Bile acid sequestering agents resins

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This class of agents was first developed for the treatment of cholestasis-related pruritus by Carey and Williams in 1960. Hashim and Van Itallie subsequently demonstrated that cholestyramine lowered plasma cholesterol and it has been in clinical use for 30 years. Other agents in this class are colestipol and the recently approved colesevelam.

Mechanism of action

The enterohepatic circulation of bile acids allows for only 6 or 7% of them to be excreted each day. These polymers with a molecular weight of over 106 are not absorbed and function by binding bile acids in the gastrointestinal lumen. Since an increase in bile acid excretion from the body and an increased production in the liver occur, relative depletion of cholesterol from the liver cells occurs inducing an increased level of hepatic LDL-receptor activity.49'50 The net effect is an increase in the catabolism of LDL-C and decreased plasma levels.

Dosage

Resins are dispensed in individual packets and are also available in a cost effective bulk formulation. Scoops, equivalent in size to the number of grams in one packet, are used to dispense from the parent container. The newest resin, cole-sevelam, has a hydrogel tablet formulation.

Results

Resins are associated with significant reductions in plasma total and LDL-C and with small increases in plasma HDL-C levels.51 Plasma triglycerides are inconsistently affected, but substantial increases may occur, if used in those with already elevated plasma triglyceride levels.52 In familial dysbeta-lipoproteinemia (type III or remnant removal disease) plasma triglyceride levels may increase by more than threefold.

Adverse reactions

No long-term adverse effects have been demonstrated.51 Drugs that are highly charged, including the cardiac glyco-sides, the anticoagulant warfarin, diuretic agents, as well as thyroid hormone, will have their absorption affected53 if taken in close proximity to resin administration. Concomitant warfarin and resin therapy may be extremely challenging.

If a resin's effect on the absorption of a specific medication is not known, the resin should be taken at least 4 hours before or 2 hours after other medications. In clinical situations of existing gastrointestinal malabsorption, the absorption of fat-soluble vitamins may also be reduced.

Clinical use

The biggest proportional reduction in lipid levels occurs at low doses and in those who have moderately elevated levels of cholesterol.54 Careful selection of the vehicle and logistics used in resin administration will promote long-term patient adherence. Premixing with cold water (taking advantage of the resin's hygroscopic nature) and drinking the preparation slowing is by far the most frequent and successful method of administration. Still, some patients prefer mixing with a heavily textured juice. Pre-existing gastrointestinal symptoms should be addressed before resin therapy is started. Bloating, belching and increased flatus are related to rapid ingestion. Dyspepsia and increased stool consistency or frank constipation can be managed with increases in fluids or dietary fiber intake.

The newest agent in the resin class is colesevelam, available for use in the US since 2000. It is a polymeric, high-potency, water-absorbing hydrogel with a non-systemic mechanism of action.55 Based on data from approximately 1400 subjects, colesevelam reduced LDL-C by a median of 20%; the reduction is dose-dependent. When combined with lovastatin, simvastatin, or atorvastatin, colesevelam will reduce LDL-C levels by 8 to 16% over that seen with the statin alone.55 Colesevelam has also been shown to increase HDL-C up to 9%; however, increases in triglycerides, as much as 25%, have also been reported.56 Colesevelam does not cause constipation, which is likely to improve patient adherence,55 and is formulated as a tablet, which should eliminate the palatability problems that some patients have with resin powders.56 In drug-interaction studies, colesevelam was coadministered with digoxin, warfarin, sustained-release metoprolol and verapamil, quinidine and valproic acid, and no clinically significant effects on absorption were reported.57

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