Lipid lowering drugs

Question 1

What are the classes of lipid lowering drugs

Answer 1

Niacin
Fibrates
Resins
HMG-CoA reductase inhibitors
Ezetimibe

Question 2

What is niacin

Answer 2

Is nicotinic acid/Vit B3

Question 3

Niacin MOA

Answer 3

main action: increase HDL cholesterol levels –> reduce plasma cholesterol

minor:

• inhibit lipolysis in adipose tissue –> decrease plasma TGs in VLDL, decrease plasma cholesterol in VLDL and LDL
• decrease circulating fibrinogen and increase tPA –> reverse thrombosis associated with hypercholesterolemia and atherosclerosis

Question 4

Niacin PK

Answer 4

oral administration

converted in body to nicotinamide

Question 5

Niacin clinical uses

Answer 5

widely used to lower TG, esp type 2b and 4

NOT useful for 2a as niacin does not have direct effect on cholesterol

Question 6

Niacin adverse effects

Answer 6

1. intense cutaneous flush and pruritus

2. hyperuricemia and gout

Question 7

Name 3 fibrates

Answer 7

gemfibrozil, fenofibrate, clofibrate

Question 8

Fibrates MOA

Answer 8

• are ligands for PPAR-a protein (peroxisome proliferators-activated receptor)
• -> interaction increases activity of LPL
• -> increased hydrolysis of TG into FFA for storage or use
• -> decrease plasma TG levels + reduce VLDL (secretion by liver reduced as TGs depleted)
• HDL levels rise moderately

Question 9

Fibrates clinical uses

Answer 9

hypertriglyceridemias with VLDL elevation

- 2b, 3, 4, 5 (esp 3)

Question 10

Fibrates adverse effects

Answer 10

1. GI effects
2. skin rashes
3. gall stones
4. myositis

Question 11

Name 2 bile acid binding resins

Answer 11

colestipol, cholestyramine

Question 12

resins MOA

Answer 12

• bind negatively charged bile acids and bile salts in small intestine
• -> reduce reabsorption of bile acids/salts
• -> reduces bile acid concentration –> hepatocytes increase conversion of cholesterol to bile acid to compensate
• -> reduce intracellular cholesterol concentration
• -> hepatocytes increase expression of LDLR–> increase hepatic uptake of cholesterol containing LDL –> decrease plasma LDL
• may increase VLDL
• little effect on HDL

Question 13

resins clinical uses

Answer 13

1. treatment for 2a

2. treat LDL elevations in 2b when used together with niacin

Question 14

resins adverse effects

Answer 14

1. GI effects

2. impaired absorption of fat soluble vitamins ADEK (absorbed at terminal ileum with bile acid)

Question 15

Name HMG-CoA reductase inhibitors (statins)

Answer 15

atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin

HMG = 3-hydroxy-3-methylglutarate

Question 16

Statins MOA

Answer 16

• HMG CoA reductase is enzyme in rate limiting step in cholesterol synthesis –> statins inhibit cholesterol synthesis
• depletion of intracellular cholesterol –> hepatocytes increase expression of LDLR –> more uptake of LDL from circulation –> decrease plasma LDL

Question 17

Statins PK

Answer 17

oral, given in evening
- HMG CoA reductase activity is highest in evening when there is synthesis of basal amounts of cholesterol (no dietary intake here) –> most effective inhibition at this time

Question 18

Statins clinical uses

Answer 18

for all hyperlipoproteinemias (statins reduce cholesterol levels)

reduces risk of coronary events and mortality in IHD

Question 19

Statins adverse effects

Answer 19

1. Liver: biomedical abnormalities in function (some enzymes get upregulated)
2. Muscle: myopathy, rhabdomyolysis - muscle weakness, tea coloured urine

Question 20

Statins contraindications

Answer 20

pregnancy, nursing mothers, teenagers/children

- cholesterol vital for brain development

Question 21

Ezetimibe MOA

Answer 21

selective inhibitor of cholesterol transport protein NPC1L1 (inhibit dietary uptake)

Question 22

Is ezetimibe effective in absence of dietary cholesterol

Answer 22

Yes - inhibit enterohepatic recycling of cholesterol (recycling of bile salts which are subsequently converted to cholesterol in liver)

Question 23

Ezetimibe PK

Answer 23

oral, readily absorbed

conjugated in intestinal wall to active glucuronide

Question 24

Ezetimibe clinical uses

Answer 24

reduce LDL

• alone: 18% reduction
• Vytorin (ezetimibe + simvastatin) more effective

Question 25

Ezetimibe adverse effects

Answer 25

low incidence of reversible impaired hepatic function (should undergo routine enzyme function test)