section 20.3
Lipoprotein-Associated Disorders
449
C h o le s ty r a m in e
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C o le stip o l
F I G U R E 2 0 -1 1
Structures of bile acid séquestrants. Cholestyramine and colestipol are hydrophilic yet water-insoluble, nondigestible,
and nonabsorbable synthetic resins. They bind bile acids in the intestine to increase their loss in feces and thereby
decrease plasma cholesterol levels.
1. The steroid ring of cholesterol is not degradable
within the body. The principal avenue of cholesterol
secretion is via bile acid excretion in the feces.
Cholestyramine and colestipol (Figure 20-11) are
nonabsorbable resins that bind bile acids in the
intestine, causing their excretion in feces and
interruption of their enterohepatic circulation. The
decreased return of bile acids to the liver increases
conversion of cholesterol to bile acids and increases
the concentration of LDL receptors on hepatocytes.
This action mediates increased removal of plasma
LDL and decreased cholesterol levels. Bile acid
sequestrants are most effective in patients with
heterozygous FH or polygenic hypercholesterolemia.
It is not effective in patients with homozygous FH
who are completely deficient in LDL
receptors.
2. Nicotinic acid reduces the levels of VLDL and LDL
by inhibiting hepatic secretion of VLDL and by
suppressing mobilization of fatty acid from adipose
tissues. It is used in the treatment of types II, III, IV,
and V hyperlipoproteinemia because of its ability to
bring about large reductions in cholesterol and
triacylglycerol levels, but many patients experience
side effects such as flushing, hyperpigmentation,
gastrointestinal upset, diarrhea, liver function
abnormalities, hyperuricemia, and glucose
intolerance. The effect of nicotinic acid on
lipoprotein metabolism is not shared by
nicotinamide and is not related to its
vitamin function (Chapter 38).
3. The fibric acid derivatives
clofibrate
and
gemfibrozil
(Figure 20-12) promote rapid turnover of VLDL by
activating lipoprotein lipase. Gemfibrozil also inhibits
VLDL secretion. Use of fibric acids may result in a
modest elevation of plasma HDL cholesterol in
hypertriacylglycerolemic subjects. Occasional side
effects include abdominal discomfort and cholesterol
gallstones.
4.
Probucol
(Figure 20-12) significantly reduces plasma
cholesterol levels but has no effect on triacylglycerols.
It may act via blockage of intestinal cholesterol
transport. HDL cholesterol levels are reduced by this
drug. No consistent side effects have been reported.
5. HMG-CoA reductase inhibitors (statins) inhibit the
regulatory step in the biosynthesis of cholesterol.
They lower serum cholesterol and LDL cholesterol by
inhibition of hepatic cholesterol synthesis and, more
importantly, by up-regulating LDLreceptor activity.
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F I G U R E 2 0 - 1 2
Structures of plasma lipid-lowering drugs.
