Atorvastatin

Atorvastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Atorvastatin is used in the treatment of Heterozygous familial hypercholesterolemia, Heterozygous familial hypercholesterolemia (pediatrics), Homozygous familial hypercholesterolemia, and Prevention of atherosclerotic cardiovascular disease. It is also used in the treatment of Transplantation, post-heart; Transplantation, and post kidney.

Atorvastatin is rapidly absorbed from the gastrointestinal tract. Bioavailability is Approx 12-14%. The Volume of distribution was Approx 381 L. The Plasma protein binding is ≥98%. It is metabolized in the liver by CYP3A4 isoenzyme to active ortho- and parahydroxylated derivatives and inactive β-oxidation metabolites. It Undergoes extensive first-pass metabolism in the gastrointestinal mucosa and liver.

It is excreted mainly via bile; via urine (<2%, as an unchanged drug). The elimination half-life was approx 14 hours.

Atorvastatin shows common side effects like Headache, dizziness, diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Atorvastatin is available in the form of an Oral Tablet.

Atorvastatin is available in India, Germany, Italy, Netherlands, and Sweden.

Atorvastatin selectively and competitively inhibits HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to produce mevalonate. The reduction of mevalonate production results in a compensatory increase in the expression of LDL receptors and stimulation of LDL catabolism, consequently lowering LDL-cholesterol levels.

The onset of Action of Atorvastatin is within (Initial effect) 3-5 days.

The Duration of Action of Atorvastatin is within 20 to 30 hours.

The Tmax of Atorvastatin is approximately 1-2 hours, and Cmax is within 1.95–252 μg/ml.

Atorvastatin is available in the form of Oral Tablet.

Atorvastatin tablet is taken orally, usually once daily.

Atorvastatin is used in the treatment of Heterozygous familial hypercholesterolemia, Heterozygous familial hypercholesterolemia (pediatrics), Homozygous familial hypercholesterolemia, and Prevention of atherosclerotic cardiovascular disease. It is also used in the treatment of Transplantation, post-heart, Transplantation, and post-kidney.

Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. By preventing the conversion of HMG-CoA to mevalonate, statin medications decrease cholesterol production in the liver. Atorvastatin also increases the number of LDL receptors on the surface of hepatic cells.

Atorvastatin is approved for use in the following clinical indications

Heterozygous familial hypercholesterolemia: To reduce elevated total cholesterol (total-C), LDL cholesterol (LDL-C), apolipoprotein B (apo B), and triglyceride levels, and to increase HDL cholesterol in patients with primary hypercholesterolemia.

Heterozygous familial hypercholesterolemia (pediatrics): To reduce total-C, LDL-C, and apo B levels in pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia with LDL-C ≥190 mg/dL, LDL-C ≥160 mg/dL with a positive family history of premature cardiovascular disease (CVD), or LDL-C ≥160 mg/dL with two or more other CVD risk factors.

Homozygous familial hypercholesterolemia: To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Prevention of atherosclerotic cardiovascular disease:

Primary Prevention of atherosclerotic cardiovascular disease (ASCVD): To reduce the risk of myocardial infarction (MI), stroke, revascularization procedures, and angina in adult patients without a history of coronary heart disease (CHD) but who have multiple CHD risk factors.

• Although not approved, there have been certain off label use documented for Atorvastatin which include:-

Transplantation, post heart; Transplantation, post kidney.

Atorvastatin is available in various strengths as 10 mg, 20 mg, 40 mg, 80 mg.

Atorvastatin is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient
• Altered kidney function: Mild to severe impairment: No dosage adjustment necessary.

• Hemodialysis, intermittent (thrice weekly): Poorly dialyzed: No supplemental dose or dosage adjustment necessary.

• Peritoneal dialysis: No dosage adjustment is necessary.

• CRRT: No dosage adjustment necessary.

• PIRRT (e.g., sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).

• Dosage Adjustment in Hepatic impairment Patient

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

• Dosage Adjustment for Pediatric Patients:-

Heterozygous familial and nonfamilial hypercholesterolemia:

• Note: Begin treatment if, after adequate trial (6 to 12 months) of intensive lifestyle modification emphasizing body weight normalization and diet, the following are present
• LDL-C ≥190 mg/dL.

• LDL-C remains ≥160 mg/dL and 2 or more cardiovascular risk factors: family history of premature atherosclerotic cardiovascular disease (<55 years of age); overweight; obesity; or other elements of insulin resistance syndrome.

• LDL-C ≥130 mg/dL and diabetes mellitus.

• Children 6 to <10 years of age (Tanner stage I): Limited data available: Oral: Initial: 5 mg once daily; if target LDL-C not achieved after 4 weeks, may increase incrementally by doubling dose (10 mg/day, 20 mg/day) at monthly intervals until target LDL-C; usual maximum daily dose: 40 mg/day; however, in some cases doses up to 80 mg/day have been used; dosing based on a long-term trial (3 years) of 272 patients (age range: 6 to 15 years); doses of 80 mg/day were used in 12 patients <10 years of age; over the 3 year study duration, similar efficacy was observed without growth or maturation impairment.

• Children and Adolescents 10 to 17 years: Oral: Initial: 10 mg once daily; if target LDL-C not achieved after 4 weeks, may increase incrementally by doubling dose (20 mg/day, 40 mg/day) at monthly intervals until target LDL-C up to a maximum daily dose: 80 mg/day .

