Hyperlipidaemias Flashcards
What is atherosclerosis?
build up of plaque in arteries = thickening or hardening of arteries
What are the stages of atherosclerosis?
- LDLs travel through endothelial barrier lumen
- LDL oxidised
- macrophages attracted to oxidied LDL, also enter artery wall
- macrophage phagocytose oxidised LDL = foam cell
- foam cells expand
- undergo death, release lipid content = recruitment of inflammatory cytokines
- growth factors released = smooth muscle proliferation = ⬆ collagen synthesis = hardening of plaque - plaque-> narrowing of artery
- plaque can rupture -> thrombosis = risk of clots
what is foam cell filled with?
lipids
whats plaque in wall (atherosclerosis) made of? 5
dead foam cells foam cells immune cells collagen smooth muscle cells
What is the structure of lipoproteins?
lipid core of trigl + cholesterol esters
coat containing apoproteins - mediate binding of lipoproteins with tissues in body using receptors on those tissues
what about a lipoprotein affects which tissue and receptor it will bind to?
coat containing apoproteins- type affects..
name some lipproteins
chylomicrons
VLDL
LDL
HDL
transport pathways of lipoproteins?
exogenous
endogenous
Which lipid pathway involves lipids in the diet?
exogenous
What are lipids (TGs and cholesterol esters) emulsified by in the GIT?
bile acids
lipids are emsulsified in the GIT.. what are absorbed into?
chylomicrons
Explain how a foam cell is formed?
- LDL travels through endothelial barrier -> lining of artery
- LDL oxidised
- macrophages attracted and enter lining
- macrophages phagocytose oxidised LDL forming a foam cell
What do foam cells do after they are formed?
- continue to expand
- undergo death
- release lipid content and recruit inflammatory cytokines
- release growth factors
- smooth muscle proliferates
- increased collagen synthesis
- plaque hardens
What is the consequence of plaque rupturing?
thrombosis
Describe the exogenous lipid pathway
involves lipid in the diet
emulsified by bile acids in the GIT
lipids absorbed into chylomicons
triglycerides hydrolysed by lipoportein lipase, produces free fatty acids = absorbed and stored in fat and muscle tissues
chylomicron remnants - taken up by hepatocytes = store of cholesterol
Describe the endogenous lipid pathway
liver
makes C and TG from exogenous pathway
lipids excreted into VLDL
TGS hydrolysed by same enzyme, fatty acids produced and stored in tissues
LDLS now contain mainly cholesterol esters
extrahepatic
cholesterol from cell turnover absorbed into HDL
cholesterol esters transferred to LDL and VLDL
increased HDL promotes LDL removal
What are TGs hydrolysed by to produce free fatty acids?
lipoprotein lipase
Where are free fatty acids absorbed and stored?
fat and muscle tissues
What are chylomicrons an excess of?
TG
what are chylomicron REMNANTS an excess of and how do they appear in liver?
CE (cholesterol)
yellow!
What are chylomicrons taken up in order to contribute to the store in the liver?
hepatocytes
Endogenous pathway:
2 sites
liver
extrahepatic (reverse cholesterol transport)
liver makes cholesterol (C) and TG + C from what pathway?
exogenous
What is Acetyl co enzyme A converted to in the liver?
what enz is involved?
ACoA —- > MVA (Mevalonate)
HMG CoA reductase
After mevalonate is formed what gets secreted into VLDLs?
lipids (both TG and cholesterol esters CE)
In the endogenous pathway VLDLs travel through muscle and fat tissue and bind to receptors on the wall of muscle and fat tissue. What are they hydrolysed to?
free fatty acids
What do LDLs mostly contain at the end of the endogenous pathway in the liver?
cholesterol esters
The extra hepatic pathway is called the reverse cholesteral transport. What is absorbed into HDL from cell turnover?
cholesterol
and from developing plaques
HDLs contain cholesterol esters in the extra hepatic pathway but do not travel. What happens to them instead?
transferred to VLDLs and LDLs via CETP, change in apoprotein = more likely to be taken up by hepatocytes due to ⬆ levels of HDLs
Give 3 uses of LDLs in the body?
membranes, steroids and bile acids
What is dyslipidaemia? and how fixed?
high LDL (i.e. cholesterol) - drugs given
low HDL - exercise, less alcohol
Drugs used for prevention even if lipids are normal should only be used if what are present?
other risk factors
What is hyperlipidaemia usually an increase of?
lipoproteins
What are the types of hyperlipidaemia?
primary (genetic)
risk of atherosclerosis
secondary
metabolic disorders
diabetes, hyperthyroidism, renal disease, alcoholism
Primary hyperlipidaemia is genetic, how many phenotypes are there?
6, differ in lipoprotein class affected
How can increased LDLs increase the risk of atherosclerosis and thrombosis?
