Drugs Used In The Treatment Of Hyperlipidemia

Front 1

List some modifiable and non-modifiable risk factors for CHD.

Back 1

MODIFIABLE
-cigarette smoking
-HTN
-Low HDL
-obesity

NON-MODIFIABLE
-age
-family history

Front 2

How do you diagnose metabolic syndrome?

(hint: criteria)

Back 2

Patient with 3 of the following 5 risk factors has metabolic syndrome:

(1) HTN (>130/85)

(2) low HDL (<40 mg/dl for men; <50 mg/dl for women)

(3) obesity

(4) hyperglycemia

(5) elevated TG's

Front 3

Prior to starting a patient on a lipid-lowering drug, what do you need to rule out?

Back 3

Need to rule out secondary causes of hyperlipidemia

-type II diabetes
-hypothydroidism
-chronic renal failure
-current medications

Front 4

What is the primary therapy of hyperlipoproteinemia?

Back 4

THERAPEUTIC LIFESTYLE CORRECTION (TLC)

Patient needs good dietary control and an excerice regimen - this is the cornerstone of correcting primary hyperlipidemias!

Front 5

List the 3 bile acid sequestrants.

How do they lower plasma cholesterol content?

Back 5

(1) cholestyramine
(2) colestipol
(3) colesevelam

These bind bile acids in the intestines, forming insoluble complexes that are excreted in the feces. The bile acids, as a result, are not being recycled, so more hepatic cholesterol continues to be broken down into bile acids to normalize bile acid levels. This bile acid depletion and subsequent decrease in steady state levels of cholesterol leads to increased levels of HMG CoA reductase and the up-regulation of LDL receptors. This conversion of cholesterol into bile acids lowers plasma cholesterol concentrations

Front 6

Cholestyramine leads to..

(a) inhibition of HMG CoA reductase
(b) significantly decreased TG's
(c) increased absorption of warfarin
(d) increased bile acid excretion

Back 6

Cholestyramine (a bile acid sequestrant) leads to...

(d) increased bile acid excretion

Bile acid sequestrants do not inhibit HMG CoA reductase - they increase the levels.

They can cause increased TG levels.

They decrease absorption of warfarin and digoxin.

Front 7

What are the adverse effects of bile acid sequestrants?

Which of the 3 sequestrants causes less of these side effects?

Back 7

(1) bloating, gas
(2) constipation

Colesevelam - because it is not a resin - is less likely to cause these effects.

Front 8

Describe the drug interactions associated with bile acid sequestrants

Back 8

Bile acid sequestrants impair the absorption of
--warfarin
--digoxin
--vitamins A, D, E, K

Front 9

Cholestyramine (and other drugs in its class) is contraindicated in patients with elevated levels of (blank).

Back 9

Cholestyramine (and other drugs in its class) is contraindicated in patients with elevated levels of TRIGLYCERIDES (>400mg/dl).

Front 10

List the 6 HMG-CoA Reductase Inhibitors.

How do they lower plasma cholesterol?

Back 10

(1) atorvastatin
(2) fluvastatin
(3) lovastatin
(4) pravastatin
(5) rosuvastatin
(6) simvastatin

These drugs are competitive inhibitors of HMG CoA reductase. They decrease liver cholesterol synthesis, which leads to an up-regulation of LDL receptors, which leads to increased plasma LDL clearance.

Front 11

TRUE or FALSE

Statins are equally efficacious.

Back 11

FALSE

Statins are NOT equally efficacious.

The starting dose of one statin may be half of the starting dose of another statin, yet produce a much larger decrease in LDL levels.

Front 12

What is the most efficacious class of drugs for lowering LDL-C?

Back 12

HMG CoA reductase inhibitors (statins)

Front 13

How does doubling the dose of statin affect LDL-C?

How does adding a bile acid sequestrant to a statin affect LDL-C?

