|Composition||Atorvastatin 10mg + Vitamin D3 1000 IU Tablets|
|Indication||In dyslipidemiafor prevention of events associated with cardiovascular disease with vitamin D deficiency|
|Mechanism of Action||
Atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductasecatalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.
Cholecalciferol is a secosteroid, that is, a steroid molecule with one ring open. Cholecalciferol is inactive: it is converted to its active form by two hydroxylations: the first in the liver, the second in the kidney, to form calcitriol, whose action is mediated by the vitamin D receptor, a nuclear receptor which regulates the synthesis of hundreds of enzymes and is present in virtually every cell in the body.
ATORVASTATIN is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to ATORVASTATIN dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMGCoAreductase 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].
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 and Use In Specific Populations, Nursing Mothers].
ATORVASTATIN is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition 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]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
ATORVASTATIN and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic 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
Metabolism Within the liver, cholecalciferal is hydroxylated to calcidiol (25-hydroxycholecalciferol) by the enzyme 25-hydroxylase. Within the kidney, calcidiol serves as a substrate for 1-alpha-hydroxylase, yielding calcitriol (1,25-dihydroxycholecalciferol), the biologically active form of vitamin D3.
Diabetes mellitus type 2, an uncommon class effect of all statins. Myopathy with elevation of creatine kinase (CK, aka CPK) and rhabdomyolysis are the most serious side effects, occurring rarely at a rate of 2.3 to 9.1 per 10,000 person-years among patients taking atorvastatin. As mentioned previously, atorvastatin should be discontinued immediately if this occurs.
The following have been shown to occur in 1–10% of patients taking atorvastatin in clinical trials.
High-dose atorvastatin have also been associated with
worsening glycemic control.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
As directed by physician.