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
* Selective, competitive inhibitor of HMG-CoA reductase, an enzyme
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
* 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.
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
* 98% bound to plasma proteins
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
* 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
concentrations of atorvastatin are 30-40% higher elderly (> 65 years)
subjects but LDL-C reduction is comparable to younger patients
Pharmacokinetic data not available
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 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
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
* 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.
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.
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.
(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.
The dosage of atorvastatin in patients with homozygous FH is 10
to 80 mg daily, administered as an adjunct to other lipid-lowering
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 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.
* 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.
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
Muscle : Rhabdomyolysis
with acute renal failure secondary to myoglobinuria has been reported
with other drugs in this class.
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)