Week 8 - Lipid Lowering Drugs Flashcards
Lipids Key Info
- Are hydrophobic molecules (NEED transport to allow them to be soluble)
- Involved in cell structure (cell membrane), storage roles, signalling mediators
- Can be biosynthesised in liver or from diet (food)
2 Types:
- Cholesterol (component in plasma membrane)
- stored + regulated by liver
- fatty acids
- Triglyceride (glycerol + 3 fatty acids)
What is the role of lipoproteins in lipid transport
- Allow lipids to circulate / transport them around body by making them more soluble
- Are macromolecular complexes of lipids + proteins
List the 5 different classes of lipoproteins + their functions
More triglyceride (TG) = less dense the molecule is
- bigger molecules have more TG + smaller have less
- Chylomicrons
- very large + have high TG
- made in guts
- transport fats + cholesterol absorbed from intestine
- chylomicron remnants are formed when lipase removes TG - Very Low Density Lipoproteins (VLDL)
- high TG = less dense
- made in liver
- transport TG + cholesterol from liver to tissues
- IDL and LDL are made from VLDL
- lipoproteins lipase removes TG from VLDL to form above
- lipase breakdowns TG to produce free fatty acids (used in biosynthesis or energy production) - Intermediate Density Lipoprotein (IDL)
- Low Density Lipoproteins (LDL)
- BAD cholesterol
- accumulates at site of endothelial damage = atherosclerosis (narrowed airways)
- small + has low TG = is dense
- excessive LDL = ↑ risk of CVD + atherosclerosis
- is removed by LDL receptors in liver
- LDL receptor is found on membrane surface of cell
- LDL particle binds + endocytosis occurs
- bound LDL moves into cell + dissociates from receptor
- LDL is processed + receptor moves back to membrane - High Density Lipoprotein
- GOOD cholesterol
- very small = has low TG
- transport cholesterol from tissues to liver to be converted into bile salts or excreted (= OPPOSES atherosclerosis)
(clears cholesterol from cells that no longer need it)
- low levels of HDL = dyslipidaemia
Liver removes excess cholesterol + bile salts hydrolyse them
How does hyperlipidiaemia contribute to development of atherosclerosis
Hyperlipidaemia = very high levels of lipoproteins + lipids
what is Inherited Hypercholesterolaemia
- Mutation in genes (e.g. PCSK9) which causes reduced LDL endocytosis
= LDL cholesterol accumulates (as its not removed)
Mutation in PCSK9:
- PCSK9 (a protein) binds to LDL receptor causing degradation of receptor
- takes LDL receptor out of cycle = receptor can’t return to surface membrane of cell
- binds before nedocytossi occurs
- blocking this gene = ↑ LDL receptor expression (as receptor can return to membrane surface)
- If DONT have this mutation = ↓ LDL levels + ↓ CV risk
Aims of Treatment
- ↓ total blood cholesterol (to <5mmol/l)
- ↓ Non-HDL and LDL cholesterol = ↓ CV risk
- ↑ HDL
Diet can improve hyperlipidaemia
- eat stanols at the same time you eat food contains cholesterol
- stanols ↓ absorption of dietary cholesterol
Non-HDL = Total cholesterol - HDL
Explain the mechanism of statins
- Block / inhibit cholesterol biosynthesis
= total cholesterol level ↓ - ↓ LDL levels and HDL levels ↑
- ↑ LDL receptors = ↑ removal of LDL
- 1st LINE
- Statins target HMG-CoA reductase (inhibits enzyme)
- HMG-CoA reductase converts HMG-CoA into mevalonic acid
- mevalonic acid is converted into cholesterol
- inhibitor of enzyme = ↓ cholesterol synthesis - Lower cholesterol by 20-30%
- even a 5% reduction in cholesterol is significant
SIDE EFFECTS:
- AVOID grapefruit juice ~ they inhibit CYP3A enzyme = statin accumulates (esp. simvastatin)
- Avoid in pregnancy
- Muscle pain
Explain the mechanism of PCSK9 inhibitors
↑ expression of LDL receptors on surface of cell membrane
- Inhibition leads to ↑ LDL receptor expression = ↑ LDL clearance from blood
- PCSK9 causes LDLR to not return to membrane surface / receptor is degraded - ONLY used in HIGH RISK patients, who’s hyperlipidaemia is uncontrolled by drugs
Explain the mechanism of ezetimibe
Blocks cholesterol absorption = ↓ total cholesterol level
- Blocks NPC1L1 cholesterol transporter (in enterocytes ~ small intestines)
= micellar cholesterol (dietary cholesterol mixed with bile salts) can’t enter gut
= ↓ distribution of dietary cholesterol as less cholesterol is available to be packed into chylomicrons (which is made in gut)
Can be used alone OR with with statins / dietary changes
SIDE EFFECTS:
- GI disturbance (diarrhoea, abdominal pain)
Explain the mechanism of Resins (bile acid sequestrates)
- Block cholesterol absorption
- ↑ LDL receptor expresion in liver = ↑ LDL removal from blood
- ↑ conversion of cholesterol to bile acids (in liver)
- Prevent absorption of cholesterol so it can be used to create bile acids
- Bile acids emulsify cholesterol (to form micellar cholesterol) in guts
SIDE EFFECTS:
- GI disturbance (diarrhoea, abdominal pain)
- Interfere with vitamin absorption = supplements needed
Explain the mechanism of fibrates
↓ High TG levels
↑ Lipoprotein lipase
↑ LDL receptors
↑ HDL level
↓ LDL production
- 1st LINE (in patients with very HIGH TG levels)
- PPAR alpha agonist
- ↑ Lipoprotein lipase (enzyme) = circulating TG is removed from chylomicron
- chylomicron remnants contain cholesterol are taken into liver + removed (bile salts) = ↓ total cholesterol in blood
Explain the mechanism of nicotinic acid
- ↑ HDL levels
- ↓ VLDL release, ↓ circulating TG and ↓ LDL
- ↓ cholesterol + TG
MoA NOT UNDERSTOOD
- activates nicotine acid receptor = ↓ release of fatty acids = ↓ TG synthesis and ↓ VLDL release by liver
