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

→ Inhibit HMG - coA reductase so reduced conc of cholesterol in cell → low intracellular cholesterol stimulates synthesis of LDL receptor → more LDL uptake from blood

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, rarely rhabdomyolysis
• 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 two common fabric aid derivatives

Answer 7

fenofibrate and gemfibrozil

Question 8

What are the indications for fibric acid derivatives?

Answer 8

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

Question 9

What are the contraindications for fibric acid derivatives?

Answer 9

• Hepatic or renal dysfunction
• Pre-existing gallbladder disease

Question 10

What are the possible adverse effects of fibric acid derivatives?

Answer 10

• GI upset
• Cholelithiasis
• Myositis
• Abnormal LFTs

Question 11

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

Answer 11

• 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

Question 12

What are the possible adverse effects of nicotinic acid?

Answer 12

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

Question 13

What are the contraindications of nicotinic acid?

Answer 13

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

Question 14

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

Answer 14

Ezetimibe selectively inhibits intestinal cholesterol absorption:

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

Question 15

What are the possible adverse effects of ezetimibe

Answer 15

• Headache
• Abdominal pain
• Diarrhoea

Question 16

Describe how lipid lowering drugs can be used in combination therapy

Answer 16

Statin plus:

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

Question 17

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

Answer 17

• Benefit (CV risk reduction)
• Cost
• ADRs

Question 18

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

Answer 18

⇒ 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 19

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

Answer 19

Question 20

Provide two examples of a lipid-lowering drug

Answer 20

• Simvastatin: prodrug that is activated by first pass metabolism
• Atorvastatin

Question 21

which factors increase levels of statins in the body

Answer 21

→ CYP3A4 breaks down statin

→ amiodarone, macrolides, grapefruit all inhibit CYP3A4 so reduction in the breakdown of statin

Question 22

Cholesterol break down

Answer 22

• 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

Question 23

when can fatty acid streaks start to occur

Answer 23

• at any age
  *

Question 24

how can statins cause an antinflammatory effect

Answer 24

• reduced proliferation of anti-inflammatory cells into plaque, plasma, CRP, adhesion molecules and cytokines

Question 25

how can statins cause improved plaque conc

Answer 25

increases collagen and increases SMC

Question 26

how do statins improve vascular endothelial function?

Answer 26

• increase NO and vascular endothelium growth factor (VEGF)
• decrease in endothelin so reduced vasoconstriction

Question 27

how do statins improve haemostasis

Answer 27

• reduced plasma fibrinogen and platelet aggregation
• increase in fibrinolysis

Question 28

how do statins act as an antioxidant

Answer 28

reduce superoxide formation

Question 29

who should you avoid giving statins to?

Answer 29

• people with renal/hepatic impairments
• pregnant/breastfeeding → cholesterol is important in development of a baby

Question 30

what is a big side effect of statins you should be aware of

Answer 30

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

Question 31

Ezetimibe few ADR

Answer 31

prodrug that undergoes hepatic metabolism so undergoes significant enterohepatic circulation so most ADRS are related to the GI tract

Question 32

statin doses for primary prevention

Answer 32

CVD risk > 10%

20mg atorvastatin

Question 33

if someone has had a stroke or heart attack how much statin do you prescribe

Answer 33

80mg atorvastatin to prevent another stroke

Question 34

when is simvastatin taken

Answer 34

1. Most cholesterol production occurs during night, So it has a greater effect at reducing levels at night
2. It has a short half life, during night there is less interference with elimination and metabolism so might have a longer lasting effect

Question 35

PCSK9 inhibitors

Answer 35

→ 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

Question 36

what are some examples of PCSK9 Inhibitors

Answer 36

‘mab’

→ Alirocumab

→ evolocumab

Question 37

how does Inclisiran work

Answer 37

SiRNA that reduces the synthesis of PCSK9

Question 38

what are some common side effects of statins

Answer 38

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

Question 39

what are some secondary causes of hypercholesterolaemia

Answer 39