Bile Acid-Binding Resins

BILE ACID-BINDING RESINS

Colestipol, cholestyramine, and colesevelam are useful only forisolated increases in LDL. In patients who also have hypertriglyc-eridemia, VLDL levels may be further increased during treatment with resins.

Chemistry & Pharmacokinetics

The bile acid-binding agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intes-tinal lumen and prevent their reabsorption. The resin itself is not absorbed.

Mechanism of Action

The bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum (Figure 35–2). Excretion is increased up to tenfold when resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver via 7α-hydroxylation, which is normally controlled by negative feed-back by bile acids. Decreased activation of the FXR receptor by bile acids may result in a modest increase in plasma triglycerides but can also improve glucose metabolism in patients with diabe-tes. The latter effect is due to increased secretion of the incretin glucagon-like peptide-1 from the intestine, thus increasing insulin secretion. Increased uptake of LDL and IDL from plasma results from up-regulation of LDL receptors, particularly in liver. Therefore, the resins are without effect in patients with homozy-gous familial hypercholesterolemia who have no functioning receptors but may be useful in patients with receptor-defective combined heterozygous states.

Therapeutic Uses & Dosage

The resins are used in treatment of patients with primary hyper-cholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. If resins are used to treat LDL elevations in persons with combined hyperlipidemia, they may cause an increase in VLDL, requiring the addition of a sec-ond agent such as niacin. Resins are also used in combination with other drugs to achieve further hypocholesterolemic effect . They may be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation. Because the resins bind digitalis glycosides, they may be useful in digitalis toxicity.

Colestipol and cholestyramine are available as granular prepara-tions. A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is recommended. Total dosages of 30–32 g/d may be needed for maximum effect. The usual dosage for a child is 10–20 g/d. Granular resins are mixed with juice or water and allowed to hydrate for 1 minute. Colestipol is also available in 1 g tablets that must be swallowed whole, with a maximum dose of 16 g daily. Colesevelam is available in 625 mg tablets and as a suspension (1875-mg or 3750-mg packets). The maximum dose is six tablets or 3750 mg as suspension, daily. Resins should be taken in two or three doses with meals. They lack effect when taken between meals.

Toxicity

Common  complaints  are  constipation  and  bloating,  usually relieved by increasing dietary fiber or mixing psyllium seed with the resin. Resins should be avoided in patients with diver-ticulitis. Heartburn and diarrhea are occasionally reported. In patients who have preexisting bowel disease or cholestasis, ste-atorrhea may occur. Malabsorption of vitamin K occurs rarely, leading to hypoprothrombinemia. Prothrombin time should be measured frequently in patients who are taking resins and anti-coagulants. Malabsorption of folic acid has been reported rarely. Increased formation of gallstones, particularly in obese persons, was an anticipated adverse effect but has rarely occurred in practice.

Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic acid, phenylbutazone, aspirin, and ascorbic acid, among others. In gen-eral, additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorp-tion. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors.