hmg coa reductase inhibitors
cholesterol absorption inhibitors
- Adjuctive therapy to diet in the management of primary hyperlipidemia or mixed hyperlipidema.
- Adjuctive therapy to diet in the management of homozygous familial hypercholesterolemia, used with other lipid-lowering agents.
- Atorvastatin– Inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme which is responsible for catalyzing an early step in the synthesis of cholesterol.
- Ezetimibe– Inhibits absorption of cholesterol in the small intestine.
Lowering of lipids with decreased progression of atherosclerosis.
Absorption: Atorvastatin– rapidly absorbed but undergoes extensive gastrointestinal and hepatic metabolism resulting in 14% bioavailability (30% for lipid-lowering activity). Ezetimibe– following absorption, rapidly converted to the active metabolite ezetimibe-glucaronide. Bioavailability is variable.
Distribution: Atorvastatin– probably enters breast milk.
Protein Binding: Atorvastatin– ≥98%.
Metabolism and Excretion: Atorvastatin– extensively metabolized by the liver, most during first pass; excreted in bile and feces. <2% excreted unchanged by the kidneys. 2 metabolites have lipid-lowering activity. Ezetimibe– undergoes enterhepatic recycling, mostly eliminated in feces, minimal renal excretion.
Half-life: Atorvastatin– 14 hr (lipid-lowering activity due to atorvastatin and its metabolites–20–30 hr). Ezetimibe– 22 hr.
TIME/ACTION PROFILE (cholesterol-lowering effect)
|atorvastatin PO||unknown||unknown||20–30 hr†|
- Active liver disease or unexplained persistent elevations in AST and ALT
- Concurrent use of cyclosporine, gemfibrozil, or tipranavir/ritonavir
- OB: Potential for fetal anomalies
- Lactation: May appear in breast milk.
Use Cautiously in:
- History of liver disease
- Alcoholism or chronic alcohol use (> 2 glasses/day may ↑ risk of hepatic toxicity)
- Renal impairment
- Concurrent use of lopinavir/ritonavir (use lowest dose possible)
- Concurrent use of clarithromycin, darunavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir, itraconazole, saquinavir/ritonavir (daily dose should not exceed ezetimibe 10 mg/atorvastatin 20 mg)
- Concurrent use of nelfinavir or bocepravir (daily dose should not exceed ezetimibe 10 mg/atorvastatin 40 mg)
- Geri: Elderly may be at ↑ risk for myopathy;
- OB: Women of childbearing age;
- Pedi: Safe and effective use in children has not been established.
Adverse Reactions/Side Effects
CNS: dizziness, fatigue
GI: abdominal pain, ↑ liver enzymes, nausea
Derm: hot flushes
F and E: hyperkalemia
MS: MYOPATHY/RHABDOMYOLYSIS, arthralgia, musculoskeletal pain, muscle weakness
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- ↑ risk of myopathy/rabdomyolysis with some CYP3A4 inhibitors, colchicine, cyclosporine, and fibric acid derivatives ; concurrent use with cyclosporine, gemfibrozil, tipranavir/ritoavir, and telaprever is contraindicated, concurrent use with some other CYP3A4 inhibitors requires lower dose.
- ↑ risk of myopathy/rhabdomyolysis with concurrent use of fenofibrates and lipid-lowering dose of niacin (>1 g/day)
- ↑ risk of cholelithiasis with fenofibrates .
- Concurrent use with cholestyramine may ↓ effectiveness of ezetimibe.
- May ↑ levels of norethindrone and ethinyl estradiol .
- Rifampin should be taken simultaneously to avoid multiple effects on blood levels.
- May ↑ effects of warfarin .
- May slightly ↑serum digoxin levels.
Grapefruit juice ↑ levels and risk of rhabdomyolysis (avoid >1 qt/day).
PO (Adults) Starting dose– ezetimibe 10 mg/atorvastatin 10 mg or ezetimibe 10 mg/atorvastatin 20 mg; starting dose in patients requiring >55% decrease in LDL-C– ezetimibe 10 mg/atorvastatin 40 mg; concurrent use of clarithromycin, darunavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir, itraconazole, saquinavir/ritonavir – daily dose should not exceed ezetimibe 10 mg/atorvastatin 20 mg); concurrent use of nelfinavir or bocepravir– (daily dose should not exceed ezetimibe 10 mg/atorvastatin 40 mg).
Tablets: ezetimibe 10 mg/atorvastatin10 mg, ezetimibe 10 mg/atorvastatin 20 mg, ezetimibe 10 mg/atorvastatin 40 mg, ezetimibe 10 mg/atorvastatin 80 mg
- Obtain a diet history, especially with regard to fat consumption.
Lab Test Considerations: Evaluate serum cholesterol and triglyceride levels before initiating, after 2–4 wk of therapy, and periodically thereafter.
- Monitor liver function tests prior to initiation of therapy and as clinically indicated. If symptoms of serious liver injury, hyperbilirubinemia, or jaundice occur discontinue atorvastatin/ezetimibe and do not restart. May also cause ↑ alkaline phosphatase and bilirubin levels. Temporarily withhold or discontinue atorvastatin/ezetimibe with an acute, serious myopathy or occurence of risk factors predisposing to hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures.
- If patient develops muscle tenderness during therapy, CPK levels should be monitored. If CPK levels are >10 times the upper limit of normal or myopathy occurs, therapy should be discontinued. Monitor for signs and symptoms of immune-mediated necrotizing myopathy (IMNM) (proximal muscle weakness and ↑ serum creatine kinase), persisting despite discontinuation of statin therapy. Perform muscle biopsy to diagnose; shows necrotizing myopathy without significant inflammation. Treat with immunosuppressive agents.
- May cause ↑ in fasting serum glucose levels and in HbA1c.
- May cause ↑ AST, ALT and creatine phophokinase.
- May cause hyperkalemia.
- Noncompliance, related to diet and medication regimen (Patient/Family/Teaching)
- PO Administer as a single dose any time of day, without regard to food. Swallow tablets whole, do not crush, break, dissolve or chew.
- If also taking bile acid sequestrants, administer atorvastatin/ezetimibe at least 2 hr before or at least 4 hrs after.
- Instruct patient to take medication as directed. If a dose is missed, omit and resume usual schedule with next dose. Do not double up on missed doses. Advise patient to avoid drinking more than one quart of grapefruit juice or 2 glasses of alcohol per day during therapy. Medication helps control but does not cure elevated serum cholesterol levels. Instruct patient to read Patient Leaflet prior to starting therapy and with each Rx refill in case of changes.
- Advise patient that this medication should be used in conjunction with diet restrictions (fat, cholesterol, carbohydrates, alcohol), exercise, and cessation of smoking. Atorvastatin/ezetimibe does not assist with weight loss.
- Instruct patient to notify health care professional promptly if unexplained muscle pain, tenderness, or weakness occurs, especially if accompanied by fever or malaise.Also notify health care professional if signs of liver problems (feeling tired or weak; loss of appetite; upper belly pain; dark urine; or yellowing of skin or whites of eyes).
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any other Rx, OTC, or herbal products.
- Advise patient to notify health care professional of medication regimen prior to treatment or surgery.
- Instruct female patients to notify health care professional promptly if pregnancy is planned or suspected or if breastfeeding. HMG-CoA reductase inhibitors are contraindicated in pregnancy.
Decrease in levels of serum total cholesterol, LDL cholesterol, and triglycerides in patients who cannot control levels by diet and exercise alone.
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