Atorvastatin , marketed under the trade name Lipitor , among others, is a member of the class of drugs known as statins, used primarily as lipid-lowering agents and for the prevention of events associated with cardiovascular disease. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in the production of cholesterol in the body.
Atorvastatin was first made in August 1985 at Warner-Lambert's Parke-Davis research facility in Ann Arbor, Michigan by a team led by Bruce Roth. From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug at the time, with more than US $ 125 Ã, billion in sales for approximately 14.5 Ã, years. By 2016, in the UK, the cost of atorvastatin is about Ã, Â £ 2 per month.
Video Atorvastatin
Medical use
The main uses of atorvastatin are for the treatment of dyslipidemia and prevention of cardiovascular disease:
Dyslipidemia
- Hypercholesterolemia (familial and nonfamilial heterozygotes) and mixed dyslipidemia (Fredrickson type IIa and IIb) to lower total cholesterol, LDL-C, apo-B, triglyceride, and CRP levels and increase HDL levels.
- Heterozygos familial hypercholesterolaemia in pediatric patients
- Homozygous familial hypercholesterolemia
- Hypertriglyceridemia (Fredrickson Type IV)
- Primary disbetalipoproteinemia (Fredrickson Type III)
- Combined hyperlipidemia
Cardiovascular Disease
- Primary prevention of heart attacks, strokes, and the need for revascularization procedures in patients with risk factors such as age, smoking, high blood pressure, low HDL-C, and family history of early heart disease but have not developed heart disease coronary that is clinically proven.
- Secondary prevention of myocardial infarction, stroke, unstable angina, and revascularization in people with coronary heart disease.
- Myocardial infarction and stroke prophylaxis in patients with type II diabetes
Other uses
Recent studies have shown that high-dose statin therapy plays a role in plaque stabilization in people with acute coronary syndromes and thrombotic strokes.
Maps Atorvastatin
Administration
Atorvastatin can be used in combination with bile acid sequestrants and ezetimibe to increase the decrease in cholesterol levels. However, it is not advisable to combine statin drug treatment with other cholesterol-lowering drugs, especially fibrates, as this may increase the risk of adverse myopathy-related side effects.
While many statin drugs should be administered at bedtime for optimal effect, atorvastatin can be given anytime throughout the day, during which it is steadily steamed once a day at the same time.
Specific population
- Geriatric : Atorvastatin plasma concentrations in healthy elderly subjects are higher than in young adults, and clinical data show a greater decrease in LDL at each dose for patients in the population compared with adults young.
- Pediatric : Pharmacokinetic data is not available for this population.
- Gender : Plasma concentrations are generally higher in women than in men, but there is no clinically significant difference in the reduction of LDL between men and women.
- Kidney damage : Kidney disease has no effect on plasma atorvastatin concentration and the dose need not be adjusted for this patient.
- Hemodialysis : Hemodialysis will not significantly alter the drug level or alter the clinical effects of atorvastatin.
- Liver disorders : In patients with chronic alcoholic liver disease, the rate of atorvastatin may increase significantly depending on the level of liver disease.
Contraindications
- Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice
- Unexplained upgrades at the AST or ALT level
- Pregnancy: Atorvastatin can cause fetal damage by affecting serum cholesterol and triglyceride levels, which are important for fetal development.
- Breastfeeding: A small amount of other statin drugs have been found to enter breast milk, although atorvastatin has not been studied, in particular. Due to the risk of disrupting the metabolism of baby's lipid metabolism, atorvastatin is not considered compatible with breastfeeding.
- CPK levels are significantly increased or if myopathy is suspected or diagnosed after atorvastatin dosing has begun. Very rarely, atorvastatin can cause rhabdomyolysis, and may very seriously cause acute renal failure due to myoglobinuria. If rhabdomyolysis is suspected or diagnosed, atorvastatin therapy should be discontinued immediately. The likelihood of developing myopathy increases with co-administration of cyclosporine, fibrat acid derivatives, erythromycin, niacin, and azole antifungals.
