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

904 diminished remnant cholesterol content may decrease atherogenesis
directly, as chylomicron remnants are very atherogenic lipoproteins.
In experimental animal models of remnant dyslipidemia,
ezetimibe profoundly diminished diet-induced atherosclerosis (Davis
et al., 2001a).
Reduced delivery of intestinal cholesterol to the liver by chylomicron
remnants stimulates expression of the hepatic genes regulating
LDL receptor expression and cholesterol biosynthesis. The
greater expression of hepatic LDL receptors enhances LDL-C clearance
from the plasma. Indeed, ezetimibe reduces LDL-C levels by
15-20% (Gagné et al., 2002; Knopp et al., 2003).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Combination Therapy (Ezetimibe plus Statins). The maximal efficacy
of ezetimibe for lowering LDL-C is 15-20% when used as
monotherapy (Knopp et al., 2003). This reduction is equivalent to, or
less than, that attained with 10- to 20-mg doses of most statins.
Consequently, the role of ezetimibe as monotherapy of patients with
elevated LDL-C levels appears to be limited to the small group of
statin-intolerant patients.
The actions of ezetimibe are complementary to those of
statins. Statins, which inhibit cholesterol biosynthesis, increase intestinal
cholesterol absorption (Miettinen and Gylling, 2003).
Ezetimibe, which inhibits intestinal cholesterol absorption, enhances
cholesterol biosynthesis by as much as 3.5 times in experimental
animals (Davis et al., 2001b). Dual therapy with these two classes of
drugs prevents both the enhanced cholesterol synthesis induced by
ezetimibe and the increase in cholesterol absorption induced by
statins. This combination provides additive reductions in LDL-C
levels irrespective of the statin employed (Ballantyne et al., 2004;
Ballantyne et al., 2003; Melani et al., 2003).
A combination tablet containing ezetimibe, 10 mg, and various
doses of simvastatin (10, 20, 40, and 80 mg) has been approved
(VYTORIN). At the highest simvastatin dose (80 mg), plus ezetimibe
(10 mg), average LDL-C reduction was 60%, which is greater than
can be attained with any statin as monotherapy (Feldman et al., 2004).
Despite the robust laboratory-based efficacy of this combination, the
clinical cardiovascular benefits remain controversial when the combination
is compared to effects of statins alone (Kastelein et al., 2008;
Mitka, 2009).
Absorption, Fate, and Excretion. Ezetimibe is highly water insoluble,
precluding studies of its bioavailability. After ingestion, it is
glucuronidated in the intestinal epithelium and absorbed and then
enters an enterohepatic recirculation (Patrick et al., 2002).
Pharmacokinetic studies indicate that about 70% is excreted in the
feces and about 10% in the urine (as a glucuronide conjugate)
(Patrick et al., 2002). Bile-acid sequestrants inhibit absorption of
ezetimibe, and the two agents should not be administered together.
Otherwise, no significant drug interactions have been reported.
Adverse Effects and Drug Interactions. Other than rare allergic
reactions, specific adverse effects have not been observed in patients
taking ezetimibe. The safety of ezetimibe during pregnancy has not
been established. With doses of ezetimibe sufficient to increase exposure
10-150 times compared with a 10-mg dose in humans, fetal
skeletal abnormalities were noted in rats and rabbits. Since all statins
are contraindicated in pregnant and nursing women, combination
products containing ezetimibe and a statin should not be used by
women in childbearing years in the absence of contraception.
Therapeutic Use. Ezetimibe (ZETIA) is available as a 10-mg tablet
that may be taken at any time during the day, with or without food.
Ezetimibe may be taken with any medication other than bile-acid
sequestrants, which inhibit its absorption.
CLINICAL SUMMARY
Patients with any type of dyslipidemia (e.g., elevated
levels of cholesterol, low levels of HDL-C with or without
hypercholesterolemia, or moderately elevated
triglyceride levels with low HDL-C levels) are at risk of
developing atherosclerosis-induced vascular disease.
Maintaining ideal body weight, eating a diet low in
saturated fat and cholesterol, and regular exercise are
the cornerstones of managing dyslipidemia. In the
absence of vascular disease, type 2 diabetes mellitus,
or metabolic syndrome, adoption of these behaviors
will alleviate the need for cholesterol-lowering medications
in many subjects. Following assessment of their
future risk for a vascular disease event, patients should
be treated to achieve target lipid values. In virtually
every type of dyslipidemic patient, statins have been
proven to reduce the risk of subsequent CHD events
and nonhemorrhagic stroke. For this reason, statin therapy
should be the first-line choice when choosing
between classes of lipid-lowering agents.
A second principle is to treat with statin doses
adequate to reduce the patient’s lipid values to goal levels.
Most patients are not adequately treated and do not
reach goal values. Safety is greatly enhanced if doctors
discuss with their patients the rare but serious side
effects of hepatotoxicity and rhabdomyolysis with associated
renal failure.
Finally, patients with low HDL-C levels may not
receive the maximum benefit of lipid-lowering therapy
as prescribed by the ATP III guidelines based on levels
of LDL-C or non-HDL-C. For this reason, treatment of
patients with low HDL-C levels should be based on both
LDL-C levels and the ratio of total cholesterol:HDL-C
(Table 31–9).
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