Clinical pharmacology
Cholesterol and triglycerides in the bloodstream circulate as part of lipoprotein
complexes. These complexes can be separated by density ultracentrifugation into high
(HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein
fractions. Triglycerides (TG) and cholesterol synthesized in the liver are incorporated into
very low density lipoproteins (VLDLs) and released into the plasma for delivery to
peripheral tissues. In a series of subsequent steps, VLDLs are transformed into
intermediate density lipoproteins (IDLs), and cholesterol-rich low density lipoproteins
(LDLs). High density lipoproteins (HDLs), containing apolipoprotein A, are
hypothesized to participate in the reverse transport of cholesterol from tissues back to the
liver.
PRAVACHOL produces its lipid-lowering effect in two ways. First, as a consequence of
its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in
intracellular pools of cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of
circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic
synthesis of VLDL, the LDL precursor.
Clinical and pathologic studies have shown that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B − a
membrane transport complex for LDL) promote human atherosclerosis. Similarly,
decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein
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. Like LDL, cholesterol-
enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also
promote atherosclerosis. Elevated plasma TG 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 determined. In both normal volunteers and patients with
hypercholesterolemia, treatment with PRAVACHOL reduced Total-C, LDL-C, and
apolipoprotein B. PRAVACHOL also reduced VLDL-C and TG and produced increases
in HDL-C and apolipoprotein A. The effects of pravastatin on Lp (a), fibrinogen, and
certain other independent biochemical risk markers for coronary heart disease are
unknown. Although pravastatin is relatively more hydrophilic than other HMG-CoA
reductase inhibitors, the effect of relative hydrophilicity, if any, on either efficacy or
safety has not been established.
Pravachol
Cholesterol
Liver enzymes
Drug interactions
Dosage and administration
Pharmacokinetics metabolism
Skeletal muscle
Clinical pharmacology