Lipid-Lowering Drugs

Question 1

List 5 classes of drugs used to lower lipid levels, and give examples of each

Answer 1

Statins - atorvastatin, simvastatin
Nicotinic acid - niacin
Fibrates - fenofibrate, gemfibrozil
Bile-acid resins - cholestyramine
Cholesterol absorption inhibitor - ezetimibe

Question 2

What class of drug is ezetimibe?

Answer 2

Cholesterol absorption inhibitor

Question 3

Name 3 fibrates

Answer 3

Fenofibrate
Gemfibrozil
Bezafibrate

Question 4

Briefly describe the mechanism of action of statins

Answer 4

Inhibit HMG-CoA reductase, which catalyses the rate-limiting step of cholesterol synthesis in hepatocytes
Therefore decreases cholesterol synthesis
Reduced level of cholesterol in hepatocytes also increases LDL receptor expression - increased uptake of LDLs from blood

Question 5

Compare the half-lives of simvastatin and atorvastatin

Answer 5

Simvastatin - short half-life. Must be taken at night

Atorvastatin - longer half-life. Can be taken whenever

Question 6

List 3 ADRs of statins

Answer 6

Increased liver enzymes, myopathy, rhabdomyolysis

Question 7

What aspects of statins’ PK gives rise to particular DDIs?

Answer 7

• Some uptake via OATP2 in PCT - therefore reduced action by OATP2 inhibitors
• CYP metabolism - increased/decreased by inhibitors/inducers

Question 8

Why are statins not as efficacious in certain familial hyperlipidaemias?

Answer 8

Some familial hyperlipidaemias relate to lack of LDL receptors - hence expression cannot be increased, and therefore LDL levels will not fall.

Question 9

What is the general mechanism of action of niacin?

Answer 9

Inhibits lipolysis in adipose tissue, therefore reducing fatty acid levels and VLDL production

Question 10

List 4 ADRs associated with niacin, and any measures that can be taken to reduce any of them

Answer 10

Intense cutaneous flushing/warmth/itching - reduced by aspirin
Nausea
Hepatotoxicity
Increased risk of gout

Question 11

What is niacin particularly useful for?

Answer 11

Familial hyperlipidaemias

Question 12

What are fibrates mainly used for?

Answer 12

Increased TAG levels

Question 13

What is the mechanism of action fibrates?

Answer 13

They are peroxisome proliferator-activated receptor agonists - this increases the production of lipoprotein lipase, which hydrolyses TAGs in lipoproteins, hence reducing TAG levels

Question 14

Are fibrates well-tolerated?

List 3 significant ADRs

Answer 14

• Very common (hence not well tolerated) = GI disturbance

- More serious but less common - myosotis, increased risk of gallstones

Question 15

Can fibrates be given with statins? Explain

Answer 15

Yes, except for Gemfibrozil - increases risk of rhabdomyolysis

Question 16

Outline the mechanism of action of cholestyramine

Answer 16

Bile-acid resin - binds negatively-charged bile acids in small intestine - prevents their absorption - excreted in faeces.
In turn, this means that in hepatocytes more cholesterol is converted to bile acids, which in turn are excreted - hence decreases cholesterol concentration in blood.

Question 17

What is unusual about bile acid sequestrants’ PK?

Answer 17

Not absorbed or metabolised - act in gut lumen and then excreted

Question 18

List 1 ADR and 1 DDI of cholestyramine

Answer 18

• GI upset

- Interferes with other drugs’ absorption

Question 19

Name a cholesterol absorption inhibitor

Answer 19

Ezetimibe

Question 20

What is the mechanism of action of Ezetimibe?

Answer 20

Selectively inhibits absorption of dietary/biliary cholesterol in the small intestine - therefore decreases cholesterol levels in liver - therefore increases uptake from blood.

Question 21

What is the treatment algorithm for lipid-lowering drugs?

Answer 21

• First-line is statins
• Then add on one of:
  
  • A fibrate - NOT gemfibrozil
  • Niacin
  • Ezetimibe