Lipid-lowering Drugs (details) Flashcards
HMG-CoA reductase inhibitors, PCSK9 inhibitors, fibrates, omega-3-acid ethyl esters, bile acid binding resins, inhibitors of intestinal sterol absorption
What is the MOA of HMG-CoA reductase inhibitors?
1) Inhibition of HMG-CoA reductase, which is involved in the rate-limiting step of cholesterol synthesis
2) Up-regulates LDL receptors on the cell surface
- depletion of intracellular cholesterol in the liver causes the cell to increase the number of specific cell-surface LDL receptors that can bind and internalise circulation LDLs.
What are the clinical uses of HMG-CoA reductases inhibitors?
1) Lower plasma cholesterol levels
2) Reduce the risk of coronary events and mortality in patients with ischemic heart disease
What are the PK properties of HMG-CoA reductase inhibitors?
- Oral administration
- first-pass extraction (hepatic)
- given in the evening
What are the adverse effects of HMG-CoA reductase inhibitors?
1) Liver: biomedical abnormalities in liver function
2) Muscle: myopathy and rhabdomyolysis
3) Tea coloured urine due to the breakdown of muscles
What are the contraindications of HMG-CoA reductase inhibitors?
- Pregnancy
- Nursing mothers
- Children or teenagers: affects neurodevelopment of fetuses and children
What is the MOA of PCSK9 inhibitors?
1) Targets LDL for degradation in lysosomes
2) Reduced LDL receptor degradation: more cell-surface LDL receptors that can bind to and internalise circulation LDLs
What are the clinical uses of PCSK9 inhibitors?
1) Lowers plasma cholesterol levels in familial hypercholesterolemias, especially those intolerant to statins
2) Indicated in patients with clinically significant atherosclerotic CVD requiring additional plasma cholesterol lowering after being on diet control and maximally tolerated stain therapy
What are the PK/PD features of PCSK9 inhibitors?
1) They are monoclonal antibodies and thus require administration via injection (either IV or SC)
2) When combined with statins, plasma cholesterol levels are lowered 50-60% above that achieved by statin therapy alone
What are the adverse effects of PCSK9 inhibitors?
1) Injection site inflammatory reactions (erythema, itchiness,swelling, pain or tenderness)
2) Increased incidence of nasopharyngitis and sinusitis
What are the contraindications of PCSK9 inhibitors
Patients who develop hypersensitivity reactions (eg: hypersensitivity vasculitis or serious allergies requiring hospitalisation)
What is the MOA of fibrates?
Used when TG levels are very high
Interacts with PPAR alpha protein –> increased activity of lipoprotein lipase –> decrease in plasma TG levels –> VLDL levels decrease, HDL levels increase moderately
What is the clinical use of fibrates?
Treatment of hypertriglyceridemias with VLDL elevation, especially for dysbetalipoproteinemia
If you have type IIa or IIb dyslipidemia (IIa = high LDL, IIb = high LDL, high VLDL), then don’t use fibrates
What are the adverse effects of fibrates?
1) GIT effects: nausea
2) skin rashes
3) gall-stones
4) myositis
but when in doubt, just write nausea or GI upset :)
What are the MOAs of omega-3-acid ethyl esters?
1) reduces hepatic TG production and increases TG clearance from VLDL
2) functional inhibition of diglyceride acyltransferase (responsible for TG biosynthesis) as EPA and DHA are poor substrates for the enzyme
3) increase free fatty acid breakdown via beta-oxidation
What are the clinical uses of omega-3-acid ethyl esters?
1) used in conjunction with dietary measured for hypertriglyceridemia monotherapy
2) used for for familial combined hyperlipidemia (high LDL and VLDL) in combination with statins when control of TG is insufficient
NOT indicated for hyperchylomicronemia
