Atorvastatin

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Atorvastatin
Atorvastatin2DCSD.svg
Atorvastatin3Dan.gif
Systematic (IUPAC) name
(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
Clinical data
Trade names Lipitor,Atorva
AHFS/Drugs.com monograph
MedlinePlus a600045
Licence data US Daily Med:link
Pregnancy cat. D (AU) X (US)
Legal status Prescription Only (S4) (AU) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 12%
Metabolism Hepatic - CYP3A4
Half-life 14 h
Excretion Bile
Identifiers
CAS number 134523-00-5 YesY
ATC code C10AA05
PubChem CID 60823
DrugBank APRD00055
ChemSpider 54810 YesY
UNII A0JWA85V8F N
KEGG D07474 YesY
ChEBI CHEBI:39548 YesY
ChEMBL CHEMBL1487 YesY
PDB ligand ID 117 (PDBe, RCSB PDB)
Chemical data
Formula C33H35Ca2FN2O5 
Mol. mass 558.64
 N (what is this?)  (verify)

Atorvastatin (INN) /əˌtɔrvəˈstætən/, marketed by Pfizer as a calcium salt under the trade name Lipitor,[1] is a member of the drug class known as statins, which are used primarily for lowering blood cholesterol and for 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 production of cholesterol in the body.

Atorvastatin was first synthesized in 1985 by Bruce Roth, an alumnus of Saint Joseph's University, while he was working for the Parke-Davis Company (since acquired by Warner-Lambert and the Pfizer Company). Although Atorvastatin was the fifth drug in the class of statins to be developed, clinical trials showed that Atorvastatin caused a more dramatic reduction in LDL-C than the other statin drugs. From 1996 to 2012 under the trade name Lipitor, Atorvastatin became the world's best-selling drug of all time, with more than $125 billion in sales over approximately 14.5 years.[2] When Pfizer's patent on Lipitor expired on November 30, 2011,[3] generic Atorvastatin became available in the United States. Initially, Atorvastatin was manufactured only by generic drugmakers Watson Pharmaceuticals and India's Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month's supply—until other manufacturers were able to supply the drug in May 2012.[4]

Medical uses[edit]

Indicated Uses[edit]

The primary uses of Atorvastatin for which it has official indication are for the treatment of dyslipidemia and the prevention of cardiovascular disease:[5]

Dyslipidemia[edit]

Cardiovascular disease[edit]

Other Uses[edit]

There have been recent studies suggesting that high-dose statin therapy plays a plaque-stabilizing role in patients suffering from acute coronary syndrome and thrombotic stroke[21][22]

Dosing and Administration[edit]

General Dosing Considerations[edit]

Adult patients taking Atorvastatin for dyslipidemias or for cardiovascular disease prevention may take a dose of Atorvastatin ranging from 10 mg-80 mg daily.[13] It is common practice for physicians to begin dosing at 10–20 mg daily, and then increase a patient's daily dosage of Atorvastatin according to the patient's response to the medication.

It is recommended that pediatric patients with dyslipidemias begin treatment with 10 mg daily Atorvastatin. The maximum recommended dose for children is 20 mg/day, however doses may be increased according to the goal of therapy under supervision of a physician.[13]

Atorvastatin may be used in combination with bile acid sequestrants and ezetimibe to increase the reduction in cholesterol levels. However, It is not recommended to combine statin drug treatment with certain other cholesterol-lowering drugs, particularly fibrates, because this may increase the risk of myopathy-related adverse effects.[13]

While many statin medications should be administered at bedtime for optimal effect, atorvastatin can be dosed at any time of day, as long as it is continually dosed once daily at the same time.[23][24]

Dosing in Specific Populations[edit]

  • Geriatric: Plasma concentrations of Atorvastatin in healthy elderly subjects are higher than those in young adults, and clinical data suggests a greater degree of LDL-lowering at any dose for patients in the population as compared to young adults.[13]
  • Pediatric: Pharmacokinetic data is not available for this population.[13]
  • Gender: Plasma concentrations are generally higher in women than in men, but there is no clinically significant difference in the extent of LDL reduction between men and women.[13]
  • Renal Impairment: Renal disease has no influence on plasma concentrations of Atorvastatin and dosing need not be adjusted in these patients.[13]
  • Hemodialysis: Hemodialysis will not significantly alter drug levels or change clinical effect of Atorvastatin.[13]
  • Hepatic Impairment: In patients with chronic alcoholic liver disease, levels of Atorvastatin may be significantly increased depending upon the extent of liver disease.[13]

Contraindications[edit]

Adverse Effects[edit]

Major Adverse Effects[edit]

