Hyperlipidaemias

Question 1

What is atherosclerosis?

Answer 1

build up of plaque in arteries = thickening or hardening of arteries

Question 2

What are the stages of atherosclerosis?

Answer 2

1. LDLs travel through endothelial barrier lumen
2. LDL oxidised
3. macrophages attracted to oxidied LDL, also enter artery wall
4. macrophage phagocytose oxidised LDL = foam cell
5. foam cells expand
   - undergo death, release lipid content = recruitment of inflammatory cytokines
   - growth factors released = smooth muscle proliferation = ⬆ collagen synthesis = hardening of plaque
6. plaque-> narrowing of artery
7. plaque can rupture -> thrombosis = risk of clots

Question 3

what is foam cell filled with?

Answer 3

lipids

Question 4

whats plaque in wall (atherosclerosis) made of? 5

Answer 4

dead foam cells
foam cells
immune cells
collagen
smooth muscle cells

Question 5

What is the structure of lipoproteins?

Answer 5

lipid core of trigl + cholesterol esters

coat containing apoproteins - mediate binding of lipoproteins with tissues in body using receptors on those tissues

Question 6

what about a lipoprotein affects which tissue and receptor it will bind to?

Answer 6

coat containing apoproteins- type affects..

Question 7

name some lipproteins

Answer 7

chylomicrons
VLDL
LDL
HDL

Question 8

transport pathways of lipoproteins?

Answer 8

exogenous

endogenous

Question 9

Which lipid pathway involves lipids in the diet?

Answer 9

exogenous

Question 10

What are lipids (TGs and cholesterol esters) emulsified by in the GIT?

Answer 10

bile acids

Question 11

lipids are emsulsified in the GIT.. what are absorbed into?

Answer 11

chylomicrons

Question 12

Explain how a foam cell is formed?

Answer 12

• LDL travels through endothelial barrier -> lining of artery
• LDL oxidised
• macrophages attracted and enter lining
• macrophages phagocytose oxidised LDL forming a foam cell

Question 13

What do foam cells do after they are formed?

Answer 13

• continue to expand
• undergo death
• release lipid content and recruit inflammatory cytokines
• release growth factors
• smooth muscle proliferates
• increased collagen synthesis
• plaque hardens

Question 14

What is the consequence of plaque rupturing?

Answer 14

thrombosis

Question 15

Describe the exogenous lipid pathway

Answer 15

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

Question 16

Describe the endogenous lipid pathway

Answer 16

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

Question 17

What are TGs hydrolysed by to produce free fatty acids?

Answer 17

lipoprotein lipase

Question 18

Where are free fatty acids absorbed and stored?

Answer 18

fat and muscle tissues

Question 19

What are chylomicrons an excess of?

Answer 19

TG

Question 20

what are chylomicron REMNANTS an excess of and how do they appear in liver?

Answer 20

CE (cholesterol)

yellow!

Question 21

What are chylomicrons taken up in order to contribute to the store in the liver?

Answer 21

hepatocytes

Question 22

Endogenous pathway:

2 sites

Answer 22

liver

extrahepatic (reverse cholesterol transport)

Question 23

liver makes cholesterol (C) and TG + C from what pathway?

Answer 23

exogenous

Question 24

What is Acetyl co enzyme A converted to in the liver?

what enz is involved?

Answer 24

ACoA —- > MVA (Mevalonate)

HMG CoA reductase

Question 25

After mevalonate is formed what gets secreted into VLDLs?

Answer 25

lipids (both TG and cholesterol esters CE)

Question 26

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?

Answer 26

free fatty acids

Question 27

What do LDLs mostly contain at the end of the endogenous pathway in the liver?

Answer 27

cholesterol esters

Question 28

The extra hepatic pathway is called the reverse cholesteral transport. What is absorbed into HDL from cell turnover?

Answer 28

cholesterol | and from developing plaques

Question 29

HDLs contain cholesterol esters in the extra hepatic pathway but do not travel. What happens to them instead?

Answer 29

transferred to VLDLs and LDLs via CETP, change in apoprotein = more likely to be taken up by hepatocytes due to ⬆ levels of HDLs

Question 30

Give 3 uses of LDLs in the body?

Answer 30

membranes, steroids and bile acids

Question 31

What is dyslipidaemia? and how fixed?

Answer 31

high LDL (i.e. cholesterol) - drugs given low HDL - exercise, less alcohol

Question 32

Drugs used for prevention even if lipids are normal should only be used if what are present?

Answer 32

other risk factors

Question 33

What is hyperlipidaemia usually an increase of?

Answer 33

lipoproteins

Question 34

What are the types of hyperlipidaemia?

Answer 34

primary (genetic) risk of atherosclerosis secondary metabolic disorders diabetes, hyperthyroidism, renal disease, alcoholism

Question 35

Primary hyperlipidaemia is genetic, how many phenotypes are there?

Answer 35

6, differ in lipoprotein class affected

Question 36

How can increased LDLs increase the risk of atherosclerosis and thrombosis?

