DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 31–10
Dose (mg) of Statins Required to Achieve Various Reductions in Low-Density-Lipoprotein
Cholesterol from Baseline
20-25% 26-30% 31-35% 36-40% 41-50% 51-55%
Atorvastatin — — 10 20 40 80
Fluvastatin 20 40 80
Lovastatin 10 20 40 80
Pitavastatin 1 2 4
Pravastatin 10 20 40
Rosuvastatin — — — 5 10 20, 40
Simvastatin — 10 20 40 80
the mechanisms of action for non–lipid-lowering roles
of statins have not been established, and it is not known
whether these potential pleiotropic effects represent a
class-action effect, differ among statins, or are biologically
or clinically relevant. Until these questions are
resolved, selection of a specific statin should not be
based on any one of these effects. Nevertheless, the
potential importance of the non-lipid roles of statins
merits discussion.
Statins and Endothelial Function. A variety of studies have established
that the vascular endothelium plays a dynamic role in vasoconstriction/relaxation.
Hypercholesterolemia adversely affects the
processes by which the endothelium modulates arterial tone. Statin
therapy enhances endothelial production of the vasodilator nitric
oxide, leading to improved endothelial function. Statin therapy
improves endothelial function independent of changes in plasma
cholesterol levels.
Statins and Plaque Stability. The vulnerability of plaques to rupture
and thrombosis is of greater clinical relevance than the degree of
stenosis they cause (Corti et al., 2003). Statins affect plaque stability
in a variety of ways. They inhibit monocyte infiltration into the
artery wall and inhibit macrophage secretion of matrix metalloproteinases
in vitro. The metalloproteinases degrade extracellular matrix
components and thus weaken the fibrous cap of atherosclerotic
plaques.
Statins also appear to modulate the cellularity of the artery
wall by inhibiting proliferation of smooth muscle cells and enhancing
apoptosis. It is debatable whether these effects would be beneficial
or harmful if they occurred in vivo. Reduced proliferation of
smooth muscle cells and enhanced apoptosis could retard initial
hyperplasia and restenosis, but they also could weaken the fibrous
cap and destabilize the lesion. Interestingly, statin-induced suppression
of cell proliferation and the induction of apoptosis have been
extended to tumor biology. The effects of statins on isoprenoid
biosynthesis and protein phenylation associated with reduced synthesis
of the cholesterol precursor mevalonate may alter the development
of malignancies (Li et al., 2003; Wong et al., 2002).
Statins and Inflammation. Appreciation of the importance of inflammatory
processes in atherogenesis is growing, and statins may have
an anti-inflammatory role. Statins decreased the risk of CHD and levels
of CRP (an independent marker for inflammation and high CHD
risk) independently of cholesterol lowering (Libby and Aikawa, 2003;
Libby and Ridker, 2004). Body weight and the metabolic syndrome
are associated with elevated levels of highly sensitive CRP, leading
some to suggest that the CRP may simply be a marker of obesity and
insulin resistance (Pearson et al., 2003). It remains to be determined
whether the CRP is simply a marker of inflammation or if it contributes
to the pathogenesis of atherosclerosis. The clinical utility of
measuring CRP with “highly sensitive” assays appears to be limited
to those primary prevention subjects with a moderate (10-20%) 10-year
risk of sustaining a CHD event. Values of highly sensitive CRP
>3 mg/L suggest that such patients should be managed as secondary
prevention patients (Pearson et al., 2003).
Statins and Lipoprotein Oxidation. Oxidative modification of LDL
appears to play a key role in mediating the uptake of lipoprotein cholesterol
by macrophages and in other processes, including cytotoxicity
within lesions. Statins reduce the susceptibility of lipoproteins to oxidation
both in vitro and ex vivo.
Statins and Coagulation. The most compelling evidence of a
non–lipid-lowering effect of a statin is the rosuvastatin-mediated
reduction in venous thromboembolic events, a prespecified endpoint,
in JUPITER. This trial demonstrated a 43% reduction in venous
thromboembolic events in patients treated with rosuvastatin, 20 mg
daily, compared with placebo during a median follow-up period of
1.9 years (Glynn et al., 2009). Statins reduce platelet aggregation
and reduce the deposition of platelet thrombi. In addition, the different
statins have variable effects on fibrinogen levels. Elevated
plasma fibrinogen levels are associated with an increase in the incidence
of CHD.
Absorption, Metabolism, and Excretion
Absorption from the Small Intestine. After oral administration, intestinal
absorption of the statins is variable (30-85%). All the statins,
except simvastatin and lovastatin, are administered in the β-hydroxy
acid form, which is the form that inhibits HMG-CoA reductase.
Simvastatin and lovastatin are administered as inactive lactones that
must be transformed in the liver to their respective β-hydroxy acids,
simvastatin acid (SVA) and lovastatin acid (LVA). There is extensive
first-pass hepatic uptake of all statins, mediated primarily by
the organic anion transporter OATP1B1 (see Chapter 5).