Lipid-Altering Drugs

Question 1

List the 4 HMG CoA-R Inhibitors

Answer 1

Atorvastatin
Lovastatin
Simvastatin
Statin

Question 2

Bile-Acid binding resin

Answer 2

Cholestyramine

Question 3

Niacin

Answer 3

.

Question 4

List the 3 fibric acids (fibrates)

Answer 4

PPAR activators
Gemfibrozil
Fenofibrate

Question 5

Cholesterol absorption inhibitor

Answer 5

Ezetimibe

Question 6

Omega-3 Fatty acid

Answer 6

.

Question 7

Proprotein convertase subtilisin/kesin 9 (PCSK9)

Answer 7

.

Question 8

microsomal triglyceride transfer protein

Answer 8

.

Question 9

Apolipoprotein B-100

Answer 9

.

Question 10

Statin MOA

Answer 10

• competitive inhibitor or active site on HMG CoA reductase (sterically prevent substrate from binding)
• structural analog
• rate-limiting step in cholesterol biosynthesis

Question 11

Statin pharmacokinetics

Answer 11

• extensive first pass metabolism (good thing! prevents drug from getting into circulation)
• • LIMITS SYSTEMIC BIOAVAILABILITY
• • TARGETS LIVER (site of action)
• HIGH PLASMA-PROTEIN BINDING

Question 12

Statin activation

Answer 12

All statins except simvastatin and lovastatin are in HYDROXY ACID form (active)
- PRO-DRUGS: sim. and lova. are administered as INACTIVE LACTONES, transformed in liver

Question 13

Statin metabolism

Answer 13

ator, lova, and simva are metabolized by CYP 3A4

Question 14

Statin half-lives

Answer 14

Variable

• Lova 1-4 hrs
• Simva 1-2 hrs
• Atorva 20 hrs

Question 15

Statin SE

Answer 15

• MYOPATHY
• • associated with genetic mut (SLCO1B1 - reduced hepatic uptake)
• RHABDOMYOLYSIS
• • marked CK and creatinine elevation (breakdown of muscle fibers) –> renal damage

Question 16

Which drugs will increase myopathy associated with increased plasma concentrations of statins?

Answer 16

drugs met by 3A4

• macrolide abx (erythromycin)
• azole antifungals (itraconazole)
• cyclosporine
• HIV protease inhibitors

Question 17

Statin CIs

Answer 17

liver disease

PREGNANT/LACTATING or likely to become pregnant

Question 18

Statin lipoprotein profile: TGs

Answer 18

o TG: the higher the baseline TG level, the greater the TG-lowering effect

Question 19

Statin lipoprotein profile: LDL

Answer 19

decrease by 20-55% - BEST

Question 20

Statin lipoprotein profile: HDL

Answer 20

increase by 5-10%

Question 21

Statin clinical use:

Answer 21

first-line therapy in hypercholesterolemia when at risk for MI

Question 22

Cholestyramine MOA

Answer 22

Highly positively charged → binds negatively charged bile acids –>excreted in stool –> hepatic bile-acid synthesis increases –> liver chol. content decreases –> stimulates production of LDL receptors

Question 23

what is the dominant mechanism for controlling LDL plasma concentration?

Answer 23

regulation of LDL receptor pathywas

Question 24

cholestyramine SE

Answer 24

o Constipation/bloating
o Interferes with absorption of other drugs
o Modest INCREASE in TG – with time, returns to baseline

Question 25

cholestyramine lipoprotein profile: TG

Answer 25

* Normal levels – only transient increase | * >250 mg/dL – further significant increase

Question 26

cholestyramine lipoprotein profile: LDL

Answer 26

decreased by 12-15%

Question 27

cholestyramine lipoprotein profile: HDL

Answer 27

increase by 4-5%

Question 28

use of cholestyramine:

Answer 28

o Hypercholesterolemia (not recommended for pts with increased TG) • 2nd tx: used if statins are insufficient o 11-20y

Question 29

what is the main effect of niacin?

Answer 29

decrease TG (does not decrease cholesterol)

Question 30

Niacin MOA at adipose

Answer 30

inhibits FFA mobilization

Question 31

niacin MOA at liver

Answer 31

decreases syntheiss of VLDL-TG

Question 32

niacin method of admin

Answer 32

oral - 3 different formulations (intermediate, long acting, extended release)

Question 33

SE of niacin

Answer 33

- pt compliance/SE - Both elevated TG and cholesterol - Low HDL - Care when combined with statins

Question 34

niacin CIs

Answer 34

o Peptic ulcer o Gout o Hepatic Disease o Diabetes

Question 35

what is the risk when combining niacin with statins?

Answer 35

increases risk of myopathy (unk. mechanism)

Question 36

niacin lipoprotein profile: TG

Answer 36

decreased by 35-50%

Question 37

niacin lipoprotein profile: LDL

Answer 37

decreased by 25%

Question 38

niacin lipoprotein profile: HDL

Answer 38

increased by 15-30%

Question 39

niacin lipoprotein profile: Lp(a)

Answer 39

reduced by 40% → may be risk factor

Question 40

niacin uses

Answer 40

o Hypercholesterolemia & hyper-TG • High LDL + low HDL o Typically not 1st-line therapy for hypercholesterolemia • Severe cases that do not respond to resins • d/t SE o Only lipid-lowering drug that reduces Lp(a)

Question 41

Ezetimibe MOA

Answer 41

o Protein transporter – Niemann Pick C10-like protein or NPC1L1 o Decreased rate of cholesteryl ester incorporation into chylomicrons → reduced cholesterol flux from intestine to liver

Question 42

Ezetimibe met

Answer 42

PRODRUG – met via glucuronidation

Question 43

Ezetimibe admin and T1/2

Answer 43

oral; 22hrs

Question 44

ezetimibe SE

Answer 44

well tolerated | - absorption decreased by cholestyramine

Question 45

Ezetimibe lipoprotein profile: TG

Answer 45

decreased by 5%

Question 46

Ezetimibe lipoprotein profile: LDL

Answer 46

decreased by 15-20%

Question 47

Ezetimibe lipoprotein profile: HDL

Answer 47

increased by 1-2%

Question 48

Ezetimibe uses

Answer 48

o Primary hypercholesterolemia o Combined with statins • Simvastatin + ezetimibe • Further decreases in LDL-cholesterolemia • Two differing pharmacological approaches

Question 49

Fibrates MOA

Answer 49

– primarily lower levels of TG-rich lipoproteins via regulation of TX

Question 50

which fibrate is the prodrug?

Answer 50

fenofibrate

Question 51

which fibrate has the longer T 1/2?

Answer 51

fenofibrate (20 hrs) (gemfibrozil 1 hr)

Question 52

fibrate SE

Answer 52

o Well tolerated • GI • Increased risk of gall stones • Heme/hepatic function abnormalities • Increased CK if combined with statin → renal failure • CI – renal impairment • Gemfibrozil can increase systemic statin concentrations by blocking transporter in liver

Question 53

fibrate uses

Answer 53

o Pts with high TGs + low HDL associated with metabolic syndrome/DM-II o Not used as primary therapy in patients with elevated hypercholesterolemia w/o hyper-TG

Question 54

fibrate lipoprotein profile

Answer 54

``` o TG – decreases 30-50% o LDL – decreases 15-20% • Highly variable • 2nd generation drugs (fenofibrate) more likely to decrease LDL 15-20% in patients with TG <400 mg/dL o HDL – increases 5-15% ```