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

reversible side effects include toxic amblyopia and toxic maculopathy.
Atrial tachyarrhythmias and atrial fibrillation have been reported,
more commonly in elderly patients. Niacin, at doses used in humans,
has been associated with birth defects in experimental animals and
should not be taken by pregnant women.
Therapeutic Use. Niacin is indicated for hypertriglyceridemia and
elevated LDL-C; it is especially useful in patients with both hypertriglyceridemia
and low HDL-C levels. There are two commonly
available forms of niacin. Crystalline niacin (immediate-release or
regular) refers to niacin tablets that dissolve quickly after ingestion.
Sustained-release niacin refers to preparations that continuously
release niacin for 6-8 hours after ingestion. NIASPAN is the only preparation
of niacin that is FDA-approved for treating dyslipidemia and
that requires a prescription.
Crystalline niacin tablets are available over the counter in a
variety of strengths from 50- to 500-mg tablets. To minimize the
flushing and pruritus, it is best to start with a low dose (e.g., 100 mg
twice daily taken after breakfast and supper). The dose may be
increased stepwise every 7 days by 100-200 mg to a total daily dose
of 1.5-2 g. After 2-4 weeks at this dose, transaminases, serum albumin,
fasting glucose, and uric acid levels should be measured. Lipid
levels should be checked and the dose increased further until the
desired effect on plasma lipids is achieved. After a stable dose is
attained, blood should be drawn every 3-6 months to monitor for the
various toxicities.
Because concurrent use of niacin and a statin can cause
myopathy, the statin should be administered at no more than 25% of
its maximal dose. Patients also should be instructed to discontinue
therapy if flu-like muscle aches occur. Routine measurement of CK
in patients taking niacin and statins does not assure that severe
myopathy will be detected before onset of symptoms, as patients
have developed myopathy after several years of concomitant use of
niacin with a statin.
Over-the-counter, sustained-release niacin preparations and
NIASPAN are effective up to a total daily dose of 2 g. All doses of sustained-release
niacin, but particularly doses above 2 g/day, have been
reported to cause hepatotoxicity, which may occur soon after beginning
therapy or after several years of use (Knopp et al., 2009). The
potential for severe liver damage should preclude use of OTC preparations
in most patients, including those who have taken an equivalent
dose of crystalline niacin safely for many years and are
considering switching to a sustained-release preparation. NIASPAN
may be less likely to cause hepatotoxicity.
Fibric Acid Derivatives: PPAR Activators
History. In 1962, Thorp and Waring reported that ethyl chlorophenoxyisobutyrate
lowered lipid levels in rats. In 1967, the ester form
(clofibrate) was approved for use in the U.S. and became the most
widely prescribed hypolipidemic drug. Its use declined dramatically,
however, after the World Health Organization (WHO) reported that,
despite a 9% reduction in cholesterol levels, clofibrate treatment did
not reduce fatal cardiovascular events, although nonfatal infarcts
were reduced. Total mortality was significantly greater in the clofibrate
group. The increased mortality was due to multiple causes,
including cholelithiasis. Interpretation of these negative results was
clouded by failure to analyze the data according to the intention-totreat
principle. A later analysis demonstrated that the apparent
increase in noncardiac mortality did not persist in the clofibratetreated
patients after discontinuation of the drug (Heady et al., 1992).
Clofibrate use was virtually abandoned after publication of the
results of the 1978 WHO trial. Clofibrate as well as two other
fibrates, gemfibrozil and fenofibrate, remain available in the U.S.
Two subsequent trials involving only men have reported
favorable effects of gemfibrozil therapy on fatal and nonfatal cardiac
events without an increase in morbidity or mortality (Frick et al.,
1987; Rubins et al., 1999). A third trial of men and women reported
fewer events in a subgroup characterized by high triglyceride and
low HDL-C levels (Haim et al., 1999).
Chemistry. Clofibrate, the prototype of the fibric acid derivatives,
is the ethyl ester of p-chlorophenoxyisobutyrate. Gemfibrozil is a
nonhalogenated phenoxypentanoic acid and thus is distinct from
the halogenated fibrates. A number of fibric acid analogs (e.g.,
fenofibrate, bezafibrate, ciprofibrate) have been developed and are
used in Europe and elsewhere (see Figure 31–4 for their structural
formulas).
CLOFIBRATE
FENOFIBRATE
CIPROFIBRATE
BEZAFIBRATE
CH 3
Cl
O C COOC 2 H 5
CH 3
GEMFIBROZIL
CH 3
CH 3
O (CH 2 ) 3 C COOH
CH CH 3
3
Cl
Cl
O
CNH(CH 2 ) 2
Figure 31–4. Structures of the fibric acids.
Cl
O
C
Cl
O
O
O
CH 3 CH 3
C
CH 3
CH 3
C
CH 3
CH 3
C
COOCH
COOH
CH 3
COOH
CH 3
901
CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA