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

900 Niacin is a water-soluble B-complex vitamin that
functions as a vitamin only after its conversion to NAD
or NADP, in which it occurs as an amide. Both niacin
and its amide may be given orally as a source of niacin
for its functions as a vitamin, but only niacin affects
lipid levels. The hypolipidemic effects of niacin require
larger doses than are required for its vitamin effects.
Niacin is the best agent available for increasing HDL-C
(30-40%); it also lowers triglycerides by 35-45% (as
effectively as fibrates and the more effective statins) and
reduces LDL-C levels by 20-30%. Niacin also is the
only lipid-lowering drug that reduces Lp(a) levels significantly.
Despite its salutary effect on lipids, niacin
has side effects that limit its use (see “Adverse Effects,”
later in the chapter).
Mechanism of Action. In adipose tissue, niacin inhibits
the lipolysis of triglycerides by hormone-sensitive
lipase, which reduces transport of free fatty acids to the
liver and decreases hepatic triglyceride synthesis.
Niacin and related compounds (e.g., 5-methylpyrazine-
2-carboxylic-4-oxide, acipimox) may exert their effects
on lipolysis by inhibiting adipocyte adenylyl cyclase.
A GPCR for niacin has been identified and designated
as GPR109A; it couples to G i
(Wise et al., 2003); its
mRNA is highly expressed in the adipose tissue and
spleen, sites of high-affinity nicotinic acid binding
(Lorenzen et al., 2001). Acting on this receptor, niacin
stimulates the G i
–adenylyl cyclase pathway in
adipocytes, inhibiting cyclic AMP production and
decreasing hormone-sensitive lipase activity, triglyceride
lipolysis, and release of free fatty acids. Niacin
also may inhibit a rate-limiting enzyme of triglyceride
synthesis, diacylglycerol acyltransferase-2 (Ganji et al.,
2004).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
In the liver, niacin reduces triglyceride synthesis by inhibiting
both the synthesis and esterification of fatty acids, effects that
increase apoB degradation. Reduction of triglyceride synthesis
reduces hepatic VLDL production, which accounts for the reduced
LDL levels. Niacin also enhances LPL activity, which promotes the
clearance of chylomicrons and VLDL triglycerides. Niacin raises
HDL-C levels by decreasing the fractional clearance of apoA-I in
HDL rather than by enhancing HDL synthesis. This effect is due to
a reduction in the hepatic clearance of HDL-apoA-I, but not of cholesteryl
esters, thereby increasing the apoA-I content of plasma and
augmenting reverse cholesterol transport. In macrophages, niacin
stimulates expression of the scavenger receptor CD36 and the cholesterol
exporter ABCA1. The net effect of niacin on monocytic cells
(“foam cells”) is HDL-mediated reduction of cellular cholesterol content
(Rubic et al., 2004).
Effects on Plasma Lipoprotein Levels. Regular or crystalline niacin
in doses of 2-6 g/day reduces triglycerides by 35-50%; the maximal
effect occurs within 4-7 days. Reductions of 25% in LDL-C levels
are possible with doses of 4.5-6 g/day, but 3-6 weeks are required
for maximal effect. HDL-C increases less in patients with low HDL-
C levels (<35 mg/dL) than in those with higher levels.
Absorption, Fate, and Excretion. The pharmacological doses of
regular (crystalline) niacin used to treat dyslipidemia are almost
completely absorbed, and peak plasma concentrations (up to 0.24
mmol) are achieved within 30-60 minutes. The t 1/2
is about 60 minutes,
which accounts for the necessity of dosing two to three times
daily. At lower doses, most niacin is taken up by the liver; only the
major metabolite, nicotinuric acid, is found in the urine. At higher
doses, a greater proportion of the drug is excreted in the urine as
unchanged nicotinic acid.
Adverse Effects. Two of niacin’s side effects, flushing and dyspepsia,
limit patient compliance. The cutaneous effects include flushing
and pruritus of the face and upper trunk, skin rashes, and
acanthosis nigricans. Flushing and associated pruritus are
prostaglandin mediated. Flushing is worse when therapy is initiated
or the dosage is increased but ceases in most patients after 1-2 weeks
of a stable dose. Taking an aspirin each day alleviates the flushing in
many patients. Flushing recurs if only one or two doses are missed,
and the flushing is more likely to occur when niacin is consumed
with hot beverages (coffee, tea) or with ethanol-containing beverages.
Flushing is minimized if therapy is initiated with low doses
(100-250 mg twice daily) and if the drug is taken after breakfast or
supper. Dry skin, a frequent complaint, can be dealt with by using
skin moisturizers, and acanthosis nigricans can be dealt with by
using lotions or creams containing salicylic acid. Dyspepsia and
rarer episodes of nausea, vomiting, and diarrhea are less likely to
occur if the drug is taken after a meal. Patients with any history of
peptic ulcer disease should not take niacin because it can reactivate
ulcer disease.
The most common, medically serious side effects are hepatotoxicity,
manifested as elevated serum transaminases, and hyperglycemia.
Both regular (crystalline) niacin and sustained-release
niacin, which was developed to reduce flushing and itching, have
been reported to cause severe liver toxicity. An extended-release
niacin (NIASPAN) appears to be less likely to cause severe hepatotoxicity,
perhaps simply because it is administered once daily instead of
more frequently. The incidence of flushing and pruritus with this
preparation is not substantially different from that with regular niacin.
Severe hepatotoxicity is more likely to occur when patients take more
than 2 g of sustained-release, over-the-counter preparations. Affected
patients experience flu-like fatigue and weakness. Usually, aspartate
transaminase and ALT are elevated, serum albumin levels decline,
and total cholesterol and LDL-C levels decline substantially. In fact,
reductions in LDL-C of 50% or more in a patient taking niacin should
be viewed as a sign of niacin toxicity.
In patients with diabetes mellitus, niacin should be used cautiously
because niacin-induced insulin resistance can cause severe
hyperglycemia. Niacin use in patients with diabetes mellitus often
mandates a change to insulin therapy. In a study of patients with type
2 diabetes taking niaspan, 4% stopped taking the drug because of
inadequate glycemic control (Grundy et al., 2002). If niacin is prescribed
for patients with known or suspected diabetes, blood glucose
levels should be monitored at least weekly until proven to be
stable. Niacin also elevates uric acid levels and may reactivate gout.
A history of gout is a relative contraindication for niacin use. Rarer