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Pharmacology: Pharmacodynamics: The lowering of total cholesterol (total-C), low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apo B) have been shown to reduce the risk of cardiovascular events and mortality.
Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In both subjects and in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia and dysbetalipoproteinemia, atorvastatin has been shown to reduce levels of total-C, LDL-C, apo B and total triglycerides (TG), and raises high-density lipoprotein-cholesterol (HDL-C) levels.
Epidemiologic and clinical studies have associated the risk of coronary artery disease (CAD) with elevated levels of total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Like LDL, cholesterol-enriched lipoproteins, including VLDL, intermediate-density lipoproteins (IDL) and remnants can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with nonlipid metabolic risk factors for coronary heart disease (CHD) (metabolic syndrome). Clinical studies have also shown that serum TG can be an independent risk factor for CAD. Coronary artery disease risk is especially increased if the hypertriglyceridemia is due to increased IDL or associated with decreased HDL or increased LDL-C. In addition, high TG levels are associated with an increased risk of pancreatitis. Although epidemiological and preliminary clinical evidence link low HDL-C levels and high TG levels with CAD and atherosclerosis, the independent effect of raising HDL or lowering TG on the risk of coronary and cerebrovascular morbidity and mortality has not been demonstrated in prospective, well-controlled outcome studies. Other factors eg, interactions between lipids/lipoproteins and endothelium, platelets and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications. Regardless of the intervention used (low fat/low-cholesterol diet, partial ileal bypass surgery or pharmacologic therapy), effective treatment of hypercholesterolemia/dyslipidemia has consistently been shown to reduce the risk of CAD.
Atorvastatin reduces LDL-C and the number of LDL particles, lowers very low-density lipoprotein-cholesterol (VLDL-C) and serum TG, reduces the number of apo B-containing particles and also increases HDL-C. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a condition that rarely responds to any other lipid-lowering medication. In addition to the previously mentioned effects, atorvastatin reduces IDL-C and apolipoprotein E (apo E) in patients with dysbetalipoproteinemia (type III).
In patients with type II hyperlipidemia, atorvastatin improved endothelial dysfunction. Atorvastatin significantly improved flow-mediated endothelium-dependent dilatation induced by reactive hyperemia, as assessed by brachial ultrasound (p<0.01).
Mechanism of Action: Atorvastatin is a synthetic lipid-lowering agent. It is a selective, competitive inhibitor of HMG-CoA reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
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 low-density lipoprotein (LDL) receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL-C and the number of LDL particles. Atorvastatin also reduces VLDL-C, serum TG and IDL, as well as the number of apo B containing particles, but increases HDL-C. Elevated serum cholesterol due to elevated LDL-C is a major risk factor for the development of cardiovascular disease (CVD). Low serum concentration of HDL-C is also an independent risk factor. Elevated plasma TG is also a risk factor for CVD, particularly if due to increased IDL or associated with decreased HDL-C or increased LDL-C.
Epidemiologic, clinical and experimental studies have established that high LDL-C, low HDL-C and high plasma TG promote human atherosclerosis and are risk factors for developing CVD. Some studies have also shown that the total cholesterol (TC):HDL-C ratio (TC:HDL-C) is the best predictor of CAD. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.
Pharmacokinetics: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximal plasma concentrations (Cmax) occur within 1-2 hrs. Extent of absorption and plasma atorvastatin concentrations increase in proportion to atorvastatin dose. Atorvastatin tablets are 95-99% bioavailable compared to solutions. The absolute bioavailability (parent drug) of atorvastatin is approximately 12% 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 first-pass metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9% as assessed by Cmax and area under the concentration-time curve (AUC), respectively, LDL-C reduction and HDL-C elevation are similar when atorvastatin is given with and without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following drug administration in the evening compared with morning dosing. However, LDL-C reduction and HDL-C elevation are the same regardless of the time of drug administration.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 L. 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.
Metabolism: Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives by cytochrome P-450 3A4 (CYP3A4) and to various β-oxidation products. In vitro, inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Atorvastatin and its metabolites are eliminated by biliary excretion.
Excretion: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life (t½) of atorvastatin in humans is approximately 14 hrs, but the t½ for inhibitory activity for HMG-CoA reductase is 20-30 hours due to the contribution of longer-lived active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Special Populations: Pediatrics: Assessment of pharmacokinetic parameters eg, Cmax, AUC and bioavailability of atorvastatin in pediatric patients (>10 to <17 years, postmenarche) was not performed during the 6-month, placebo-controlled trial referred to earlier (see Use in children under Precautions).
Geriatrics: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (≥65 years) compared with younger individuals. LDL-C reduction, however, is comparable to that seen in younger patient populations.
Gender: Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men; however, there is no clinically significant difference in LDL-C reduction between men and women.
Race: Plasma concentrations of atorvastatin are similar in Black and White subjects.
Hepatic Insufficiency: Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
Renal Insufficiency: Plasma concentrations and LDL-C lowering efficacy of atorvastatin are similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of atorvastatin should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance (CrCl) <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see Dosage & Administration, Precautions and Interactions).
