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* Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. These complexes can be separated into
- HDL (high-density lipoprotein),
- IDL (intermediate-density lipoprotein),
- LDL (low-density lipoprotein), and
- VLDL (very-low-density lipoprotein) fractions * Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues
* LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor
* Elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk



* Synthetic lipid-lowering agent
* Selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts
3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.



* Liver is the primary site of action
* Lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase
* Lowers cholesterol synthesis in the liver
* Increases the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL
* Reduces LDL production and the number of LDL particles
* Reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s)
* Reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia.
* Reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.



* Rapidly absorbed after oral administration
* Maximum plasma concentrations occur within 1 to 2 hours
* Low systemic availability (parent drug : 14%approx.; systemic HMG-CoA reductase inhibitory activity 30% approx. ) attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. * Plasma atorvastatin concentrations are 30% approx. lower following evening administration compared with morning; however, LDL-C reduction is similar
* 98% bound to plasma proteins


Pharmacokinetics (contd.)

* Metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. HMG-CoA reductase inhibitory activity of ortho- and parahydroxylated metabolites is similar to atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites
* Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism;
* Mean plasma elimination half-life is 14 hours approx., 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.


Special Populations

Geriatric: Plasma concentrations of atorvastatin are 30-40% higher elderly (> 65 years) subjects but LDL-C reduction is comparable to younger patients

Pediatric: Pharmacokinetic data not available

Gender: Plasma concentrations in women are 20% approx. higher for Cmax and 10% approx. lower for AUC than in men; however, LDL-C reduction is similar

Renal Insufficiency: Renal disease does not influence plasma concentrations or LDL-C reduction of atorvastatin; dose adjustment in renal dysfunction is not necessary

Hemodialysis: Studies have not been conducted in patients with end-stage renal disease, but hemodialysis is not expected to significantly enhance clearance of atorvastatin

Hepatic Insufficiency: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased



* As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb).
* As adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson Type IV).
* For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
* To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.

Prior to initiating therapy with atorvastatin, secondary causes for hypercholesterolemia (eg, poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, and alcoholism) should be excluded, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG.


Atorvastatin has been shown to be the most effective statin drug yet, capable of reducing LDL cholesterol by up to 60% at its highest 80 mg dose, compared to simvastatin at 40%. Atorvastatin also can lower triglyceride levels by 20% to 40% which is significantly better than other drugs.

After diet and exercise, current guidelines recommend treatment with drugs for the following target LDL cholesterol levels: 130 for patients who already have heart disease, 160 for patients at high risk for heart disease, and 190 for everyone else.



Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

The recommended starting dose of atorvastatin is 10 mg once daily. The dosage range is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. Therapy should be individualized according to goal of therapy and response. LDL-C levels be used to assess treatment response. If LDL-C levels are not available, total-C may be used to monitor therapy.

Homozygous Familial Hypercholesterolemia
The dosage of atorvastatin in patients with homozygous FH is 10 to 80 mg daily, administered as an adjunct to other lipid-lowering treatments

Concomitant Therapy
Atorvastatin may be used in combination with a bile acid binding resin for additive effect. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided



Adverse Effects

* Generally well-tolerated
* Adverse effects usually mild and transient
* The most frequent adverse events were constipation, flatulence, dyspepsia, and abdominal pain



* Active liver disease or unexplained persistent elevations of serum transaminases.
* Hypersensitivity
* Pregnancy and Lactation. HMG-CoA reductase inhibitors decrease cholesterol synthesis and synthesis of other substances derived from cholesterol. Thus, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.




Liver Dysfunction : HMG-CoA reductase inhibitors have been associated with abnormalities of liver function. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.

Skeletal Muscle : Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class.

Atorvastatin therapy should be withheld or discontinued in any patient with a condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures)