Antidyslipidaemics: Statins & Fibrates Flashcards
What are the two intermediates between acetyl coenzyme A and cholesterol?
Describe how cholesterol is obtained, and how it is transported
It’s either endogenously synthesised, or taken in via the diet. It’s transported by 5 lipoproteins: HDL, LDL, IDL, VLDL, chylomicrons
What are the functions of each HDL and LDL
HDL: Carries peripheral cholesterol back to the liver
LDL: carries cholesterol from the liver to the peripheries
What are the two ways body cells can obtain cholesterol?
and how is cellular cholesterol regulated?
- Synthesise their own (de novo)
- Remove (trap) it from the extracellular space (via cell-surface LDL receptors that bind to the apoB proteins)
It can be regulated by adjusting/targetting:
- Cholesterol de novo synthesis
- number of LDL receptors (can increase response to cellular cholesterol demand ie. transcription)
How is cholesterol uptaken into cells
LDL uptake by cells is by receptor mediated endocytosis.
apolipoprotein B100 binds to LDL receptors. It promotes LDL internalisation into endocytic vesicles and fusion of the vesicles with lysosomes.
LDL-receptors (LDL-R) are recylced back to the cell surface.
The Lipoprotein particle is then hydrolysed into amino acids and free cholesterol.
When sufficient LDL has been take up the number of LDL receptors expressed decreaes when LDL is uptaken by the cell, and HMG CoA reductase also decreases.
What three regulatory effects does cholesterol have on the cell?
Intracellular choelsterol has three regulatory effects on the cell
- decreases activity of HmG CoA reductase
- Activates ACAT(acetylCoA:cholesterolacyltransferase), to esterify free cholesterol into cholesteryl ester than can be stored in the cell.
- Inhibits the transcription of the gene encoding the LDL receptor, and, thereby, decreases further uptake of cholesterol by the cell.
How does high LDL result in atherosclerosis?
LDL can be oxidised by macrophages in the intimal layer to become foam cells.
What does elevated LDL cause?
A much higher risk of atherosclerosis. Since there’s more LDL, more LDL can get oxidised to produce more foam cells - this results in more cell matrix degredation and cell proliferation (smooth muscle).
What is high cholesterol associated with?
- High LDL
- More oxidised LDL
- Loss of Apo B receptors
Deficiency of Apo B receptors causes familial hypercholesterolaemia - causes high LDL, and thus high cholesterol
What are the 3 classes of endogenous CE attenuators we need to know?
- Statins
- Fibrates
- Nicrotinic acid, niacin, omega-3
What is the exogenous CE uptake inhibitor we can use?
Ezetemibe - it’s a cholesterol uptake inhibitor
Why are statins described as pleiotropic drugs?
Pleiotropic drugs are drugs which have actions other than what it was designed to do.
Statins are pleiotropic drugs because of their effect on HMG-CoA. Mevalonic acid, which is produced by HMG-CoA reductase reaction, is the precursor not only for cholesterol but also other nonsteroidal isoprenoid compounds.
Inhibition of HMG-CoA reductase may result in pleiotropic effects, independent of their hypocholesterolemic properties.
What is the MOA of statins?
Statins are reversible, competitive HMGCoA inhibitors - this stops the cholesterol synthesis pathway.
- Statins mainly decrease hepatic de novo cholesterol synthesis.
- Also causes increased LDL receptor synthesis
- This results in increases LDL clearance, causing a decreased plasma LDL cholesterol and TGs.
- Slightly increases plasma HDL-cholesterol
What are the pleiotropic effects of statins?
Statins are shown to reduce inflammatory process. Statins exert anti-inflammatory effects by preventing binding of transcription factor for NFκB to DNA target.
They also activate peroxisome proliferator-activated receptors (PPARα & PPARγ)
- inhibits uptake of LDL by macrophage to reduce c-reactive protein release by 15 - 47%
- Increases endogenous NO release to produce systemic vasodilation
- Many other effects associated with this pleiotropic drug class
What are the PK for Atorvastatin (Statin)
- Active statin metabolits eliminated in bile after extensive 1st pass hepatic metabolism and CYP3A4.
- T1⁄2: atorvastatin ~14h but metabolites ~25h half life.
- Hepatic impairment increases atorvastatin retention, renal impariment has no major impact
What is the MOA of Ezetimibe?
Ezetimibe impairs dietary and bilary choleterol absorption at the brush broder of the intestines.
- Reduced hepatic cholesterol results in LDL receptor upregulation.
What is the MOA of fibrates (PPARα activators)
e.g. Bezafibrate
MOA: Increases FA oxidation in muscle and liver and lipogenesis in the liver
- Effective at reducing VLDL & TG (10% LDL)
- Increases HDL level
- Fibrates bind to and activate peroxisome proliferatoractivated receptor alpha (PPAR), nuclear receptor expressed in hepatocytes, skeletal muscle, macrophages, and the heart.
- Activates peroxisome proliferator response elements (PPREs) in the promoter regions of specific genes producing specific protein translation
- Fibrates also lower LDL levels modestly by a PPARα- shift in hepatocyte metabolism toward FA- oxidation.