Hyperlipidemia

• Children and Adolescents 10 to 17 years (males and postmenarchal females): Oral: Initial: 10 mg once daily; if LDL-C target not achieved after 1 to 3 months, may increase to meet target LDL-C; in pediatric patients with heterozygous familial hypercholesterolemia, a maximum titrated dose based upon LDL response: 80 mg/day was used

Transplantation post-heart; Prevention of cardiac allograft vasculopathy (CAV):

• Note: Initiate following heart transplantation regardless of baseline cholesterol levels in children and adolescents with high risk for rejection and CAV (eg, re-transplantation, elevated panel reactive antibodies) . Significant drug interactions between statins and immunosuppressant drugs are frequent; many interactions can increase statin serum concentrations and risk of toxicity (eg, myopathy).

• Children and Adolescents: Oral: 0.2 mg/kg/day rounded to nearest 2.5 mg increment; maximum daily dose: 20 mg/day.

Hypercholesterolemia:

• Before initiation of therapy, patients should be placed on a standard cholesterol lowering diet for 3 to 6 months and the diet should be continued during drug therapy. Atorvastatin serum concentration may be increased when taken with grapefruit juice; avoid concurrent intake of large quantities (>1.2 liters/day).

• Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects.

Atorvastatin is contraindicated in patients with

• Active liver disease, unexplained persistent serum transaminase elevation.
• Pregnancy and lactation.
• Concomitant use with ciclosporin, systemic fusidic acid, telaprevir, glecaprevir/pibrentasvir and tipranavir/ritonavir combinations.

HDL Cholesterol

A paradoxical, severe, and reversible decrease in HDL-C (as low as 2 mg/dL) with a simultaneous decrease in apolipoprotein A1 has been reported within 2 weeks to years after initiation of fibrate therapy; clinical significance unknown.

● Venous thromboembolism

Use has been associated with pulmonary embolism and deep vein thrombosis. Use with caution in patients with risk factors for venous thromboembolism.

● Serum Creatinine

Elevations in serum creatinine have been reported in patients on Atorvastatin. These elevations tend to return to baseline following discontinuation of Atorvastatin. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Atorvastatin. Renal monitoring should also be considered for patients taking Atorvastatin and are at risk for renal insufficiency, such as the elderly and patients with diabetes.

● Cholelithiasis

Atorvastatin , like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Atorvastatin therapy should be discontinued if gallstones are found.

● Coumarin Anticoagulants

Caution should be exercised when Atorvastatin is given in conjunction with coumarin anticoagulants. Atorvastatin may potentiate the anticoagulant effects of these agents resulting in prolongation of the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized.

● Pancreatitis

Pancreatitis has been reported in patients taking Atorvastatin, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

● Hematologic Changes

Mild to moderate decreases in hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Atorvastatin therapy. However, these levels stabilize during long term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Atorvastatin. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of Atorvastatin administration.

● Hypersensitivity Reactions

Acute hypersensitivity reactions including severe skin rashes such as Steven-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with Atorvastatin. Urticaria was seen in 1.1 vs. 0% and rash in 1.4 vs. 0.8% of Atorvastatin and placebo patients respectively in controlled trials.

Atorvastatin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

There is no available information on the presence of Atorvastatin in human milk, the effects of the drug on the breastfed infant, or the effects on milk production. Atorvastatin is present in the milk of rats and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with Atorvastatin and for 5 days after the final dose.

Atorvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established, and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Atorvastatin may cause fetal harm when administered to a pregnant woman. Atorvastatin should be discontinued as soon as pregnancy is recognized.

Grapefruit or grapefruit juice intake may elevate serum concentrations of Atorvastatin. Red yeast rice may increase risk for toxic effects. Large consumption of alcoholic beverages may potentiate risk for hepatic impairment. Decreased plasma concentrations with St. John's wort.

• Common Adverse effects

Myopathy, myalgia, diabetes mellitus, persistent serum transaminase elevations. Rarely, immune-mediated necrotising myopathy (IMNM), interstitial lung disease, Myopathy, myalgia, diabetes mellitus, persistent serum transaminase elevations. Rarely, immune-mediated necrotising myopathy (IMNM), interstitial lung disease.

• Less Common Adverse effects:

Malaise, asthenia, fatigue, pyrexia. Hepatobiliary disorders: Cholestasis, Headache, dizziness, paresthesia, amnesia. Psychiatric disorders: Insomnia, nightmares

• Rare Adverse effects

Gynecomastia. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, pharyngolaryngeal pain. Skin and subcutaneous tissue disorders: Alopecia, skin rash, pruritus, urticaria. Vascular disorders: Epistaxis.

• May increase risk of myopathy and rhabdomyolysis with moderate to potent CYP3A4 inhibitors (e.g. HIV and HCV protease inhibitors, itraconazole, ketoconazole, clarithromycin, erythromycin, verapamil, diltiazem), Atorvastatin, gemfibrozil, ezetimibe, niacin, colchicine, fixed combination of lopinavir/ritonavir. Concomitant use with CYP3A4 inducers (e.g. rifampicin, efavirenz, phenytoin), Al or Mg antacids, and colestipol may reduce plasma concentrations of Atorvastatin. May increase serum levels of digoxin and oral contraceptives (e.g., norethindrone, Ethinyl estradiol).
• Potentially Fatal: Concomitant use with ciclosporin, telaprevir, glecaprevir/pibrentasvir and tipranavir/ritonavir combinations may potentiate risk of myopathy or rhabdomyolysis. Coadministration with or within 7 days of stopping systemic fusidic acid may increase risk of fatal rhabdomyolysis.

The common side effects of Atorvastatin include the following

Common

● Constipation, diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Geriatric Use

Atorvastatin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Atorvastatin exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made based on renal function. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Atorvastatin.

There is no specific treatment for Atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically,

And supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to

Significantly enhance Atorvastatin clearance.

Pharmacodynamic

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

Pharmacokinetics

• Absorption

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 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

• Distribution

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

• Metabolism

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. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

• Excretion

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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