2013-09-16 Lipid-Lowering Drugs Flashcards
What are Total cholesterol:
- desirable
- borderline
- high risk
Total cholesterole levels
- desirable: 200
- high risk: >240
What are HDL:
- Grrreat!
- desirable
- borderline
- high risk
HDL Levels
- Grrreat!: >60
- desirable: >50
- borderline: >40
- high risk: <40
What are LDL:
- Grrreat!
- desirable
- borderline
- high risk
LDL Levels:
-Grrreat!: 160
What is the basics of cholesterol metabolism? Where do the various drug classes act? [sketch it]
check slide 5
Cholestyramine (Questran™, colestipol)
[See Rang card for colestyramine]
Classs? PD? PK? Toxicity? Interactions? Special Uses? Dose?
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; 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 ADRs
Nicotinic acid (niacin, Niacor™, others) [See Rang card, too]
Classs? PD? PK? Toxicity? Interactions? Special Uses? Dose?
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 in liver; modestly effective as single agent, usually used in combination; can also raise HDL cholesterol
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
Notes from class: studies show no increased benefits when added to statin regimen; reserve only for those who can’t take statin
Gemfibrozil (Lopid™, others; fenofibrate)
Class? PD? PK? Toxicity? Interactions? Special Uses? Dose?
Almost never used anymore; still on Step 1
Drug class: Pharm–Fibric acid derivative; Rx–Lipid-lower agent
Pharmacodynamics: 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 (i.e. familial) 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 (liver, muscle) as well
Special considerations:
Indications and dose/route: 600 mg po twice daily
Lovastatin/Mevacor™ (also atorvastatin/Lipitor™, others; generic lovastatin and generic pravastatin are both available at Wal-Mart for $4 per month for lower doses)
[See Rang card for Simvastatin]
Class? PD? PK? Toxicity? Interactions? Special Uses? Dose?
Drug class: Pharm class–Lactone; 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 LDL receptors on hepatocytes, so that liver cells can import more cholesterol. Leads to reduction in LDL-chol (10-50%), increase in HDL (small)
Pharmacokinetics: About 30% absorbed; onset of action 3 days; peak effects in several weeks; excreted in feces; metabolized primarily by CYP 3A4
Toxicity: check LFTs and CPK during first year of use, because of risk of hepatitis, myopathy, myositis, and even rhabdomyolysis (rare!!!)
Interactions with other drugs: 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
Special considerations: Avoid in patients with pre-existing hepatitis, muscle disease, and pregnancy (X)
Indications and dose/route: 20 mg po daily, with dinner; may increase to 80 mg po daily, or switch to more potent statin (e.g. atorvastatin or rosuvastatin)
Exetimibe (Zetia^TM)
[See Rang card, too]
Class? PD? PK? Toxicity? Interactions? Special Uses? Dose?
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 decreas F
Special considerations: Use with caution in patients with hepatic or renal impairment
Indications and dose/route: 10 mg po daily
CRP and statins?
CRP is a inflammatory marked associated w/ increased CV risk.
Trials have shown rosuvastatin (newest, still brand-name only statin) lowers both LDL and CRP, however, other statins may work, too, they just have not been studied.
A SNP in what gene is associated w/ dramatically increased risk of myopathy in pts taking statins?
SLCO1B1 (Solute carrier organic anion transporter family member 1B1)
—involved in drug transport