Answer 36

LDL contains apoprotein similar to plasminogen, competes for receptors so less plasmin therefore thombus can form (inc thrombosis)

Question 37

List 3 things that can cause secondary hyperlipidaemia?

Answer 37

diabetes, hyperthyroidism and alcoholism

Question 38

HMC CoA reductase inhibitors/ statins such as atorvastatin, simvastatin and pravastatin can be used to....

Answer 38

reduce high cholesterol levels

Question 39

describe statins

Answer 39

prodrugs | potent competitive inhibitors of HMG CoA reductase

Question 40

What statins work to decrease the synthesis of?

Answer 40

cholesterol

Question 41

Why is the synthesis of cholesterol in the hepatocytes not reduced as much as we would like?

Answer 41

- 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

Question 42

What do the increased LDL receptors on hepatocytes bind to in the blood which has been shown to be clinical benefit of statins?

Answer 42

circulating LDL particles in blood | = reduces LDL blood cholesterol levels

Question 43

Why are statins contraindicated in pregnancy?

Answer 43

lipids are necessary for proper fetal development | ..decreased synthesis of cholesterol affects fetal development

Question 44

What statin would be used for - high intensity - low intensity

Answer 44

- atorvastatin | - pravastatin

Question 45

side effects of statins?

Answer 45

myositis hepatitis rhabomyolysis

Question 46

another word for hmg reductase inhibitor?

Answer 46

statin

Question 47

How does PCSK9 increase circulating LDLs?

Answer 47

binds to LDL-R and promotes its degredation

Question 48

What does a PCSK9 inhibitor do? work?

Answer 48

Increase the number of LDL receptors available increase uptake into hepatocytes to decrease plasma LDL

Question 49

example of PCSK9 inhibitor?

Answer 49

evolocumab (monoclonal antibody)

Question 50

What type of drug would be used for increased TGs? give examples

Answer 50

Fibrates | bezafibrate, gemfibrozil

Question 51

How do fibrates work?

Answer 51

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

Question 52

What types of lipids can increase with fibrates?

Answer 52

HDLs

Question 53

one adverse effect of fibrates ?

Answer 53

myositis esp w xs alcohol; care with statins

Question 54

fibrates uses?

Answer 54

increased TGs esp type IIb | - statin 1st choice!

Question 55

Why are resins lost along with bile acids and cholesterol?

Answer 55

too big

Question 56

What can be reabsorbed/used via enterohepatic circulation?

Answer 56

bile acids

Question 57

bile acids essential for ?

Answer 57

cholesterol absorption and reabsorbed via enterohepatic recirculation

Question 58

How do bile acid-binding resins work?

Answer 58

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

Question 59

which type of lipid increases with bile acid binding resins?

Answer 59

TGs

Question 60

List some cons of bile acid binding resins?

Answer 60

resins unpleasant, GI side effects and cause vitamin deficiency not first line... combine w statin

Question 61

How does ezetimibe work?

Answer 61

inhibits intestinal absorption of cholesterol by blocking receptor uptake (transport protein NPC1L1)

Question 62

Can ezetimibe be used with statins?

Answer 62

not first line on its own but yes

Question 63

Ezetimibe has a higher potency than resins (dose 10mg) but has no effect on the absorption of what?

Answer 63

fat soluble vitamins

Question 64

Describe use of ezetimibe.

Answer 64

inhibits intestinal absorption of cholesterol blocks receptor uptake no evidence of decreased atherosclerosis more specific action in gut

Question 65

How do nicotinic acids work?

Answer 65

decreased synthesis of TGs = less VLDLs = less LDL = more HDL

Question 66

Why can nicotinic acid cause pruritis?

Answer 66

releases prostaglandins

Question 67

Name two other common side effects of nicotinic acid?

Answer 67

common intense flush and jaundice

Question 68

Why might fish oil be good for patients after MI?

Answer 68

alpha tricglycerides improve survival

Question 69

Whats the mechanism of fish oil?

Answer 69

decreases clotting by inhibiting platelet aggregation and prolonging of clot formation

Question 70

Why is fish oil not suitable for type 2 hyperlipidaemia?

Answer 70

cholesterol levels increase

Question 71

What effect might fish oil have on platelets and clotting?

Answer 71

inhibit aggregation and reduce clotting

Question 72

What is the first line drug class for primary prevention hyperlipidaemia ( and for all diabetics over 40)?

Answer 72

statins

Question 73

What are two other drugs/ drug classes that statins can be combined with?

Answer 73

PCSK9 inhibitors and ezetimibe

Question 74

For the secondary prevention of hyperlipidaemia, statins are first line. What may be added to the regimen and used in combination with statins?

Answer 74

fibrate or bile acid resin or nicotinic acid care w fibrate+ statin

Question 75

secondary prevention drug to be used on its own, w/out statin?

Answer 75

nicotinic acid

Question 76

What is the first line drug class used in the treatment of hyperlipidaemia?

Answer 76

statins

Question 77

drugs for hyperlipidaemia MoA?

Answer 77

inc chol- statin + ezetimibe/ PCSK9 inhibitor or in TG- statin? + fibrate (myositis!)