Lipid Lowering

Question 1

Cholestyramine: classes

Answer 1

bile acid sequestrant

cholesterol reduction

Question 2

Cholestyramine: PD

Answer 2

forms a non-absorbable complex with bile acids in small bowel (releasing Cl); inhibits enterohepatic reuptake of intestinal bile salts; increases fecal loss of bile acids > increases bile acid synthesis > increases cholesterol synthesis > increases expression of LDL receptors on cell surface of hepatocytes > reduces LDL chol by 10-20% (maximum)

Question 3

Cholestyramine: PK

Answer 3

virtually no absorption; excreted in feces; peak effect 3 weeks

Question 4

Cholestyramine: Tox

Answer 4

> 10% of patients have GI problems including gas, bloating, diarrhea, constipation; may interfere with absorption of fat-soluble vitamins, and drugs including digoxin, warfarin, thyroxine

Question 5

Cholestyramine: Interactions

Answer 5

may diminish absorption of statins, steroids, digoxin, warfarin

Question 6

Cholestyramine: special

Answer 6

provided as a powder for oral suspension; be sure to drink liquids with it

Question 7

Cholestyramine: Misc

Answer 7

our earliest lipid-lowering drug, not used much now due to ADRs. may be used if patient can’t afford a statin.

Question 8

Colestipol: what is the class representative?

Answer 8

Cholestyramine

Question 9

Nicotinic Acid/Niacin: classes

Answer 9

pharmacologic class–vitamin; therapeutic class–cholesterol-lowering agent

Question 10

Nicotinic Acid/Niacin: PD

Answer 10

lowers BOTH TG and LDL-chol; decreased production of VLDL > decreased production of LDL > increase in LDL receptor in liver; modestly effective as single agent, usually used in combination; can also raise HDL cholesterol

Question 11

Nicotinic Acid/Niacin: PK

Answer 11

well absorbed, large first pass effect (to nicotinamide); Tmax 45 min; half-life 45 min; urinary excretion of unchanged drug and metabolite

Question 12

Nicotinic Acid/Niacin: Tox

Answer 12

many patients develop skin flushing, which can be lessened by taking aspirin; some patients develop hepatitis

Question 13

Nicotinic Acid/Niacin: interaction

Answer 13

absorption decreased by cholestyramine

Question 14

Nicotinic Acid/Niacin: Special

Answer 14

in 1930s found to be a vitamin (B3) that cured pellagra; renamed niacin in 1940s; partially converted in the body to nicotinamide, which is NOT active in lowering lipids, but is active in forming NAD; avoid in patients with CAD, heavy ethanol use

Question 15

Gemfibrozil: classes

Answer 15

Pharm–Fibric acid derivative; Rx–Lipid-lower agent

Question 16

Gemfibrozil: PD

Answer 16

cellular mechanism of action remains unclear (prob related to inhibit lipolysis and decrease hepatic fatty acid uptake, inhibit hepatic secretion of VLDL); produces slight reduction in LDL-chol levels (-4%); most useful in treatment of hypertriglyceridemia in types IV and V hyperlipidemia (-31%); may increase HDL-chol (+6%)

Question 17

Gemfibrozil: PK

Answer 17

well absorbed; oxidized in liver to two inactive metabolites; half-life 1-2 h;

Question 18

Gemfibrozil: Tox

Answer 18

elevation of LFTs; myositis; GI distress; avoid in patients with renal, hepatic, or biliary tract disease, can cause hepatitis

Question 19

Gemfibrozil: Interactions

Answer 19

therapeutic effects increased with statins, but may potentially increase toxicity (liver, muscle) as well

Question 20

Gemfibrozil: bottom line

Answer 20

only 4% effective, can cause hepatitis: no one uses due to bad risk to benefit ratio

Question 21

Clofibrate: class representative?

Answer 21

Gemfibrozil

Question 22

Lovastatin: class

Answer 22

Pharm class–Lactone; Therapeutic class–cholesterol-lowering drug; primary and secondary prevention of CAD

Question 23

Lovastatin v atorvastatin?

Answer 23

Lovastatin = original, atorvastatin = more powerful. Lovastatin: even at max dose, only 35-40% reduction in LDL chol. For pts with very high levels, have to rx other drugs (like atorvastatin). High dose of atorvastatin can reduce LDL chol by 60%.

Question 24

Lovastatin: PD

Answer 24

Parent drug (lactone) is transformed to an active metabolite, which inhibits HMG-CoA reductase, the early and rate-limiting step in the synthesis of cholesterol. Inhibition is not complete. Leads to up-regulation of LDL receptors on hepatocytes, so that liver cells can import more cholesterol. Leads to reduction in LDL-chol (10-50%), increase in HDL (small)

Question 25

Lovastatin: PK

Answer 25

About 30% absorbed; onset of action 3 days; peak effects in several weeks; excreted in feces; metabolized primarily by CYP 3A4

Question 26

Lovastatin: tox

Answer 26

check LFTs and CPK during first year of use, because of risk of hepatitis, myopathy, myositis, and even rhabdomyolysis (rapid acute death of skel muscle – rare!!!)

Question 27

Lovastatin: interactions

Answer 27

Additive effects with cholestyramine, nicotinic acid, ezetimibe; gemfibrozil and niacin may increase risk of myopathy; erythromycin and others may inhibit CYP 3A4 metabolism, thereby causing increased accumulation and toxicity

Question 28

Lovastatin: special

Answer 28

Avoid in patients with pre-existing hepatitis, muscle disease, and pregnancy (X). Want to AVOID grapefruit juice, any other drug that inhibits the activity of 3A4. Even if you take an average dose of a statin, more likely to cause side effects.

Question 29

Ezetimibe: classes

Answer 29

Pharm class–2-azetidinone compound; Therapeutic class–cholesterol absorption inhibitor

Question 30

Ezetimibe: PD

Answer 30

Selectively blocks the intestinal absorption of cholesterol and related phytosterols, by acting at the level of the small bowel brush border; causes reduction of hepatic cholesterol stores, and an increase in the blood clearance of cholesterol; when used as monotherapy, can lower LDL-chol by up to 18%; often used with a statin; recent work suggests that while it can lower LDL-chol, it may not add to overall clinical efficacy (clinical endpoints)

Question 31

Ezetimibe: PK

Answer 31

Given orally; Tmax 4-12h; extensively metabolized to the glucoronide; F 35-60%; t 1/2 = 22 h

Question 32

Ezetimibe: tox

Answer 32

HA in about 8%, diarrhea in about 4%

Question 33

Ezetimibe: interactions

Answer 33

Use in combination with dietary therapy, as monotherapy, or in combination with a statin (is available as Vitorin, ezetimibe + simvastatin); bile acid sequestrants may decreas F

Question 34

Ezetimibe: special

Answer 34

Use with caution in patients with hepatic or renal impairment