Lipid Lowering Drugs

Question 1

Ezetimibe (Zetia™)

Answer 1

• Drug class: Pharm class–2-azetidinone compound; Therapeutic class–cholesterol absorption inhibitor
• Pharmacodynamics: 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)
• Pharmacokinetics: Given orally; Tmax 4-12h; extensively metabolized to the glucoronide; F 35-60%; t 1/2 = 22 h
• Toxicity: HA in about 8%, diarrhea in about 4%
• Interactions with other drugs: Use in combination with dietary therapy, as monotherapy, or in combination with a statin (is available as Vitorin™, ezetimibe + simvastatin); bile acid sequestrants may decrease F
• Special considerations: Use with caution in patients with hepatic or renal impairment
• Indications and dose/route: 10 mg po daily

Question 2

Aliroc’umab (Praluent™)

Answer 2

• Drug class: PCSK9 inhibitor (proprotein convertase subtilisin kexin type 9 inhibitor)
• Pharmacodynamics: PCSK9 normally binds to LDL receptors on hepatocytes, promoting receptor degradation; this human monoclonal Ab targets PCSK9, prevents it from binding to LDL receptors, and thereby increases LDL receptor lifetime on hepatocyte surface, and thus increasing hepatic uptake of LDL-Chol from blood
• PK: given SC injection every 2 weeks; half-life 12 days; clearance by proteolysis
• Toxicity: injection site reactions (5%) and myalgias (5%); rare hypersensitivity reactions
• Interactions: not reported
• Special issues: not yet approved for use on its own; given to high risk patients as an adjunct to diet, inadequate response to statins; not tested yet in pregnant women, or patients who cannot tolerate statin
• Dose: 75-150 mg SC injection every 2 weeks
• Note: little data yet about long-term efficacy and safety; it is very expensive

Question 3

Nicotinic Acid (niacin)

Answer 3

• Drug class: pharmacologic class–vitamin; therapeutic class–cholesterol-lowering agent
• Pharmacodynamics: lowers BOTH TG and LDL-chol; decreased production of VLDL > decreased production of LDL > increase in LDL receptor expression in liver; modestly effective as single agent, usually used in combination; can also raise HDL; Note: recent study NEJM 2011 showed that while adding niacin to a statin can further reduce TG and raise HDL, these changes were NOT associated with improved clinical outcomes
• PK: well absorbed, large first pass effect (to nicotinamide); Tmax 45 min; half-life 45 min; urinary excretion of unchanged drug and metabolite
• Toxicity: many patients develop skin flushing, which can be lessened by taking aspirin; some patients develop hepatitis
• Interactions: absorption decreased by cholestyramine
• Special issues: 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
• Dose: pellagra 100 mg tid; hyperlipidemia 0.5-2 gm tid after meals

Question 4

. Cholestyramine (Questran™)

Answer 4

• Drug class: bile acid sequestrant; therapeutic class–cholesterol-lowering agent
• Pharmacodynamics: 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)
• PK: virtually no absorption from gut; excreted in feces; peak effect 3 weeks
• Toxicity: >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
• Interactions: may diminish absorption of statins, steroids, digoxin, warfarin;
• Special issues: provided as a powder for oral suspension; be sure to drink liquids with it
• Dose: 4 gm once a day, up to 6 times per day
• Note: our earliest lipid-lowering drug, not used much now due to GI side effects (unpleasant, poor patient compliance)

Question 5

Atorvastatin/Lipitor™

Answer 5

• Drug class: Pharm class—HMG-CoA reductase inhibitor; Therapeutic class–cholesterol-lowering drug; primary and secondary prevention of CAD
• Pharmacodynamics: 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 expression of LDL receptors on hepatocytes, so that liver cells can import more cholesterol. Leads to reduction in LDL-chol (-10 to -65%), and an increase in HDL-chol (small)
• Pharmacokinetics: Rapidly absorbed; extensively metabolized, likely mostly by CPT 3A4; metabolites account for most of its activity; active metabolites have half-life of 20-30 h
• Toxicity: check LFTs and CPK prior to use, and during first year of use, because of risk of hepatitis, and myopathy, myositis, or even rhabdomyolysis (rare!!!); most common problem seems to be myalgias (muscle aches), 3-8%
• Interactions with other drugs: Additive effects with cholestyramine, nicotinic acid, ezetimibe; gemfibrozil and niacin may increase risk of myopathy; erythromycin, cyclosporine, fluconazole, and others may inhibit CYP 3A4 metabolism, thereby causing increased accumulation and increasing toxicity
• Special considerations: Avoid in patients with pre-existing hepatitis, muscle disease, and pregnancy (X)
• Indications and dose/route: 10-20-40-80 mg po once daily

Question 6

Gemfibrozil (Lopid™)

Answer 6

• Drug class: Pharm–Fibric acid derivative; Rx–Lipid-lower agent
• Pharmacodynamics: cellular mechanism of action remains unclear (prob related to inhibition of 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%)
• Pharmacokinetics: well absorbed; oxidized in liver to two inactive metabolites; half-life 1-2 h;
• Toxicity: elevation of LFTs; myositis; GI distress; avoid in patients with renal, hepatic, or biliary tract disease
• Interactions with other drugs: therapeutic effects increased with statins, but may potentially increase toxicity as well (hepatitis, myositis) as well
• Special considerations: contraindicated in patients with renal or liver disease
• Indications and dose/route: 600 mg po twice daily