  • Myopathy with elevation of creatinine kinase (CK)[28] and rhabdomyolysis are the most serious side effects, occurring rarely at a rate of <1% of patients taking Atorvastatin.[12][27] As mentioned previously, Atorvastatin should be discontinued immediately if this occurs.
  • Liver Enzyme Abnormalities occurred in 0.7% of patients who received Atorvastatin in clinical trials. It is recommended that hepatic function be assessed with laboratory tests before beginning Atorvastatin treatment and repeated as clinically indicated thereafter. If evidence of serious liver injury occurs while a patient is taking Atorvastatin, it should be discontinued and not restarted until the etiology of the patient's liver dysfunction is defined. If no other cause is found, Atorvastatin should be discontinued permanently.[13]

Common Side Effects[edit]

The following have been shown to occur in 1–10% of patients taking Atorvastatin in clinical trials:

Atorvastatin and other statins have been associated with anecdotal reports of memory loss in the postmarketing surveillance period. According to Pfizer, the manufacturer of Lipitor, clinical trials "do not establish a causal link between Lipitor and memory loss."[30][31][32][33]

High-dose atorvastatin have also been associated with worsening glycemic control.[33][34]

Food and Drug Interactions[edit]

Interactions with clofibrate, fenofibrate, gemfibrozil, which are fibrates used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins, increase the risk of myopathy and rhabdomyolysis.[28][35][36]

Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole,[37] telithromycin, and voriconazole, may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors such as diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, or verapamil,[38] and only rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant.[26] Often, bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Only rarely, though, barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin,[39] which are also CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Oral contraceptives increased AUC values for norethindrone and ethinyl estradiol; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.[40]

Antacids can rarely decrease the plasma concentrations of statin drugs, but do not affect the LDL-C-lowering efficacy.[41]

Niacin also is proved to increase the risk of myopathy or rhabdomyolysis.[26]

Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring.[26]

Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations.[42] Grapefruit juice components are known inhibitors of intestinal CYP3A4.

Co-administration of grapefruit juice with Atorvastatin may cause an increase in Cmax and AUC, which can lead to adverse reactions or overdose toxicity.[43]

A few cases of myopthay have been reported when Atorvastatin is given with colchicine.[13]

Mechanism of Action[edit]

As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes 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. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.

Recent studies have shown that in patients suffering from acute coronary syndrome, high-dose statin treatment may play a plaque-stabilizing role. At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. However, there is an increased risk of statin-associated adverse effects with such high-dose statin treatment.[21] There is a similar thought process and risks associated with using high-dose statins to prevent recurrence of thrombotic stroke.[22]

Pharmacodynamics[edit]

The liver is the primary site of action of Atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of Atorvastatin, rather than systemic drug concentration, which correlates with extent of LDL-C reduction.[13]

Pharmacokinetics[edit]

Absorption[edit]

Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration (Tmax) of 1–2 h. The absolute bioavailability of the drug is about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Evening dose administration is known to reduce the Cmax and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin.

Distribution[edit]

The mean volume of distribution of Atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted into human breastmilk.

Metabolism[edit]

Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4.

Excretion[edit]

Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in the urine. Bile elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 h. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 h, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption.[26]

In hepatic insufficiency, plasma drug concentrations are significantly affected by concurrent liver disease. Patients with A-stage liver disease show a four-fold increase in both Cmax and AUC. Patients with B-stage liver disease show a 16-fold increase in Cmax and an 11-fold increase in AUC.

Geriatric patients (>65 years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and Cmax values that are 40% and 30% higher, respectively. Additionally, healthy elderly patients show a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses.[27]

Pharmacogenetics[edit]

Several genetic polymorphisms have been found to be associated with a higher incidence of undesirable side effects of atorvastatin. This phenomenon is suspected to be related to increased plasma levels of pharmacologically active metabolites, such as atorvastatin lactone and p-hydroxyatorvastatin. Atorvastatin and its active metabolites may be monitored in potentially susceptible patients using specific chromatographic techniques.[44]

Formulations[edit]

Pack and tablet of Atorvastatin (Lipitor) 40mg

Atorvastatin calcium tablets are marketed by Pfizer under the trade name Lipitor[45] for oral administration. Tablets are white, elliptical, and film-coated. Pfizer also packages the drug in combination with other drugs, such as with Caduet.[46] Pfizer recommends that patients do not break tablets in half to take half-doses, even when this is recommended by their doctors. When Pfizer's patent on Lipitor expired on November 30, 2011,[3] generic Atorvastatin became available in the United States. In some countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Stator, Atorvastatin Teva, Litorva, Torid, Atoris, Atorlip,Mactor, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip.[47]

Drug recall[edit]

On 9 November 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of Atorvastatin in the United States. The lots of Atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1 mm in size). Despite the contamination, the FDA received no reports of injury.[48]

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