Back 13

Doubling statin dose: leads to 5-7% further reduction in LDL-C. (Remember, the largest decrease in LDL-C occurs at the starting dose for each statin).

Adding bile acid sequestrant: 10-20% additional reduction in LDL cholesterol (and HDL increase of 0-9%)

Front 14

Your patient is on a CYP3A4 inhibitor.. Why is this important in your consideration of prescribing a statin?

Back 14

Lovastatin and simvastatin are metabolized by CYP3A4. An inhibitor of this CYP (like what your patient is currently taking) would lead to increased levels of these statins and an increased risk of myopathy.

Other options that present less of a risk of this drug interaction include fluvastatin, pravastatin and rosuvastatin. Fluvastatin is mainly metabolized by CYP2C9; Pravastatin and rosuvastatin are not signifacntly metabolized by the P450 system.

Front 15

What are the adverse effects of HMG CoA reductase inhibitors?

Back 15

(1) dose-related increase in myopathy
(2) elevation of liver enzymes

Front 16

What are the contraindications associated with statins?

Back 16

(1) active or chronic liver disease
(2) pregnancy
(3) breast feeding

Front 17

The risk of myopathy is increased in patients taking statins with the concomitant use of these three drugs:

Back 17

(1) gemfibrozil (fibrate)
(2) nicotinic acid
(3) CYP3A4 inhibitor (esp in case of lovastatin and simvastatin)

Front 18

Name the cholesterol absorption blocker discussed in class.

How does it lower plasma cholesterol?

Back 18

Ezetimibe

It inhibits intestinal NPC1L1, thus inhibiting uptake of cholesterol across the enterocyte brush border. This causes a reduction of cholesterol absorption and leads to a decrease in the delivery of intestinal cholesterol to the liver. Hepatic cholesterol levels fall and LDL receptors are upregulated which leads to increased LDL clearance from the blood.

Front 19

What is the location of action for the following:

(1) ezetimibe
(2) cholestyramine
(3) atorvastatin

Back 19

(1) ezetimibe: brush border of small intestine as inhibitor of NPC1L1

(2) cholestryamine: enterohepatic circulation by binding to bile acids

(3) atorvastatin: in liver by inhibiting HMG CoA reductase

Front 20

TRUE or FALSE

In regards to lowering LDL levels, ezetimibe is more efficacious than sequestrants.

Back 20

FALSE

Ezetimibe is less efficacious at lowering LDL levels compared to sequestrants.

Statins are more efficacious than both these groups.

Front 21

List the 3 major uses of ezetimibe.

Back 21

(1) primary hypercholesterolemia - used alone or in combination

(2) homozygous familial hypercholesterolemia - used in combination w/ a statin

(3) homozygous sitosterolemia - adjunct to diet; only medicine approved for this condition

Front 22

Name the rare genetic disorder for which ezetimibe is the only approved treatment.

Patients with this disorder have elevated levels of (blank) and (blank).

Back 22

Ezetimibe is the only medicine approved for treating homozygous sitosterolemia. It is used as adjunctive therapy to diet.

Patients have elevated levels of sitosterol and campesterol.

Front 23

List the adverse effects of ezetimibe.

Back 23

(1) diarrhea
(2) depression

Front 24

How do fibrates affect the pharmacokinetics of ezetimibe?

How does cholestyramine affect the pharmacokinetics of ezetimibe?

Back 24

Fibrates increase the bioavailability and AUC of ezetimibe.

Cholestyramine decreases the absorption of ezetimibe.

Front 25

Ezetimibe is contraindicated in patients with:

(a) gout
(b) high triglycerides
(c) liver disease
(d) hypersensitivity

Back 25

Ezetimibe is contraindicated in patients with:

(c) liver disease


(a) gout: nicotinic acid
(b) high TG's: sequestrants
(d) hypersensitivity: omega-3 PUFA

Front 26

TRUE or FALSE

Older patients usually have to take higher doses of ezetimibe because their plasma concentrations are usually 2-fold lower than those of younger patients.

