapy of lipid lowering drugs

Answer 16

• Benefit (CV risk reduction)
• Cost
• ADRs

Question 17

In three steps, explain why gemfibrozil is not the fibrate of choice in combination fibrate + statin therapy

Answer 17

⇒ 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

Question 18

Complete the table by indicating whether the drug increases/decreases or does not affect the listed lipid parameter

Answer 18

Question 19

Provide two examples of a lipid-lowering drug

Answer 19

• Simvastatin
• Atorvastatin