A-26. Agents used in dyslipidaemias.

Question 1

Statins (HMG-COA Reductase Inhibitors) drugs 4 important and 2 extra

Answer 1

Important
1.) Lovastatin
2.) Simvastatin
3.) Atorvastatin
4.) Fluvastatin
Extra
Pravastatin and Rosuvastatin

Question 2

MOA of Statins

Answer 2

1. ) Inhibits mevalonate production in all cells by HMG-CoA Reductase decreasing LDL cholesterol (main mode of action)
2. )Stimulates production of LDL-R resulting in increased LDL uptake from blood
3. ) Restores endothelial function, stabilizes atherosclerotic plaques, immunosupression, inhibition of LDL oxidation, increases fibrinolysis, inhibits SM proliferation (mild triglyceride decreas, mild HDL increase)

Question 3

Kinetics of statins

Answer 3

• Orally taken, before bedtime (cholesterol synthesis occurs mostly at night)
• Extensive first pass effect- largest effect is on liver HMG-CoA reductase
• DOA (1-3 hours) with Atorvastatin and Rosuvastatin having longer DOA
• Most metabolized by CYP450 except Pravastatin

Question 4

Side effects of statins

Answer 4

1. ) Elevated liver enzymes
2. ) Rhabdomyolysis and myopathy (statin intolerance)
   - muscle weakness, creatine kinase elevation
   - mostly in combo with other drugs via CYP3A4 or Cyp2C (macrolides+ fibrates like gemfibrozil)
3. )GI effects, insomnia, flushing

Question 5

Statin intolerance management

Answer 5

1. ) Changing statin
2. ) lowering dose
3. ) lowering dose + ezetimibe
4. ) discontinue statin and switching to PCSK9 or ezetimibe

Question 6

Indications of statins

Answer 6

1. ) Post-MI and other ACS cases
2. ) Secondary prevention of CV events in high risk patients (DM, smokers, peripheral artery disease, past stroke/TIA)
3. ) Hypercholesterolemia as first-line agent

Question 7

Contraindication of statins

Answer 7

Pregnancy due to suspected teratogenicity

Question 8

vitamine B3 drugs

Answer 8

Niacin and Nicotinic Acid

Question 9

MOA of Niacin and Nicotinic Acid

Answer 9

Activates lipoprotein lipase and inhibits VLDL secretion from liver
Decreases TAG release from adipocytes
Result is a 50% decrease in chylomicron, VLDL, TAGs (mild LDL decrease) and a 30% increase in HDL

Question 10

Kinetics of Niacin and Nicotinic Acid

Answer 10

Oral administration 2-3x/day, results after 4-6 days

Question 11

Side effects Niacin and Nicotinic Acid

Answer 11

1. ) Flushing- skin vasodilation via PGs; treat with aspirin co-admin (to decrease PGs)
2. ) Dyspepsia- take with meal, contraindicated with peptic ulcer
3. ) Increased urate- Contraindicated in gout
4. ) Teratogenic- Contraindicated in pregnancy
5. ) Insulin resistance- Contraindicated in Diabetes Mellitus
6. ) Elevated liver enzyme- Contraindicated in hepatic dysfunction; can cause severe hepatoxicity

Question 12

Bile Acid-Binding Resins

Answer 12

Cholestyramine and Colestipol

Question 13

MOA of Cholestyramine and Colestipol

Answer 13

Interrupt enterohepatic bile circulation by binding bile acids in GI tract increase fecal bile excretion. This leads to the endogenous cholesterol to be synthesized into bile acids in the liver dropping the cholesterol level.
The LDL-Receptor number increase number and turnover; (HMG-CoA reductase activity increases but overall cholesterol decreases)
*Older drugs not used that often anymore

Question 14

GI side effects of Cholestyramine and Colestipol

Answer 14

GI upset- bloating, nausea, constipation, diarrhea/steatorrhea, fat soluble vitamin deficiencies
-Contraindicated in diverticulosis; caution with warfarin due to decreased Vit K absorption via decreased bile

Question 15

Other side effects of Cholestyramine and Colestipol

Answer 15

1. ) Increased hepatic VLDL/TAG production due to liver compensation with more bile acid synthesis leading to more VLDL and TAGs made (contraindicated in hypertriglyceridemia)
2. ) Bile stones because more cholesterol levels in biliary tract leads to more stone formation
3. ) Decreased absorption of other durgs
   - digoxin, thiazides, warfarin, aspirin, and statins (give 4 hours apart)

Question 16

Cholestyramine and Colestipol Indication

Answer 16

Primary hypercholesterolemia- with isolated LDL increase; at max dose of 20% LDL reduction
-safe for use in children as well

Question 17

Cholestyramine and Colestipol Kinetics

Answer 17

Take during meal orally

Question 18

Ezetimibe MOA

Answer 18

Inhibits NPC1L1 which decreases cholesterol absorption from GI tract

Question 19

Ezetimibe Kinetics

Answer 19

Good oral absorption, serum concentration increases by fibrates and decreases by bile-binding resins

Question 20

Ezetimibe Side Effects

Answer 20

Hepatotoxic in combo with statins (Increases LFT enzymes)

• Like resins, it causes increase HMG-Coa reductase activity and increased LDL-R synthesis/LDL uptake
• rarely, diarhea

Question 21

Fibrate drugs

Answer 21

gemfibrozil and fenofibrate

Question 22

MOA of gemfibrozil and fenofibrate

Answer 22

Agonist of PPAR-alpha which stimulates LPL activity, thus increased hydrolysis and decreased (35-50%) serum levels of VLDL/chylomicron TAGs (modest LDL decrease as well)
-Modest HDL elevation (via lipoprotein A1/A2 synthesis in the liver)

Question 23

Gemfibrozil and fenofibrate indications

Answer 23

Hypertriglyceridemia

Acute Pancreatitis associated with TAGs greater than 1000 mg/dl

Question 24

Side effects of fibrates

Answer 24

1. ) Myopathy/rhabdomyolysis- especially gemfibrozil in combo with statins
2. ) Myoglobinuria can result in acute renal failure
3. ) Cholesterol gallstones due to increased cholesterol content in the the bile, better for patients with previous cholecystectomy

Question 25

Kinetics of gemfibrozil and fenofibrate

Answer 25

Good oral absorption

Question 26

How do PCSK9 inhibitors work

Answer 26

hepatic protease PCSK0 which typically breaks down LDL receptors leads to increased LDL-Rs

Question 27

What is the name of the mAb against PCSK9

Answer 27

evolocamab