Back 26

FALSE

Ezetimibe plasma concentrations in older patients are usually 2-fold HIGHER than those of younger patients. Thus, precaution needs to be taken when prescribing ezetimibe to patients 65yrs+

Front 27

Describe the two effects of nicotinic acid (low dose vs. high dose).

How does nicotinamide compare at these doses?

Back 27

Nicotiniamide is equivalent to nicotinic acid as a vitamin. Nicotinic acid is an important vitamin because it is the precursor for NAD+ and NADP+. The daily required dose of nicotinic acid is about 20mg/day.


Nicotinamide, however, does NOT show the same pharmacological effects as nicotinic acid when the latter is given at doses of 500-2000 mg/day. At these doses, nicotinic acid lowers LDL and TG's.

Front 28

Describe how niacin lowers TG and LDL levels.

Back 28

GPR109A is a nicotinic acid receptor and is abundantly expressed in fat cells. Administration of niacin leads to activation of GPR109A, which leads to the inhibition of adenylyl cyclase, decreased cAMP, and decreased lipolysis of TAG's present in fat droplets.

Lower FFA levels (due to dec lipolysis) creates a substrate shortage for hepatic TG synthesis. Less TG production means less VLDL is made and, as a result, LDL levels decrease.

Front 29

How does niacin affect Lp(a)?

Why is this important?

Back 29

Niacin decreases Lp(a) levels, which have been suggested to be an independent risk factor for coronary heart disease.

Front 30

Niacin is the most efficacious drug at producing which of the following lipoprotein effects:

(a) decreased LDL
(b) increased HDL
(c) decreased TG
(d) decreased LP(a)
(e) both a and b
(f) both a and c
(g) both b and c
(h) both b and d

Back 30

Niacin is the most efficacious drug at producing which of the following lipoprotein effects:

(h) both b and d


Niacin is the most efficacious drug for increasing HDL and decreasing LP(a).

Niacin is more effective at lowering TG levels compared to statins, but, overall, PUFA is the most efficacious in lowering TG.

Front 31

List the adverse effects of niacin.

Back 31

(1) flushing
(2) increase insulin resistance
(3) hyperuricemia
(4) hepatotoxicity
(5) headache
(6) heartburn, indigestion
(7) nausea, diarrhea

Front 32

Describe flushing as an adverse reaction to niacin.

How could a patient minimize flushing?

Back 32

Niacin - at both low and high doses - can cause flushing of the face and upper body.

The flushing occurs within 1h and can last 30-90min.

Starting with a low dose of niacin and gradually increasing it is one way to build tolerance to flushing. Another option is to take aspirin 30min before taking niacin.

Front 33

Niacin is contraindicated in patients with these conditions (list them):

Back 33

(1) active liver disease
(2) active peptic ulcer
(3) gouty arthritis
(4) relative contraindication in those with diabetes

Front 34

TRUE or FALSE

OTC nicotinic acid SR is associated with hepatotoxicity while prescription nicotinic acid ER is not associated with it (or less so).

Back 34

TRUE

Front 35

Describe the pathogenesis of niacin-induced flushing.

Back 35

The same nicotinic acid receptor found in fat cells is also found in Langerhans cells. When these receptors are stimulated, the arachidonic acid cascade is induced, leading to PG formation and subsequent vasodilation.

Front 36

Describe the mechanism of action of fibrates.

Back 36

(1) Fibrates activate PPAR-alpha
(2) PPAR-alpha binds to RXR
(3) change in gene transcription occurs

Fibrates inhibit fatty acid synthesis and increase fatty acid oxidation in liver and muscle which reduces FFA availability for TG synthesis. Less TG means less VLDL in the circulation.

Fenofibrate decreases Apo CIII which leads to increased lipoprotein lipase levels. This leads to increased lipolysis and clearance of TG-rich lipoproteins.

Fenofibrate increases LDL clearance and reduces small LDL particles.

