Colesevelam. Colesevelam (Welchol) is one of the more recent additions to the class of bile acid-sequestering agents. Its structure is rather novel, and at first glance, it appears to look like the previous examples of cholestyramine and colestipol. It does not possess the chloride ions, however, and, strictly speaking, is not an anion-exchange resin. This compound has good selectivity for both the trihydroxy and dihydroxy bile acids. The selectivity for these hydroxyl-ated derivatives lends some insight into the reduced side effects colesevelam possesses, compared with cholestyramine and colestipol. Unlike the older agents, colesevelam does not have a high incidence of causing constipation. This results from the compound's ability to "pick up" water as a result of its affinity for hydroxyl system (i.e., hydrogen bonding with either the bile acid or water). In turn, this yields softer, gel-like materials that are easier to excrete.
Nicotinic Acid. Nicotinic acid, 3-pyridinecarboxylic acid (Niacin), is effective in the treatment of all types of hyperlipoproteinemia except type I, at doses above those given as a vitamin supplement. The drug reduces VLDL synthesis and, subsequently, its plasma products, IDL and LDL. Plasma triglyceride levels are reduced because of the decreased VLDL production. Cholesterol levels are lowered, in turn, because of the decreased rate of LDL formation from VLDL. Although niacin is the drug of choice for type II hyperlipoproteinemias, its use is limited because of the vasodilating side effects. Flushing occurs in practically all patients but generally subsides when the drug is discontinued.
The hypolipidemic effects of niacin may be caused by its ability to inhibit lipolysis (i.e., prevent the release of FFAs and glycerol from fatty tissues). Therefore, there is a reduced reserve of FFA in the liver and diminution of lipoprotein biosynthesis, which reduces the production of VLDL. The decreased formation of lipoproteins leads to a pool of unused cholesterol normally incorporated in VLDL. This excess cholesterol is then excreted through the biliary tract.
Niacin (nicotinic acid) may be administered as aluminum nicotinate (Nicalex). This is a complex of aluminum hydroxy nicotinate and niacin. The aluminum salt is hydrolyzed to aluminum hydroxide and niacin in the stomach. The aluminum salt seems to have no advantage over the free acid. Hepatic reaction appears more prevalent than with niacin.
Nicotinic acid has been esterified to prolong its hypolipidemic effect. Pentaerythritol tetranicotinate has been more effective experimentally than niacin in reducing cholesterol levels in rabbits. Sorbitol and myo-inositol hexanicotinate polyesters have been used in the treatment of patients with atherosclerosis obliterans.
The usual maintenance dose of niacin is 3 to 6 g/day given in three divided doses. The drug is usually given at mealtimes to reduce the gastric irritation that often accompanies large doses.
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