Continuing Education Activity

Cholestyramine is used for the treatment of primary hypercholesterolemia. The reduction in LDL cholesterol by the resin is dose-dependent. A dose of 8 to 12 grams of cholestyramine is associated with 12% to 18% reduction in LDL-cholesterol. It also reduces the risk of coronary artery disease. Cholestyramine can be used in patients with bile-acid diarrhea or choleretic enteropathy due to limited ileal disease or resection. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of cholestyramine that is pertinent information for members of the interprofessional team when lipid lowering therapy is indicated.

Objectives:

• Identify the mechanism of action of cholestyramine.
• Outline the approved and potential indications of cholestyramine.
• Recall the potential side effects and adverse events of cholestyramine.
• Summarize the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patient receiving treatment with cholestyramine.

Indications

Cholestyramine has the following primary indications:

1. Used for patient treatment of primary hypercholesterolemia. The reduction in LDL Cholesterol by the resin is dose-dependent. A dose of 8-12 gram of Cholestyramine is associated with 12%-18% reduction in LDL-Cholesterol. One to two weeks is adequate to attain maximal LDL-Cholesterol reduction. Maximal dose of cholestyramine (24 gram) may reduce LDL-Cholesterol by as much as 25%. However, this will also lead to gastrointestinal side effects, which are often not well tolerated.[1]
2. Pruritus can occur in patients with cholestatic disease and incomplete biliary obstruction. Cholestyramine, in doses of 4 grams, one to three times daily, is effective in 80% of the cases.[2]

Other Clinical Applications:

1. Cholestyramine has been shown to decrease cardiovascular mortality and morbidity by 19% compared to placebo in patients with hypercholesterolemia as per the Lipid Research Clinic Coronary Primary Prevention Trial. Per the trial, the reduction in total cholesterol and LDL levels correlates to the decrease in the risk of coronary artery disease.[3]
2. A randomized, double-blind crossover study with 21 patients performed by Garg et al., showed that cholestyramine had glucose lowering effect when used in individuals with dyslipidemia and type 2 Diabetes mellitus. The study showed a 13% decrease in plasma glucose levels in patients after using 8 grams of cholestyramine twice daily for six weeks.[3][4]
3. Cholestyramine can be used in patients with bile-acid diarrhea or choleretic enteropathy due to limited ileal disease or resection. Diarrhea develops in these patients because of the stimulation of active chloride secretion by bile acids in the colon. However, cholestyramine is not helpful in patients with extensive ileal disease and/or resection presenting with fatty acid diarrhea. In extensive ileal disease or resection, the body cannot produce sufficient quantities of bile acid to compensate for the increased loss due to extensive bowel loss, leading to impaired micelle formation and steatorrhea.
4. There have been studies and case reports showing the effectiveness of cholestyramine as an adjunct therapy to antithyroid medications for refractory thyrotoxicosis leading to a more rapid reduction in serum thyroid hormone levels. However, the effect of cholestyramine is confined to a short period and the long-term efficacy of the drug remains unclear.
5. The inhibition of enterohepatic circulation by cholestyramine makes it an effective drug in the management of hyperthyroidism due to thyroiditis and factitious thyroid hormone use.[5][6]

Mechanism of Action

Cholestyramine is a large cationic exchange resin polymer. It is insoluble in water.

Bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum. Excretion is increased up to tenfold when cholestyramine is given, resulting in the enhanced conversion of cholesterol to bile acids in the liver via 7a-hydroxylation, which is normally controlled by negative feedback by bile acids.

Increased uptake of LDL-Cholesterol and IDL from plasma results from the upregulation of the LDL receptors, particularly in the liver. Therefore, the bile acid resins, including cholestyramine is not helpful in patients with homozygous familial hypercholesterolemia, who have no functioning receptors.

Decreased activation of the farnesoid X receptor (FXR receptor) by bile acids may result in a modest increase in plasma triglycerides but can also improve glucose metabolism in patients with diabetes. The latter effect is due to the increased secretion of the incretin glucagon-like peptide-1 (GLP-1) from the intestine, thus increasing insulin secretion.