Fenofibrate increases Apo AI and AII which are the major proteins of HDL.

The many actions of fibrates leads to:
--dec TG
--inc in large LDL particles
--inc HDL

Front 37

List the 3 major uses for fenofibrate.

Back 37

(1) dec hypertriglyceridemia
(2) inc HDL
(3) treat atherogenic dyslipidemia

Front 38

Adding a statin to a fibrate will result in which of the following?

(a) additional increase in HDL
(b) additional decrease TG
(c) additional increase in LDL

Back 38

Adding a statin to a fibrate will result in:

(b) additional decrease in TG

Front 39

List the 3 adverse reactions for fibrates.

Back 39

(1) myalgia
(2) high liver enzymes
(3) possible gallstones (esp clofibrate)

Front 40

How do fibrates affect anti-diabetic medicines?

How does fenofibrate affect warfarin INR?

Back 40

Fibrates increase the AUC of anti-diabetic meds.

Fenofibrate may prolong warfarin INR.

Front 41

Describe the dual effect of PUFA.

Back 41

At high doses of 4g/day, PUFA are indicated as an adjunct to diet for the treatment of very high TG levels.

At lower doses of 1g/day, PUFA's have been shown to reduce the incidence of coronary heart disease largely due to their ability to inhibit platelet aggregation.

Front 42

What is the major contraindication for PUFA?

Back 42

hypersensitivity to any component of the medication

Front 43

How does omega-3 PUFA affect the following:

(a) TG
(b) VLDL
(c) LDL

Back 43

Omega-3 PUFA does the following:

(a) decreases hepatic TG production

(b) decreases hepatic VLDL produciton

(c) increases levels of larger, more buoyant, less atherogenic LDL

Front 44

Omega-3 PUFA is the most efficacious drug in:

(a) decreasing LDL
(b) increasing HDL
(c) decreasing TG
(d) none of the above

Back 44

Omega-3 PUFA is the most efficacious drug in:

(c) decreasing TG

Front 45

What are the indications for orlistat?

Back 45

Orlistat is indicated for obesity management (weight loss and management).

Patients with a BMI > 30 or those with a BMI > 27 plus other risk factors are candidates for orlistat.

Front 46

For the following outcome data, name the appropriate class (or classes) of hyperlipidemia drug:

(1) primary prevention of CHD in type 2 diabetes

(2) regression of coronary atherosclerosis

(3) only produces lipoprotein effects

(4) secondary prevention of nonfatal MI and stroke

Back 46

For the following outcome data, name the appropriate class (or classes) of hyperlipidemia drug:

(1) primary prevention of CHD in type 2 diabetes = fibrates

(2) regression of coronary atherosclerosis = statins

(3) only lipoprotein effects = cholesterol absorption inhibitor

(4) secondary prevention of nonfatal MI and stroke = PUFA

Front 47

Name the appropriate class of hyperlipidemia drug that is most efficacious in producing the following:

(1) decreased LDL levels

(2) increased HDL levels

(3) decreased TG levels

(4) decreased LP(a) levels

Back 47

Name the appropriate class of hyperlipidemia drug that is most efficacious in producing the following:

(1) decreased LDL levels = statins

(2) increased HDL levels = nicotinic acid

(3) decreased TG levels = PUFA's

(4) decreased LP(a) levels = nicotinic acid

Front 48

For the following receptors, name the appropriate class of hyperlipidemia drug that acts on it to produce pharmacological effects:

(1) PPAR-alpha

(2) NPC1L1

(3) GPR109A

Back 48

For the following receptors, name the appropriate class of hyperlipidemia drug that acts on it to produce pharmacological effects:

(1) PPAR-alpha = fibrates

(2) NPC1L1 = cholesterol absorption blocker

(3) GPR109A = nicotinic acid

Front 49

For the following classes, name their contraindications:

