|Systematic (IUPAC) name|
|Licence data||US Daily Med:|
|Pregnancy cat.||C (AU) X (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Metabolism||Hepatic - CYP3A4|
| (what is this?)
Atorvastatin (INN) //, marketed by Pfizer as a calcium salt under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. 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 of Parke-Davis Warner-Lambert Company (now Pfizer). The best selling drug in pharmaceutical history, sales of Lipitor since it was approved in 1996 exceed US$125 billion, and the drug has topped the list of best-selling branded pharmaceuticals in the world for nearly a decade. When Pfizer's patent on Lipitor expired on November 30, 2011, generic atorvastatin became available in the United States, initially 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.
The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease. It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.
- Hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb) to reduce total cholesterol, LDL-C, apo-B, triglycerides levels, and CRP as well as increase HDL levels.
- Hypertriglyceridemia (Fredrickson Type IV)
- Primary dysbetalipoproteinemia (Fredrickson Type III)
- Secondary prevention in people with coronary heart disease and multiple risk factors for myocardial infarction, stroke, unstable angina, and revascularization
- Myocardial infarction and stroke prophylaxis in patients with type II diabetes
Concomitant therapy considerations: may be used in combination with bile acid resins. It is not recommended to combine statin treatment with fibrates because of the increased risk of myopathy-related adverse reactions. Drug dose must be adjusted according to age of patient, and must be lowered in hepatic insufficiency.
- Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice
- Unexplained elevations in AST or ALT levels
Precaution must be taken when treating with atorvastatin, because rarely it may lead to rhabdomyolysis, and it may be very serious leading to acute renal failure due to myoglobinuria. If rhabdomyolysis is suspected or diagnosed, atorvastatin therapy should be discontinued immediately. However, trials show atorvastatin may be protective of kidney function. Also, atorvastatin should be discontinued if a patient has markedly elevated CPK levels or if a myopathy is suspected or diagnosed. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals.
Atorvastatin is absolutely contraindicated in pregnancy; it is likely to cause harm to fetal development because of the importance of cholesterol and various products in the cholesterol biosynthesis pathway for fetal development, including steroid synthesis and cell membrane production. Nursing mothers are not recommended to take atorvastatin due to the possibility of adverse reactions in nursing infants, since experiments with rats indicate atorvastatin is likely to be secreted into human breast milk.
As stated earlier, myopathy with elevation of creatinine kinase (CK) and rhabdomyolysis are the most serious side effects, although rare at <1%. Headache is the most common side effect, occurring in more than 10% of patients. Side effects that occur in 1–10% of patients taking atorvastatin include:
- Insomnia and dizziness
- Chest pain and peripheral edema
- Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea
- Urinary tract infection
- Arthralgia, myalgia, back pain, arthritis
- Sinusitis, pharyngitis, bronchitis, rhinitis
- Infection, flu-like syndrome, allergic reaction
Atorvastatin and other statins are associated with anecdotal reports of memory loss by consumers, which have been seen in clinical practice in a tiny percentage of users, particularly women. Evidence is conflicting with anecdotal reports contrasting with a well-established association of high cholesterol with dementia. However, it is known that cholesterol synthesis is necessary for normal neuron functioning. According to Pfizer, the manufacturer of Lipitor, clinical trials "do not establish a causal link between Lipitor and memory loss."
High-dose atorvastatin had also been associated with worsening glycemic control.
Drug and food interactions
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.
Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole, 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, and only rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant. 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, 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.
Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations. 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.
Mechanism of action
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.
In clinical trials, drugs that block cholesterol uptake like ezetimibe combine with and complement those that block biosynthesis like atorvastatin or simvastatin in lowering cholesterol or targeting levels of LDL.
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.
Atorvastatin is highly protein bound (≥98%).
The primary proposed mechanism of atorvastatin metabolism is 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.
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.
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.
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.
Atorvastatin calcium tablets are marketed by Pfizer under the trade name Lipitor for oral administration. Tablets are white, elliptical, and film-coated. Pfizer also packages the drug in combination with other drugs, such as with Caduet. Pfizer recommends that patients do not break tablets in half to take half-doses, even when this is recommended by their doctors. In some countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Stator, Atoris, Atorlip,Mactor, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip.
On 23 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, a development that could further dent its image in the world's largest prescription drug market, in which the company faced an earlier ban. (The 80-mg dose of atorvastatin was not recalled.) Controlled by Japan's Daiichi Sankyo Co., Ranbaxy has had a troubled history in the United States, where in 2009 the Food and Drug Administration banned shipments from some of its manufacturing plants to the United States.
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