Cholestyramine also interferes with the metabolism of thyroid hormone. Thyroid hormone is metabolized mainly in the liver where it is conjugated to glucuronides and sulfates. These conjugation products then enter the enterohepatic circulation by excretion into the bile. A fraction of conjugated products are deconjugated in the intestine, and free hormones are reabsorbed. In states of thyrotoxicosis, there is increased enterohepatic circulation of thyroid hormone. Cholestyramine decreases reabsorption of thyroid hormone from enterohepatic circulation.[5][6]

Administration

Cholestyramine is available as a granular preparation. Cholestyramine should ideally be taken with breakfast when it is given to treat pruritus associated with cholestasis. Symptoms of pruritus are less frequent in the morning as it is believed that the pruritogenic factors are concentrated in the gallbladder during overnight fasting. Most patients with chronic cholestasis and partial biliary obstruction will notice some relief of their symptoms after a week of therapy. If not, another 4-gram dose may be given after breakfast. Additional doses, if needed, can be taken with meals 2-3 times daily; the response with additional doses is not marked. The lowest possible dose that controls pruritus should be used. Care should be exercised when taking other medications which have the potential to mix with cholestyramine, leading to diminished efficacy. The maintenance dose is usually 4 grams/day, but the effective dose for treatment of cholestasis ranges from 4 to 16 grams/day.

Although cholestyramine lowers serum bile acid levels by inhibiting the reabsorption of bile acids from small bowel, other bile acid sequestrants such as colesevelam do not relieve pruritus in cholestasis. Thus binding of other pruritogens, stimulating the release of other endogenous anti-opioid agents such as cholecystokinin might explain why cholestyramine is effective in the relief of pruritus in other non-cholestatic disorders such as polycythemia vera and uremia.

Adverse Effects

• Common adverse effects are dyspepsia and bloating. These symptoms can be decreased if cholestyramine is completely suspended in liquid several hours before ingestion.
• Constipation is a common side effect which can be prevented with adequate water and fiber intake.
• Decreased palatability due to gritty sensation from drinking the powdered solution of cholestyramine.
• Cholestyramine is considered a safe medication since it is not systemically absorbed. However, in rare instances such as in patients with renal insufficiency and patients on aldosterone antagonists such as spironolactone, it is known to cause hyperchloremic metabolic acidosis.
• Cholestyramine is a cationic resin which exchanges chloride anions for bile acids in the lumen of the small intestine, resulting in fecal excretion of bile acids. The chloride and bicarbonate anti-porter present at the apical brush border of the duodenum causes increased absorption of chloride and secretion of bicarbonate leading to hyperchloremic metabolic acidosis. This effect is more pronounced in patients with impaired urinary acidification due to renal insufficiency and medications such as spironolactone since there is no adequate renal compensation.[7]

Contraindications

Cholestyramine is contraindicated in cases of severe hypertriglyceridemia and complete biliary obstruction.

Toxicity

• Interference with absorption of fat-soluble vitamins such as vitamin K which can lead to derangements in clotting factors. Patients may require supplementation of fat-soluble vitamins especially if they are on long-term cholestyramine therapy.

• Cholestyramine can interfere with the absorption of many medications such as digitalis glycosides, propranolol, thiazides, warfarin, tetracycline, thyroxine, iron salts, statins (pravastatin and fluvastatin), ezetimibe, phenobarbital, non-steroidal anti-inflammatory medications, loperamide, and tricyclic antidepressants. Due to drug interactions, it is advised to administer other medications 1 hour before or 4 hours after taking cholestyramine.[8]

Enhancing Healthcare Team Outcomes

Cholestyramine has been around for over half a century. Most clinicians, sadly, do not know that is it a useful therapeutic agent for the treatment of both hypercholesterolemia and pruritus. Healthcare workers who have patients with chronic pruritus should be familiar with this agent as it can improve the quality of life. Primary caregivers, nurse practitioners, internists and other physicians who deal with patients with liver failure may find the drug useful for managing pruritus. Cholestyramine is a relatively safe drug, but patients need to be educated on how to use it for maximal efficiency and prevention of drug interactions. For those healthcare workers who would like to use the drug, the pharmacist is the ideal person to provide more practical details on dosage and duration.[9][10]