Adverse effects
Major
- Diabetes mellitus type 2, an unusual class effect of all statins.
- Myopathy with increased creatine kinase (CK, alias CPK) and rhabdomyolysis are the most serious adverse events, rarely seen at levels of 2.3 to 9.1 per 10,000 person-years among patients taking atorvastatin. As mentioned earlier, atorvastatin should be stopped immediately if this happens.
- Persistent liver abnormalities occur in 0.7% of patients receiving atorvastatin in clinical trials. It is recommended that liver function be assessed by laboratory tests before initiating atorvastatin treatment and repeated as a clinical indication afterwards. If evidence of serious liver injury occurs when the patient takes atorvastatin, it should be stopped and not restarted until the etiology of the patient's liver dysfunction is defined. If no other cause is found, atorvastatin should be stopped permanently.
General
The following has been shown to occur in 1-10% of patients taking atorvastatin in clinical trials:
- Painful joints
- Loose debris
- Digestive Disorder
- Muscle aches
- Nausea
High doses of atorvastatin are also associated with worsening blood glucose.
More
In 2014, the Food and Drug Administration (FDA) reports memory loss, forgetfulness and confusion with all statin products including atorvastatin. The symptoms are not serious, and they are rare and can be reversed when treatment with drugs ceases.
Interactions
Interactions with clofibrate, fenofibrate, gemfibrozil, the fibrates used in accessory therapy in various forms of hypercholesterolaemia, usually in combination with statins, increase the risk of myopathy and rhabdomyolysis.
Giving along with atorvastatin with one of the CYP3A4 inhibitors such as itraconazole, telithromycin, and voriconazole, can increase serum atorvastatin concentrations, which can cause adverse reactions. This is less likely with other CYP3A4 inhibitors such as diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporin, protease inhibitor, or verapamil, and rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant. Often, bosentan, phosphenytoin, and phenytoin, which is a CYP3A4 inducer, can decrease plasma concentrations of atorvastatin. Only rarely, though, barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin, which also induce CYP3A4, can lower plasma concentrations of atorvastatin. Oral contraceptives increase the value of AUC for norethisterone and ethinylestradiol; this increase should be considered when choosing oral contraceptives for women using atorvastatin.
Rare antacids may decrease plasma concentrations of statin drugs, but do not affect the efficacy of LDL-C-decrease.
Niacin is also shown to increase the risk of myopathy or rhabdomyolysis.
Some statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to changes occurring or the need for clinical monitoring. An increase in digoxin levels due to atorvastatin is a 1.2-fold increase in the area under the curve (AUC), resulting in small drug-drug interactions. The American Heart Association states that combinations of digoxin and atorvastatin make sense. In contrast to some other statins, atorvastatin does not interact with warfarin concentration clinically significant (similar to pitavastatin).
Vitamin D supplements lower atorvastatin and active metabolite concentrations, but synergistically reduce LDL and total cholesterol concentrations. The grapefruit juice component is known as the intestinal CYP3A4 inhibitor.
Co-administration of grapefruit juice with atorvastatin may cause increased C max and AUC, which may cause adverse reactions or overdose toxicity.
Several cases of myopathy have been reported when atorvastatin is given with colchicine.
Action mechanism
Like other statins, atorvastatin is a competitive HMG-CoA reductase inhibitor. Unlike most others, however, it is a truly synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is a rate-limiting step in liver cholesterol biosynthesis. Inhibition of enzymes decreases de novo cholesterol synthesis, enhancing the expression of low-density lipoprotein (LDL receptor) receptors in hepatocytes. It increases the absorption of LDL by hepatocytes, lowering the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces levels of triglycerides in the blood and slightly increases levels of HDL-cholesterol.
