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| __NOTOC__
| | #REDIRECT [[Atorvastatin#Pharmacology]] |
| {{Atorvastatin}}
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| {{CMG}}; {{AE}} {{PB}}
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| ==Clinical Pharmacology==
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| ====Mechanism of Action====
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| Atorvastatin is a selective, competitive inhibitor of [[HMG-CoA reductase]], the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including [[cholesterol]]. [[Cholesterol]] and [[triglyceride]]s circulate in the bloodstream as part of [[lipoprotein]] complexes. With ultracentrifugation, these complexes separate into [[HDL]] (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. [[Triglycerides]] ([[TG]]) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from [[VLDL]] and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), [[LDL]]-cholesterol ([[LDL]]-C), and [[apolipoprotein B]] (apo B) promote human atherosclerosis and are risk factors for developing [[cardiovascular disease]], while increased levels of [[HDL]]-C are associated with a decreased cardiovascular risk.
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| In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting [[HMG-CoA reductase]] and [[cholesterol]] synthesis in the liver and by increasing the number of hepatic [[LDL]] receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces [[LDL]] production and the number of [[LDL]]particles. atorvastatin reduces [[LDL]]-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).
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| A variety of clinical studies have demonstrated that elevated levels of total-C, [[LDL]]-C, and [[apo B]] (a membrane complex for [[LDL]]-C) promote human atherosclerosis. Similarly, decreased levels of [[HDL]]-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.
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| Atorvastatin reduces total-C, [[LDL]]-C, and [[apo B]] in patients with homozygous and heterozygous FH, nonfamilial forms of [[hypercholesterolemia]], and mixed [[dyslipidemia]]. atorvastatin also reduces [[VLDL]]-C and [[TG]] and produces variable increases in [[HDL]]-C and apolipoprotein A-1. atorvastatin reduces total-C, [[LDL]]-C, [[VLDL]]-C, [[apo B]], [[TG]], and non-[[HDL]]-C, and increases [[HDL]]-C in patients with isolated [[hypertriglyceridemia]]. atorvastatin reduces intermediate density [[lipoprotein]] [[cholesterol]] ([[IDL]]-C) in patients with [[dysbetalipoproteinemia]].
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| Like [[LDL]], cholesterol-enriched [[triglyceride]]-rich lipoproteins, including [[VLDL]], intermediate density lipoprotein ([[IDL]]), and remnants, can also promote [[atherosclerosis]]. Elevated plasma triglycerides are frequently found in a triad with low [[HDL]]-C levels and small [[LDL]] particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma [[TG]] has not consistently been shown to be an independent risk factor for [[CHD]]. Furthermore, the independent effect of raising [[HDL]] or lowering [[TG]] on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
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| ===Pharmacodynamics===
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| Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and [[LDL]] clearance. Drug dosage, rather than systemic drug concentration, correlates better with [[LDL]]-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)]. | |
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| ===Pharmacokinetics===
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| =====Absorption=====
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| Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatindose. The absolute bioavailability of [[atorvastatin]] (parent drug) is approximately 14% and the systemic availability of [[HMG-CoA reductase]] inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, [[LDL]]-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].
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| =====Distribution=====
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| Mean volume of distribution of atorvastatin is approximately 381 liters. atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3)].
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| =====Metabolism=====
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| Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitroinhibition of [[HMG-CoA reductase]] by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for [[HMG-CoA reductase]] is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with [[erythromycin]], a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
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| =====Excretion=====
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| Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for [[HMG-CoA reductase]]is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
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| ======Specific Populations======
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| Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5)].
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| =====Pediatric=====
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| Pharmacokinetic data in the pediatric population are not available.
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| =====Gender=====
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| Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
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| =====Renal Impairment=====
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| Renal disease has no influence on the plasma concentrations or [[LDL]]-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5), Warnings and Precautions, Skeletal Muscle (5.1)].
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| =====Hemodialysis=====
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| While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
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| =====Hepatic Impairment=====
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| In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B
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| {|
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| |[[Image:Pharmacokinetics of Atorvastatin1.PNG|thumb|1200px]]
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| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LIPITOR (ATORVASTATIN CALCIUM) TABLET, FILM COATED [PARKE-DAVIS DIV OF PFIZER INC] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c6e131fe-e7df-4876-83f7-9156fc4e8228#nlm34089-3 | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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