Hyperlipidaemia

Question 1

describe what HDL particles do

Answer 1

transport excess cholesterol from tissues to liver for elimination

Question 2

describe what LDL particles do

Answer 2

transport cholesterol from liver to muscle and adipose tissue

Question 3

describe what VLDLs do

Answer 3

transport newly synthesised TG from liver to muscle and adipose tissue

Question 4

describe what chylomicrons do

Answer 4

transport lipids from intestines to liver muscle and adipose tissue

Question 5

when do we start treatment for hyperlipidaemia?

Answer 5

• high CVD risk (>15%)
• moderate risk (10-15%): if lifestyle modification is inadequate after 3-6 months

Question 6

common examples of statins?

Answer 6

atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin

Question 7

MoA of statins?

Answer 7

• competitively inhibit HMG-CoA reductase (which is involved in cholesterol synthesis)
• HMG-CoA reductase inhibition –> decreased hepatic cholesterol synthesis –> increased demand for cholesterol –> increased expression of LDL receptors –> increased plasma LDL clearance –> decreased plasma LDL

Question 8

other potential beneficial actions of statins?

Answer 8

• decrease plasma TG
• increase plasma HDL
• improved endothelial function
• reduced vascular inflammation
• reduced platelet agreeability
• increased neovascularisation of ischaemic tissue
• stabilisation of atherosclerotic plaque
• antithrombotic actions
  enhanced fibrinolysis

Question 9

pharmacokinetics of statins?

Answer 9

• metabolism: liver CYP450 enzymes (except pravastatin which is renally cleared)
• excretion: biliary

Question 10

which statins have short half-lives

Answer 10

fluvastatin, pravastatin, simvastatin (1.5-4h)

Question 11

which statin have long half-lives

Answer 11

atorvastatin, rosuvastatin (20-30h)

Question 12

adverse effects of statins?

Answer 12

• common: myalgia, mild GI disturbances, elevated aminotransferase concentrations
• rarely: rhabdomyolysis

Question 13

clinical use of statins?

Answer 13

• hypercholesterolaemia
• high risk of coronary heart disease, with or without hypercholesterolaemia

Question 14

MoA of ezetimibe?

Answer 14

decreases absorption of exogenous cholesterol by blocking transport protein NPC1L1 in small intestine enterocytes –> increased cholesterol demand –> increased LDL receptors expression –> increased plasma LDL clearance –> decreased plasma LDL concentration

Question 15

adverse effects of ezetimibe?

Answer 15

• generally very well tolerated
• headache, abdominal pain, diarrhoea

Question 16

clinical use of ezetimibe?

Answer 16

hypercholesterolaemia (when statins are not well tolerated or can be added to statins)

Question 17

what does bile acids facilitate?

Answer 17

• lipids absorption and regulate cholesterol homeostasis
• primary pathway for cholesterol catabolism

Question 18

where are bile acids synthesised?

Answer 18

synthesised in liver via cholesterol oxidation

Question 19

what mechanism is bile acids recycled through?

Answer 19

enterohepatic recirculation, where about 95% of bile acids are delivered to duodenum and reabsorbed within ileum

Question 20

common example of bile-acid binding resins?

Answer 20

cholestyramine

Question 21

MoA of bile acid binding resins?

Answer 21

bind bile acids in intestinal lumen, preventing reabsorption and increase bile acid excretion in faeces —> decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acids –> increased demand for cholesterol –> increased LDL receptors expression –> increased plasma LDL clearance –> reduced plasma LDL concentration

Question 22

what are some problems with therapy with bile acid binding resins?

Answer 22

• increase plasma TG (avoid use if plasma TG >3mmol/L)
• decreased absorption of fat-soluble vitamins (ADEK)
• decreased absorption of some orally administered drugs (take other medications 1 hour before or 4 hours after the resin)
• low patient adherence levels due to its unpleasant texture

Question 23

adverse effects of bile acid binding resins?

Answer 23

• GI disturbances - constipation, abdominal pain, flatulence, dyspepsia, nausea, vomiting, diarrhoea. anorexia, increase TG

Question 24

clinical use of bile acid binding resins?

Answer 24

combination treatment when stain alone is inadequate

Question 25

common examples of PCSK9 inhibitors?

Answer 25

alirocumab, evolocimab

Question 26

what are PCSK9 inhibitors?

Answer 26

monoclonal antibody

Question 27

what does PCSK9 usually do?

Answer 27

binds to LDL receptors and promotes lysosomal degradation, and decreases hepatic LDL uptake - this leads to an increase in plasma LDL

Question 28

MoA of PCSK9 inhibitors?

Answer 28

bind and inhibits PCSK9 –> increase LDL receptors –> decreased plasma LDL concentration

Question 29

adverse effects of PCSK9