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

Mechanism of Action. The bile-acid sequestrants are
highly positively charged and bind negatively charged
bile acids. Because of their large size, the resins are not
absorbed, and the bound bile acids are excreted in the
stool. Because more than 95% of bile acids are normally
reabsorbed, interruption of this process depletes
the pool of bile acids, and hepatic bile-acid synthesis
increases. As a result, hepatic cholesterol content
declines, stimulating the production of LDL receptors,
an effect similar to that of statins. The increase in
hepatic LDL receptors increases LDL clearance and
lowers LDL-C levels, but this effect is partially offset
by the enhanced cholesterol synthesis caused by
upregulation of HMG-CoA reductase. Inhibition of
reductase activity by a statin substantially increases the
effectiveness of the resins.
The resin-induced increase in bile-acid production is accompanied
by an increase in hepatic triglyceride synthesis, which is of
consequence in patients with significant hypertriglyceridemia (baseline
triglyceride level >250 mg/dL). In such patients, bile-acid
sequestrant therapy may cause striking increases in triglyceride levels.
Use of colesevelam to lower LDL-C levels in hypertriglyceridemic
patients should be accompanied by frequent (every 1-2 weeks) monitoring
of fasting triglyceride levels until the triglyceride level is stable,
or the use of colesevelam in these patients should be avoided.
Effects on Lipoprotein Levels. The reduction in LDL-C by resins
is dose dependent. Doses of 8-12 g of cholestyramine or 10-15 g of
colestipol are associated with 12-18% reductions in LDL-C.
Maximal doses (24 g of cholestyramine, 30 g of colestipol) may
reduce LDL-C by as much as 25% but will cause gastrointestinal
side effects that are poorly tolerated by most patients. One to two
weeks is sufficient to attain maximal LDL-C reduction by a given
resin dose. In patients with normal triglyceride levels, triglycerides
may increase transiently and then return to baseline. HDL-C levels
increase 4-5%. Statins plus resins or niacin plus resins can reduce
LDL-C by as much as 40-60%. Colesevelam, in doses of 3-3.75 g,
reduces LDL-C levels by 9-19%.
Adverse Effects and Drug Interactions. The resins are generally
safe, as they are not systemically absorbed. Because they are administered
as chloride salts, rare instances of hyperchloremic acidosis
have been reported. Severe hypertriglyceridemia is a contraindication
to the use of cholestyramine and colestipol because these resins
increase triglyceride levels. At present, there are insufficient data on
the effect of colesevelam on triglyceride levels.
Cholestyramine and colestipol both are available as a powder
that must be mixed with water and drunk as a slurry. The gritty sensation
is unpleasant to patients initially but can be tolerated.
Colestipol is available in a tablet form that reduces the complaint of
grittiness but not the gastrointestinal symptoms. Colesevelam is
available as a hard capsule that absorbs water and creates a soft,
gelatinous material that allegedly minimizes the potential for gastrointestinal
irritation.
Patients taking cholestyramine and colestipol complain of
bloating and dyspepsia. These symptoms can be substantially
reduced if the drug is completely suspended in liquid several hours
before ingestion (e.g., evening doses can be mixed in the morning
and refrigerated; morning doses can be mixed the previous evening
and refrigerated). Constipation may occur but sometimes can be prevented
by adequate daily water intake and psyllium, if necessary.
Colesevelam may be less likely to cause the dyspepsia, bloating, and
constipation observed in patients treated with cholestyramine or
colestipol.
Cholestyramine and colestipol bind and interfere with the
absorption of many drugs, including some thiazides, furosemide,
propranolol, L-thyroxine, digoxin, warfarin, and some of the statins.
The effect of cholestyramine and colestipol on the absorption of
most drugs has not been studied. For this reason, it is wise to administer
all drugs either 1 hour before or 3-4 hours after a dose of
cholestyramine or colestipol. Colesevelam does not appear to interfere
with the absorption of fat-soluble vitamins or of drugs such as
digoxin, lovastatin, warfarin, metoprolol, quinidine, and valproic
acid. The maximum concentration and the AUC of sustained-release
verapamil are reduced by 31% and 11%, respectively, when the drug
is co-administered with colesevelam. The effect of colesevelam on
the absorption of other drugs has not been tested, but it seems prudent
to recommend that patients take other medications 1 hour before
or 3-4 hours after a dose of colesevelam.
Preparations and Use. Cholestyramine resin (QUESTRAN, others) is
available in bulk (with scoops that measure a 4-g dose) or in individual
packets of 4 g. Additional flavorings are added to increase palatability.
The “light” preparations contain artificial sweeteners rather than
sucrose. Colestipol hydrochloride (COLESTID, others) is available in
bulk, in individual packets containing 5 g of colestipol, or as 1-g tablets.
Resins should never be taken in the dry form. The powdered
forms of cholestyramine (4 g/dose) and colestipol (5 g/dose) are
either mixed with a fluid (water or juice) and drunk as a slurry or
mixed with crushed ice in a blender. Ideally, patients should take the
resins before breakfast and before supper, starting with one scoop
or packet twice daily, and increasing the dosage after several weeks
or longer as needed and as tolerated. Patients generally will not take
more than two doses (scoops or packets) twice a day.
Colesevelam hydrochloride (WELCHOL) is available as a solid
tablet containing 0.625 g of colesevelam and as a powder in packets
of 3.75 g or 1.875 g. The starting dose is either three tablets taken
twice daily with meals or all six tablets taken with a meal. The tablets
should be taken with a liquid. The maximum daily dose is seven
tablets (4.375 g). The powder in the packets is first suspended in 4-
8 oz of water and should be taken with meals. Dosing of the packet
containing 3.75 g is once daily; the packet containing 1.875 g is
taken twice daily.
Niacin (Nicotinic Acid)
Niacin, nicotinic acid (pyridine-3-carboxylic acid), one
of the oldest drugs used to treat dyslipidemia, favorably
affects virtually all lipid parameters.
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CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA