Hypolipidemic Drugs

Question 1

What are 5 major categories of hypolipidemic drugs?

Answer 1

HMG-CoA reductase inhibitors (statins)
Bile-acid-binding resins
Cholesterol absorption inhibitor (Ezetimibe)
Nicotinic acid
Fibrates

Question 2

Give a brief description/overview of lipid transport and metabolism of cholesterol

Answer 2

• Cholesterol from liver excreted as VLDL
• TGs removed from VLDL by LPL
• Leaves remnants taken up by liver or processed to LDL
• LDL taken back up into liver or into peripheral tissues by binding to LDL-R
• Reverse cholesterol transport: take cholesterol out of tissue via ABCA1 to HDL
• HDL can then deliver cholesterol to liver or to steroidogenic tissues using scavenger receptor (SR-B1)
• Liver uses cholesterol to form bile acids and also secretes unchanged cholesterol into bile

Question 3

What are the features of familial hypertriglyceridemia?

Answer 3

Decreased LPL

Increased VLDL secretion

Question 4

What are the features of familial combined hyperlipidemia?

Answer 4

Increased VLDL secretion

Increased VLDL and LDL levels

Question 5

What are the features of remnant removal disease?

Answer 5

Increased VLDL secretion

Decreased remnant lipoprotein removal (mutant ApoE2)

Question 6

What are the features of familial or polygenic hypercholesterolemia?

Answer 6

Decreased LDL-receptor activity

Due to mutated/dysfunctional LDL-R, ApoB, etc

Question 7

What are the features of familial hypoalphalipoprioteinemia?

Answer 7

Decreased ApoA-1

Decreased HDL

Question 8

What is the primary lipoprotein effect of HMG Co-A reductase inhibitors (statins)?

Answer 8

Decrease LDL

Question 9

What is the primary lipoprotein effect of Bile acid binding resins?

Answer 9

Decrease LDL (but less than statins)

Question 10

What is the primary lipoprotein effect of Ezetimibe?

Answer 10

Decrease LDL

Question 11

What is the primary lipoprotein effect of nicotinic acid (niacin)?

Answer 11

Increase HDL

Question 12

What is the primary lipoprotein effect of fibrates?

Answer 12

Decrease triglycerides

Question 13

What is the mechanism of action of statins?

Answer 13

Inhibit HMG-CoA reductase, preventing the rate limiting step in the formation of cholesterol

Fall in the level of cholesterol causes an upregulation of LDL receptors in the membrane, which will lower plasma levels of LDL

Question 14

In addition to inhibiting HMG-CoA reductase, what are other effects that statins have?

Answer 14

Decreases isoprenylation of proteins - can prevent membrane trafficking of proteins
Decreases ubiquinone - can effect mitochondrial respiratory enzymes, need to supplement with CoQ10

Question 15

What drugs are in the category of statins?

Answer 15

Lovastatin (prototype)
Simvastatin
Pravastatin
Atovastatin
Rosuvastatin

Question 16

How are statins metabolized and why is it important?

Answer 16

Metabolized by CYP450 enzymes in liver

Can cause interactions with other drugs that inhibit or induce CYP450 enzymes

Question 17

What are adverse effects of statins?

Answer 17

Hepatitis
Muscle pain, myositis, rhabdomyolysis
Increased risk of new onset diabetes
Contraindicated in pregnancy
Increased risk of peripheral neuropathy

Question 18

What happens when statins and bile-acid-binding resins are used together?

Answer 18

Statin upregulates LDL-R expression, will lower LDL in plasma

A resin will absorb bile acids in gut, preventing recycling of bile acids, causing further upregulation of LDL receptor expression and further lowering of LDL in plasma

Question 19

What is the mechanism of action of bile-acid-reducing resins?

Answer 19

FXR (receptor that is sensor for bile acids) regulates expression of FGF
FGF is inhibitor of enzyme (Cyp7a1) that makes bile acid from cholesterol

When you consume bile acid binding resins, have less bile acids going into cell
FXR detects lower levels of bile acids, causing reduced transcription of FGF
Reduced FGF causes reduced inhibition of Cyp7a1 enzyme
More cholesterol used to make bile acids and excreted (since cannot be taken back up)

Question 20

What are adverse effects of resins?

Answer 20

GI distress
Adsorb anionic vitamins & drugs
Can increase plasma TGs in hypertriglyceridemia

Question 21

What is the mechanism of action of Ezeimibe?

Answer 21

Blocks intestinal uptake of cholesterol and plant sterols by the NPC1L1 receptor

Question 22

In what genetic condition is Ezetimibe very useful?

Answer 22

Sitosterolemia (plant sterol hyperabsorption)

Sitosterolemia is caused by mutations in the ATP-binding cassette transporters (ABCG5, ABCG8) that normally release plant sterols back into lumen. Elevated plant sterols causes similar detrimental effects as high LDL.

Ezetimibe blocks uptake of plant sterols and will lower levels

Question 23

What is the mechanism of action of niacin?

Answer 23

Binds niacin receptor on fat cells that inhibits lipolysis –> decreased FFA –> decreased TG synthesis –> decreased VLDL

Also decreases breakdown of ApoA1 –> increased HDL

Question 24

What is a major adverse effect of niacin?

Answer 24

Prostaglandin flush response - cutaneous vasodilation and burning sensation on face and upper body

Question 25

What is the mechanism by which niacin causes prostaglandin flush?

Answer 25

Beta arrestin signaling pathway causes production of prostaglandins (vasodilation)

Question 26

What two drugs are in the category of fibrates?

Answer 26

Gemfibrozil

Fenofibrate

Question 27

What is the mechanism of action of Fibrates?

Answer 27

Acts on PPAR-alpha - nuclear transcription factor that is a sensor for fatty acids

PPAR increases lipoprotein lipase (LPL) expression and downregulates expression of ApoCIII –> increased lipolysis

PPAR also decreases triglyceride synthesis and increases HDL

Question 28

What is the mechanism of action of PCSK9-targeted monoclonal antibodies?

Answer 28

Block interaction between PCSK9 and LDL-R

LDL-R is then recycled and able to decrease plasma LDL