(1) statins

(2) sequestrants

(3) fibrates

(4) ezetimibe

(5) omega-3 PUFA

(6) nicotinic acid

Back 49

For the following classes, name their contraindications:

(1) statins = liver disease, pregnancy, breast feeding

(2) sequestrants = high TG levels

(3) fibrates = renal, liver dysfunciton, gall bladder disease, nursing moms

(4) ezetimibe = liver disease

(5) omega-3 PUFA = hypersensitivity

(6) nicotinic acid = liver disease, peptic ulcer, gouty arthritis, relative contraindication for diabetes

Front 50

Indicate the appropriate class of hyperlipidemia drug that may cause these adverse effects:

(1) eructation

(2) diarrhea and depression

(3) bloating, gas, constipation

(4) myopathy and elevation of liver enzymes

(5) myalgia and possible gallstones

(6) flushing and increased insulin resistance

Back 50

Indicate the appropriate class of hyperlipidemia drug that may cause these adverse effects:

(1) eructation/belching = PUFA's

(2) diarrhea and depression = cholesterol absorption blocker

(3) bloating, gas, constipation = sequestrants

(4) myopathy and elevation of liver enzymes = statins

(5) myalgia, high liver enzymes, possible gallstones = fibrates

(6) flushing and increased insulin resistance= nicotinic acid

Front 51

Name the specific drug (not the class) that matches the following:

(1) causes major LDL reduction and metabolized by CYP3A4

(2) works at brush border and treats sitosterolemia

(3) causes major reduction in TG levels and can inhibit platelet aggregation

(4) activates PPAR-alpha and may prolong warfarin INR

(5) decreases LP(a) and may induce arachidonic acid cascade

(6) may cause myopathy and is metabolized by CYP2C9

(7) contraindicated in patients with high TG levels and is adjunct treatment of type II diabetes

(8) acts in enterohepatic circulation and may decrease absorption of warfarin and ezetimibe

(9) selective PPAR-alpha modulator that inhibits CYP2C8 an dmay increase the AUC for statins

Back 51

Name the specific drug (not the class) that matches the following:

(1) causes major LDL reduction and metabolized by CYP3A4 = lovastatin and simvastatin

(2) works at brush border and treats sitosterolemia = ezetimibe

(3) causes major reduction in TG levels and can inhibit platelet aggregation = PUFA

(4) full PPAR-alpha agonist and may prolong warfarin INR = fenofibrate

(5) decreases LP(a) and may induce arachidonic acid cascade = niacin

(6) may cause myopathy and is metabolized by CYP2C9 = fluvastatin

(7) contraindicated in patients with high TG levels and is adjunct treatment of type II diabetes = colesevelam

(8) acts in enterohepatic circulation and may decrease absorption of warfarin and ezetimibe = cholestyramine

(9) selective PPAR-alpha modulator that inhibits CYP2C8 and may increase the AUC for statins = gemfibrozil

Front 52

Describe the mechanism of action for orlistat.

Back 52

Orlistat inhibits gastric and pancreatic lipases in the stomach and small intestine. Thus, lipases cannot hydrolyze triglycerides into absorbable FFA's and monoglycerides. The unhydrolyzed trigs are not absorbed, leading to appx 30% reduction in fat absorption, caloric deficit and weight loss.

Front 53

Who should not take orlistat?

Back 53

Contraindications for orlistat:
--chronic malabsorption syndrome
--cholestasis
--hypersensitivity to orlistat
--pregnancy
--nursing women

Front 54

How does orlistat affect the following:

(1) cyclosporine
(2) fat soluble vitamins
(3) warfarin
(4) diabetes management

Back 54

Orlistat...

(1) decreases cyclosporine levels

(2) decreases absorption of vitamins ADEK (pts should take supplements)

(3) pts on warfarin need to be monitored since orlistat dec vit K absorption

(4) orlistat may improve metabolic control in diabetics, thus a reduction in the dose of oral hypoglycemics or insulin may be needed