Lipitor (Atorvastatin)

Lipitor - What is Lipitor?

Lipitor (Pfizer), Atorvastatin (INN), 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.

Atorvastatin calcium tablets are marketed by Pfizer under the trade name Lipitor, in tablets (10, 20, 40 or 80 mg) for oral administration. Tablets are white, elliptical, and film coated. Pfizer also packages the drug in combination with other drugs, such as is the case with its Caduet. In some countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Atoris, Atorlip, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip.

Atorvastatin inhibits HMG-CoA reductase, the rate-determining enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. This lowers the amount of cholesterol produced which in turn lowers the total amount of LDL cholesterol.

Atorvastatin was first synthesized in 1985 by Bruce Roth while working at Parke-Davis Warner-Lambert Company (now Pfizer). With 2008 sales of US$12.4 billion, Lipitor was the top-selling branded pharmaceutical in the world. US patent protection is scheduled to expire in June 2011. However, Pfizer made an agreement with Ranbaxy Laboratories to delay the generic launch in the US until November 2011.

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, the combination of ezetimibe (Zetia) and atorvastatin lowered cholesterol more effectively than Vytorin (ezetimibe + simvastatin).

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Lipitor (Atorvastatin) Pharmacokinetics

Atorvastatin has rapid oral absorption with an approximate time to maximum plasma concentration (Tmax) of 1–2 hours. The absolute bioavailability of atorvastatin is approximately 14%, however, 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. Food has been shown to reduce the rate and extent of atorvastatin absorption. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption). However, food does not affect the plasma LDL-C lowering efficacy of atorvastatin. Evening atorvastatin dose administration is known to reduce the Cmax (rate of absorption) and AUC (extent of absorption) 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 CYP 3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP 3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. Atorvastatin is also an inhibitor of cytochrome 3A4.

It is primarily eliminated via hepatic biliary excretion with less than 2% of atorvastatin recovered in the urine. Bile elimination follows hepatic and/or extra-hepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 hours, 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 4-fold increase in both Cmax and AUC. Patients with B stage liver disease show an 16-fold increase in Cmax and an 11-fold increase in AUC.

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

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Lipitor (Atorvastatin) Side Effects

Myopathy with elevation of creatinine kinase (CK) and rhabdomyolysis are the most serious side effects, although rare <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:

  • Weakness
  • Insomnia and dizziness.
  • Chest pain and peripheral edema.
  • Rash
  • 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.

Elevation of alanine transaminase (ALT) and aspartate transaminase (AST) has been described in a few cases

Other very rare side effects occurring in less than 1% of patients are: alopecia, anaphylaxis, angina, angioneurotic edema, arrhythmia, bullous rashes, cholestatic jaundice, deafness, dyspnea, erythema multiforme, esophagitis, facial paralysis, glaucoma, gout, hepatitis, hyperkinesia, impotence, migraine, myasthenia, myositis, nephritis, pancreatitis, paresthesia, peripheral neuropathy, petechiae, photosensitivity, postural hypotension, pruritus, rectal hemorrhage, rhabdomyolysis, somnolence, Stevens-Johnson syndrome, syncope, tendinous contracture, thrombocytopenia, tinnitus, torticollis, toxic epidermal necrolysis, urticaria, vaginal hemorrhage, and vomiting.

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Lipitor (Atorvastatin) Uses

FDA approved indications

  • 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.
  • Heterozygous familial hypercholesterolemia
  • Hypertriglyceridemia (Fredrickson Type IV)
  • Primary dysbetalipoproteinemia (Fredrickson Type III)
  • It has also been used in the treatment of combined hyperlipidemia.
  • Prophylaxis for myocardial infarction, stroke, unstable angina, and revascularization.*prophylaxis in patients with multiple risk factors without evident CHD.
  • Myocardial infarction and stroke prophylaxis in patients with type II diabetes.
  • Concomitant therapy considerations

Atorvastatin 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 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.

Co-administration of Atorvastatin with one of CYP3A4 inhibitors like 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 like diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, verapamil. And only rarely with other CYP3A4 inhibitors like amiodarone, and aprepitant, which are 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.

Antacids can rarely decrease the plasma concentrations of atorvastatin but do not affect the LDL-C lowering efficacy.

Niacin also is proved to increase the risk of myopathy or rhabdomyolysis 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

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