Congestive Heart Failure
Alternative Heart Disease Treatment
Lipitor is a prescription drug used along with diet to lower cholesterol.
Lipitor is the #1 prescribed drug in one of the most widely prescribed classes
of cholesterol-lowering medications, called statins.1 Lipitor along with diet
can lower your total cholesterol 29% to 45% (average effect depending on dose).
Lipitor is also shown to lower your "bad" or LDL cholesterol 39% to 60% (average
effect depending on dose).
Mechanism of Action
Atorvastatin (Lipitor) is a selective, competitive inhibitor of HMG-CoA
reductase, the rate-limiting enzyme that converts
3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols,
including cholesterol. Cholesterol and triglycerides circulate in the
bloodstream as party of lipoprotein complexes. With ultracentrifugation, these
complexes separate 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. Clinical and pathologic studies wshow
that 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.
In animal models, Atorvastatin (Lipitor) lowers plasma cholesterol and
lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in
the liver and by increasing the number of hepatic LDL receptors on the
cell-surface to enhance uptake and catabolism of LDL; Atorvastatin (Lipitor)
also reduces LDL production and the number of LDL particles. Atorvastatin (Lipitor)
reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH),
a population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C,
LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis.
Similarly, decreased levels of HDL-C (and its transport complex, apo A) are
associated with the development of atherosclerosis. Epidemiologic investigations
have established that cardiovascular morbidity and mortality vary directly with
the level of total-C and LDL-C, and inversely with the level of HDL-C. Although
frequently found in association with low HDL-C, elevated plasma TG has not been
established as an independent risk factor for coronary heart disease. The
independent effect of of raising HDL-C or lowering TG on the risk fro coronary
and cardiovascular morbidity and mortality has not been established.
Atorvastatin (Lipitor) reduces total-C, LDL-C, and apo B in patients with
homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and
mixed dyslipidemia. Atorvastatin (Lipitor) also reduces VLDL-C and TG and
produces variable increases in HDL-C and apolipoprotein A-1. The effect of
Atorvastatin (Lipitor) on cardiovascular morbidity and mortality has not been
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL,
intermediate density lipoprotein (IDL), and remnants, can also promote
atherosclerosis. Elevated plasma triglycerides are frequently found in a triad
with low HDL-C levels and small LDL particles, as well as in association with
non-lipid metabolic risk factors for coronary heart disease. As such, total
plasma TG has not consistently been shown to be an independent risk factor for
CHD. Furthermore, the independent effect of raising HDL or lowering TG on the
risk of coronary and cardiovascular morbidity and mortality has not been
Atorvastatin (Lipitor) as well as some of its metabolites are pharmacologically
active in humans. The liver is the primary site of action and the principal site
of cholesterol synthesis and LDL clearance. Drug dosage rather than systemic
drug concentration correlates better with LDL-C reduction. Individualization of
drug dosage should be based on therapeutic response.
Absorption: Atorvastatin (Lipitor) is rapidly absorbed after oral
administration; maximum plasma concentrations occur within 1 to 2 hours. Extent
of absorption increases in proportion to Atorvastatin (Lipitor) dose. The
absolute bioavailability of Atorvastatin (Lipitor) (parent drug) is
approximately 14% and the systemic availability of HMG-CoA reductase inhibitory
activity is approximately 30%. The low systemic availability is attributed to
presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass
metabolism. Although food decreases the rate and extent of drug absorption by
approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C
reduction is similar whether Atorvastatin (Lipitor) is given with or without
food. Plasma Atorvastatin (Lipitor) concentrations are lower (approximately 30%
for Cmax and AUC) following evening drug administration compared with morning.
However, LDL-C reduction is the same regardless of the time of day of drug
Distribution: Mean volume of distribution of Atorvastatin (Lipitor) is
approximately 381 liters. Atorvastatin (Lipitor) is ³98% bound to plasma
proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug
penetration into red blood cells. Based on observations in rats, Atorvastatin (Lipitor)
is likely to be secreted in human milk.
Metabolism: Atorvastatin (Lipitor) is extensively metabolized to ortho-
and parahydroxylated derivatives and various beta-oxidation products. In vitro
inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is
equivalent to that of Atorvastatin (Lipitor). Approximately 70% of circulating
inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
In vitro studies suggest the importance of Atorvastatin (Lipitor) metabolism by
cytochrome P450 3A4, consistent with increased plasma concentrations of
Atorvastatin (Lipitor) in humans following coadministration with erythromycin, a
known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite
undergoes further glucuronidation.
Excretion: Atorvastatin (Lipitor) and its metabolites are eliminated
primarily in bile following hepatic and/or extra hepatic metabolism; however,
the drug does not appear to undergo enterohepatic recirculation. Mean plasma
elimination half-life of Atorvastatin (Lipitor) in humans is approximately 14
hours, 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 (Lipitor) is recovered in urine following oral administration.
Geriatric: Plasma concentrations of Atorvastatin (Lipitor) are higher
(approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age
³65 years) than in young adults. LDL-C reduction is comparable to that seen in
younger patient populations given equal doses of Atorvastatin (Lipitor).
Pediatric: Pharmacokinetic data in the pediatric population are not
Gender: Plasma concentrations of Atorvastatin (Lipitor) in women differ
from those in men (approximately 20% higher for Cmax and 10% lower for AUC);
however, there is no clinically significant difference in LDL-C reduction with
Atorvastatin (Lipitor) between men and women.
Renal Insufficiency: Renal disease has no influence on the plasma
concentrations or LDL-C reduction of Atorvastatin (Lipitor); thus, dose
adjustment in patients with renal dysfunction is not necessary.
Hemodialysis: While studies have not been conducted in patients with
end-stage renal disease, hemodialysis is not expected to significantly enhance
clearance of Atorvastatin (Lipitor) since the drug is extensively bound to
Hepatic Insufficiency: In patients with chronic alcoholic liver disease,
plasma concentrations of Atorvastatin (Lipitor) are markedly increased. Cmax and
AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC
are approximately 16-fold and 11-fold increased, respectively, in patients with
Childs-Pugh B disease.