lipid lowering drugs

Question 1

Statins (HMG CoA reductase inhibitors) MOA

Answer 1

e. g. lovastatin (short half life, take at bedtime), atrovastatin (long half life)
- reduce VLDL and LDL level by reducing the synthesis of cholesterol
- increase the synthesis of LDL receptor on liver, thus increase LDL clearance
- reduce triglyceride level slightly
- increase HDL level slightly by reducing LDL level (reduce transfer of cholesterol to LDL)

Question 2

Statin- use

Answer 2

reduce the risk of atherosclerosis in high LDL patients

Question 3

Statin- contraindications

Answer 3

not for nursing pregnant women and children (steroid hormone and growth needed)
not so effective for homozygous familial hypercholesterolemia

Question 4

statin- adverse effects

Answer 4

• hepatotoxicity (monitor the ALT level)
• myopathy (monitor the CK level)- rhabdomyolysis and etc, increase with increased level of concentration in the plasma (old age, renal and liver dysfunction, small body size, and drug interactions)

Drug interactions:

• reduce uptake by the liver by the organic anion transporter (OATP1B1) - gemfibrosil
• reduce liver metabolism of statin by CYP450 and glucuronidase- gemfibrosil, warfarin

Question 5

Niacin (B3)

Answer 5

• reduce the hormone sensitive lipase activity (lipolysis), and thus reduce the fatty acid flux to the liver, reduce triglyceride synthesis and thus the VLDL level
• modestly increase the clearance of VLDL and chylomicrons by enhancing lipoprotein lipase activity
• reduce VLDL leads to reduce in LDL
• increase in HDL level due to reduce clearance of apo A1 by the liver (most effective)

Question 6

Niacin- side effects

Answer 6

• hepatotoxcity
• birth defect, don’t use in pregnancy
• reduce glucose tolerance, cautious in diabetes
• increase uric acid level (cautious in gout)
• flushing (tachyphylaxis in a few days, reverse by aspirin)

Question 7

Niacin- good

Answer 7

• decrease in TAG
• increase in HDL
• can be used in genetic defect people

Question 8

Fibrates- example

Answer 8

e.g. fenofibrate, gemfibrozil

Question 9

Fibrates- MOA

Answer 9

• peroxisome proliferator activated receptor alpha activator
• reduce the level of VLDL by enhancing the function of lipoprotein lipase and fatty acid oxidation in the liver (reduce TAG synthesis)
• may decrease or INCREASE LDL level
• increase in HDL, by promoting the synthesis of ApoAI and II

Question 10

Fibrate- use

Answer 10

• hypertriglyceridemia, but not hyperlipidemia

Question 11

Fibrate- side effects

Answer 11

• myopathy
• increase in liver enzyme
• increase the level of drugs like warfarin, increasing their action
  NOT use for pregnant and children

Question 12

Bile acid sequestrants (resins)- examples

Answer 12

cholestyramine

Question 13

resin- MOA

Answer 13

• increase the bile acid production from cholesterol (excretion in ileum and jejunum) by binding to bile acid to prevent their absorption
• increase the synthesis of LDL receptor to clear them (but partial offset by the increase action of HMG-CoA reductase)

Question 14

Resin- good

Answer 14

• use for 11-20 years old
• good for digoxin toxicity
• pruritus caused by bile acid accumulation and cholestasis

Question 15

Resin- bad

Answer 15

• not for familial hypercholesterolemia
• not for hypertriglyceridemia because decreased activation of farnesoid X receptor by the bile acid will increase liver TAG synthesis
• GI disturbances
• reduce absorption of lipid soluble vitamin (K), warfarin

Question 16

Cholesterol absorption inhibitor- only one

Answer 16

ezetimibe

Question 17

ezetimibe

Answer 17

• reduce the absorption by cholesterol from intestine by prevent them from incorporated into the chylomicrons (by NPC1L1)
• increase synthesis of the LDL receptor (partial offset)

Question 18

ezetimibe drug interaction

Answer 18

increases plasma conc by fibrates, decreases by resins

Question 19

PCSK9 inhibitors

Answer 19

e.g. alirocumab

reduce the degradation of LDL receptor in liver

Question 20

PCSK9 inhibitor- use

Answer 20

secondline treatment for both homo and hetero

Question 21

ATP citrate lyase inhibitor- examples and MOA

Answer 21

e.g. bempedoic acid
ATP citrate lyase is the upstream of HMG-CoA, same as statin
second line for hetero only, is a prodrug

Question 22

ATP citrate lyase- side effects

Answer 22

• hepatotoxicity
• tendon rupture
• hyperuricemia due to inhibition of organic anion transpoter 2

Question 23

ATP citrate lyase inhibitor- contraindications

Answer 23

myopathy when use with statin

Question 24

MTP (microsomal triglyceride transfer protein) inhibitor- MOA

Answer 24

• e.g. lomitapide
  inhibit the transfer of newly synthesised TAG from ER to bind to ApoB
  degradation of Apo B
  reduce release of VLDL and chylomicrons

Question 25

MTP inhibitors- use

Answer 25

• second line for homozygous

Question 26

MTP inhibitor- side effects

Answer 26

• hepatotoxicity

- contraindicated in pregnancy and concomitant intake of CYP3A4 inhibitors

Question 27

Apolipoprotein B synthesis inhibitor

Answer 27

• mipomersen
• binds to the mRNA of ApoB100 to reduce the synthesis ApoB100 thus the release of VLDL
• second line for homo

Question 28

Apolipoprotein B synthesis inhibitor- side effects

Answer 28

• mipomersen hypersensitivity
• liver disease (contraindicated), hepatotoxicity
• injection site reaction