LDL contains apoprotein similar to plasminogen, competes for receptors so less plasmin therefore thombus can form (inc thrombosis)
List 3 things that can cause secondary hyperlipidaemia?
diabetes, hyperthyroidism and alcoholism
HMC CoA reductase inhibitors/ statins such as atorvastatin, simvastatin and pravastatin can be used to….
reduce high cholesterol levels
describe statins
prodrugs
potent competitive inhibitors of HMG CoA reductase
What statins work to decrease the synthesis of?
cholesterol
Why is the synthesis of cholesterol in the hepatocytes not reduced as much as we would like?
- statins competitively inhibit HMG CoA reductase
- ⬇ cholesterol
- ⬆ transcription for genes that encodes HMG CoA enzyme and LDL receptor
- ⬆ cholesterol synthesis and LDL receptor expression on hepatocytes
What do the increased LDL receptors on hepatocytes bind to in the blood which has been shown to be clinical benefit of statins?
circulating LDL particles in blood
= reduces LDL blood cholesterol levels
Why are statins contraindicated in pregnancy?
lipids are necessary for proper fetal development
..decreased synthesis of cholesterol affects fetal development
What statin would be used for
- high intensity
- low intensity
- atorvastatin
- pravastatin
side effects of statins?
myositis
hepatitis
rhabomyolysis
another word for hmg reductase inhibitor?
statin
How does PCSK9 increase circulating LDLs?
binds to LDL-R and promotes its degredation
What does a PCSK9 inhibitor do? work?
Increase the number of LDL receptors available increase uptake into hepatocytes to decrease plasma LDL
example of PCSK9 inhibitor?
evolocumab (monoclonal antibody)
What type of drug would be used for increased TGs? give examples
Fibrates
bezafibrate, gemfibrozil
How do fibrates work?
decrease TGs
activate nuclear receptors = ⬆transcription
activation of lipoprotein lipase = ⬇VLDL production = less TGs (VLDL) = more liver uptake of LDL via more receptors for apoproteins = more HDL
What types of lipids can increase with fibrates?
HDLs
one adverse effect of fibrates ?
myositis esp w xs alcohol; care with statins
fibrates uses?
increased TGs esp type IIb
- statin 1st choice!
Why are resins lost along with bile acids and cholesterol?
too big
What can be reabsorbed/used via enterohepatic circulation?
bile acids
bile acids essential for ?
cholesterol absorption and reabsorbed via enterohepatic recirculation
How do bile acid-binding resins work?
lose cholesterol and bile acids = more synthesis of bile acids = less liver cholesterol as stores used up = more LDL receptors..
or:
Lower LDL by interrupting enterohepatic circulation of bile acids which stimulates conversation of cholesterol into bile acids
which type of lipid increases with bile acid binding resins?
TGs
List some cons of bile acid binding resins?
resins unpleasant, GI side effects and cause vitamin deficiency
not first line… combine w statin
How does ezetimibe work?
inhibits intestinal absorption of cholesterol by blocking receptor uptake (transport protein NPC1L1)
Can ezetimibe be used with statins?
not first line on its own but yes
Ezetimibe has a higher potency than resins (dose 10mg) but has no effect on the absorption of what?
fat soluble vitamins
Describe use of ezetimibe.
inhibits intestinal absorption of cholesterol
blocks receptor uptake
no evidence of decreased atherosclerosis
more specific action in gut
How do nicotinic acids work?
decreased synthesis of TGs = less VLDLs = less LDL = more HDL
Why can nicotinic acid cause pruritis?
releases prostaglandins
Name two other common side effects of nicotinic acid?
common intense flush and jaundice
Why might fish oil be good for patients after MI?
alpha tricglycerides improve survival
Whats the mechanism of fish oil?
decreases clotting by inhibiting platelet aggregation and prolonging of clot formation
Why is fish oil not suitable for type 2 hyperlipidaemia?
cholesterol levels increase
What effect might fish oil have on platelets and clotting?
inhibit aggregation and reduce clotting
What is the first line drug class for primary prevention hyperlipidaemia ( and for all diabetics over 40)?
statins
What are two other drugs/ drug classes that statins can be combined with?
PCSK9 inhibitors and ezetimibe
For the secondary prevention of hyperlipidaemia, statins are first line. What may be added to the regimen and used in combination with statins?
fibrate or bile acid resin or nicotinic acid
care w fibrate+ statin
secondary prevention drug to be used on its own, w/out statin?
nicotinic acid
What is the first line drug class used in the treatment of hyperlipidaemia?
statins
drugs for hyperlipidaemia MoA?
inc chol- statin + ezetimibe/ PCSK9 inhibitor
or
in TG- statin? + fibrate (myositis!)