Recent studies have shown that in patients suffering from acute coronary syndromes, high-dose statin treatment may play a role in plaque stabilization. At high doses, statins have anti-inflammatory effects, instigate a reduction in the nucleus of necrotic plaque, and improve endothelial function, leading to plaque stabilization and, occasionally, plaque regression. However, there is an increased risk of statin-related side-effects with high-dose statin treatment. There are similar thought processes and risks associated with the use of high-dose statins to prevent recurrence of thrombotic stroke.
Pharmacodynamics
The liver is the main place of atorvastatin action, as this is the main site of cholesterol synthesis and LDL cleansing. This is the dose of atorvastatin, rather than the concentration of the systemic drug, which correlates with the reduced rate of LDL-C. In a systematic review of Cochrane, the magnitude of atorvastatin associated with doses in blood lipids is determined. During the dose range of 10 to 80 mg/day total cholesterol decreased 27.0% to 37.9%, LDL cholesterol by 37.1% to 51.7% and triglyceride by 18.0% to 28.3%.
Pharmacokinetics
Absorption
Atorvastatin undergoes rapid absorption when taken orally, with an estimated time for maximum plasma concentration (T max ) of 1-2 hours. The absolute bioavailability of this drug is about 14%, but the systemic availability for HMG-CoA reductase activity is about 30%. Atorvastatin undergoes high bowel liberation and first flow metabolism, which is a major cause for low systemic availability. Atorvastatin with food gives a 25% reduction in C max (absorption rate) and a 9% reduction in AUC (absorption rate), although food does not affect LDL-C-lowering plasma efficacy of atorvastatin. Night dosage administration is known to reduce C max and AUC by 30% respectively. However, the administration time does not affect the efficacy of LDL-C-plasma from atorvastatin.
Distribution
The average volume of atorvastatin distribution is about 381 L. It is strongly bound to proteins (> = 98%), and studies have shown the possibility of being secreted into breast milk.
Metabolism
Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form active ortho-and parahydroxylated metabolites, as well as various beta-oxidation metabolites. Orthopedic and heavy methylylated metabolites account for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism through glucuronidation. As a substrate for CYP3A4 isozyme, it has shown susceptibility to inhibitors and CYP3A4 inducers to produce an increase or decrease in plasma concentrations, respectively. This interaction was tested in vitro by simultaneous administration of erythromycin, a known CYP3A4 isozyme inhibitor, resulting in increased plasma concentrations of atorvastatin. It is also a 3A4 cytochrome inhibitor.
Excression
Atorvastatin is primarily removed by bile excretion of the liver, with less than 2% recovering in the urine. Bile elimination follows liver and/or extrahepatic metabolism. There appears to be no entero-hepatic recirculation. Atorvastatin has an estimated half-life elimination time of 14 hours. Noteworthy, HMG-CoA reductase inhibitory activity appears to have a half-life of 20-30 hours, which is suspected as an active metabolite. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug uptake.
In liver insufficiency, plasma atorvastatin concentrations are significantly affected by concurrent liver disease. Patients with Children-Pugh Staging Liver disease showed a fourfold increase in C max and AUC. People with Pugh stadium liver disease B showed a 16-fold improvement in C max and an 11-fold increase in AUC.
Geriatric patients (<65 years) showed atorvastatin pharmacokinetic changes compared with young adults, with an average AUC and C max averages of 40% and 30% more high, respectively. In addition, healthy elderly patients exhibit a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have a lower effective dose.
Pharmacogenetic
Several genetic polymorphisms have been found to be associated with a higher incidence of undesirable side effects of atorvastatin. This phenomenon is thought to be associated with elevated plasma levels of pharmacologically active metabolites, such as atorvastatin laktone and p-hydroxyatorvastatin. Atorvastatin and its active metabolites can be monitored in potentially vulnerable patients using specialized chromatographic techniques.
