Lipid-Lowering Drugs Flashcards
List 5 classes of drugs used to lower lipid levels, and give examples of each
Statins - atorvastatin, simvastatin Nicotinic acid - niacin Fibrates - fenofibrate, gemfibrozil Bile-acid resins - cholestyramine Cholesterol absorption inhibitor - ezetimibe
What class of drug is ezetimibe?
Cholesterol absorption inhibitor
Name 3 fibrates
Fenofibrate
Gemfibrozil
Bezafibrate
Briefly describe the mechanism of action of statins
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
Compare the half-lives of simvastatin and atorvastatin
Simvastatin - short half-life. Must be taken at night
Atorvastatin - longer half-life. Can be taken whenever
List 3 ADRs of statins
Increased liver enzymes, myopathy, rhabdomyolysis
What aspects of statins’ PK gives rise to particular DDIs?
- Some uptake via OATP2 in PCT - therefore reduced action by OATP2 inhibitors
- CYP metabolism - increased/decreased by inhibitors/inducers
Why are statins not as efficacious in certain familial hyperlipidaemias?
Some familial hyperlipidaemias relate to lack of LDL receptors - hence expression cannot be increased, and therefore LDL levels will not fall.
What is the general mechanism of action of niacin?
Inhibits lipolysis in adipose tissue, therefore reducing fatty acid levels and VLDL production
List 4 ADRs associated with niacin, and any measures that can be taken to reduce any of them
Intense cutaneous flushing/warmth/itching - reduced by aspirin
Nausea
Hepatotoxicity
Increased risk of gout
What is niacin particularly useful for?
Familial hyperlipidaemias
What are fibrates mainly used for?
Increased TAG levels
What is the mechanism of action fibrates?
They are peroxisome proliferator-activated receptor agonists - this increases the production of lipoprotein lipase, which hydrolyses TAGs in lipoproteins, hence reducing TAG levels
Are fibrates well-tolerated?
List 3 significant ADRs
- Very common (hence not well tolerated) = GI disturbance
- More serious but less common - myosotis, increased risk of gallstones
Can fibrates be given with statins? Explain
Yes, except for Gemfibrozil - increases risk of rhabdomyolysis
Outline the mechanism of action of cholestyramine
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.
What is unusual about bile acid sequestrants’ PK?
Not absorbed or metabolised - act in gut lumen and then excreted
List 1 ADR and 1 DDI of cholestyramine
- GI upset
- Interferes with other drugs’ absorption
Name a cholesterol absorption inhibitor
Ezetimibe
What is the mechanism of action of Ezetimibe?
Selectively inhibits absorption of dietary/biliary cholesterol in the small intestine - therefore decreases cholesterol levels in liver - therefore increases uptake from blood.
What is the treatment algorithm for lipid-lowering drugs?
- First-line is statins
- Then add on one of:
- A fibrate - NOT gemfibrozil
- Niacin
- Ezetimibe