Chemical synthesis
The first atorvastatin synthesis in Parke-Davis that occurred during drug discovery was racemic followed by chiral chromatographic separation of enantiomers. An initial enantioselective route to atorvastatin utilizes the use of chiral ester to regulate the stereochemistry of the first of the two functional groups of alcohol through diastereoselective aldol reactions.
Once the compound enters pre-clinical development, the chemical process develops a cost-effective and scalable synthesis. In the case of atorvastatin, a key element of the overall synthesis is ensuring stereochemical purity in the final drug substance, and hence setting the first stereocenter to be a key aspect of the overall design. The final commercial production of atorvastatin relies on a chiral pool approach, in which the stereochemistry of the first functional group of alcohol is brought into synthesis - through the choice of isoaskorbat acid, a natural product derived from cheap and accessible plants.
History
Bruce Roth, employed by Warner-Lambert as a chemist in 1982, has synthesized an "experimental compound" with the CI code 991 - later called atorvastatin. Warner-Lambert's management is concerned that atorvastatin is an overwhelming version of Merck's competitors & Children's Love Co. lovastatin (brand name Mevacor). Mevacor, first marketed in 1987, is the industry's first static and synthetic version of Merck - simvastatin - in an advanced development stage. However, Bruce Roth and his bosses, Roger Newton and Ronald Cresswell, in 1985 convinced company executives to move the compound into costly clinical trials. Initial results comparing atorvastatin vs simvastatin showed that atorvastatin was significantly stronger and showed fewer side effects.
In 1994, research findings funded by Merck were published in The Lancet which concluded the efficacy of statins in lowering cholesterol in 4444 Scandinavian patients proving for the first time not only that "statins reduce 'bad' LDL cholesterol but also leading to a sharp decline in fatal heart attacks among patients with heart disease. "In 1996, Warner-Lambert signed a marketing cooperation agreement with Pfizer to sell Lipitor and in 2000 Pfizer acquired Warner-Lambert 2000 for $ 90.2 Ã , billion. Lipitor was on the market in 1996. In 2003 Lipitor has become the best-selling drug in the United States. From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug of all time, with more than $ 125 Ã, billion in sales for about 14.5 Ã, year. Lipitor itself "provides up to a quarter of Pfizer Inc.'s annual revenue over the years."
Atorvastatin calcium tablets are marketed by Pfizer under the trade name Lipitor for oral administration. The tablets are white, elliptical, and film-coated. Pfizer also bundles drugs in combination with other drugs, such as with amlodipine (brand name Caduet). Pfizer recommends that patients do not break the tablet into half to take half the dose, even when it is recommended by their doctor.
General availability
The US Patent Pfizer on Lipitor expires on November 30, 2011. Originally, generic atorvastatin was only produced by Watson Pharmaceuticals and Ranbaxy Laboratories India. The price for the generic version does not go down to another generic level - $ 10 or less for a one-month supply - until other manufacturers start supplying the drug by May 2012.
In other countries, calcium atorvastatin is made in tablet form by generic drug makers with various brand names including Stator, Atorvastatin Teva, Litorva, Torid, Atorisl, Atorlip, Mactor, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip. Pfizer also generated its own generic version with the name Zarator.
Drug recall
On November 9, 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recall the 10-, 20- and 40-mg generic dose versions of atorvastatin in the United States. Many atorvastatins, packaged in 90 bottles and 500 tablets, are recalled because of the possibility of contamination with very small glass particles similar to sand grain size (less than 1 mm). The FDA does not accept injury reports due to contamination. Ranbaxy also issued a 10 milligram tablet bottle withdrawal in August 2012 and March 2014, due to concerns that the bottle may contain larger 20 milligrams of tablets and thereby cause potential dose errors.
References
Further reading
External links
- Atorvastatin is bound to proteins in GDP
- Lipitor.com - the manufacturer's site
- MedlinePlus Drug information: Atorvastatin (Systemic) - information from USP IN Advice for Patients
- US. National Drug Library: Drug Information Portal - Atorvastatin
Source of the article : Wikipedia
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