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Cholestyramine Resin
Indications
Cholestyramine is a bile acid sequestrant. Examples of other bile acid sequestrants include colestipol and colesevelam.[1]
FDA-Approved Indications
Cholestyramine has been approved for the treatment of primary hypercholesterolemia. Per AHA/ACC guidelines, bile acid sequestrants decrease LDL-C levels by 15% to 30%, depending on the dose. The National Lipid Association (NLA) has stated that statins are the first line of cholesterol-lowering medications. Other drug therapies like bile acid sequestrants, cholesterol absorption inhibitors, fibrates, and nicotinic acid may be considered for patients with intolerance/contraindications to statin therapy. Bile acid sequestrants are preferred during pregnancy.[2][3][4][5]
Pruritus can occur in patients with cholestatic disease and incomplete biliary obstruction. A 4 g dose of cholestyramine 1 to 3 times daily is effective in 80% of the cases. The American College of Gastroenterology endorses the administration of cholestyramine to treat pruritus.[6][7][8]
Off-Label Uses
Per the Lipid Research Clinic Coronary Primary Prevention Trial, cholestyramine has been shown to reduce cardiovascular mortality and morbidity by 19% in patients with hypercholesterolemia compared to placebo. The reduction in total cholesterol and LDL levels correlates with a reduced risk of coronary artery disease. A randomized, double-blind crossover study involving 21 patients by Garg et al showed that cholestyramine reduced glucose levels when used in individuals with dyslipidemia and type 2 diabetes mellitus. The study showed a 13% decrease in plasma glucose levels in patients after administration of 8 g of cholestyramine twice daily for 6 weeks.[9][10]
Cholestyramine can be used to treat patients with bile-acid diarrhea or choleretic enteropathy due to limited ileal disease or resection.[11][12] Diarrhea develops in these patients because bile acids stimulate active chloride secretion in the colon. However, cholestyramine is not helpful in patients with extensive ileal disease or resection presenting with fatty acid diarrhea. Patients with these conditions 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.
Studies and case reports show cholestyramine's effectiveness 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 drug's long-term efficacy remains unclear. 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.[13][14][15][16][17]
Cholestyramine can help manage diarrhea and improve bowel function in children with Hirschsprung disease, as stated by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN). This medication binds bile acids, forming complexes that reduce colonic water content and slow bowel transit.[18]
According to the American Association for the Study of Liver Diseases (AASLD), cholestyramine is commonly used to manage pruritus in patients with cholestatic liver diseases. The drug binds bile acids in the gastrointestinal tract, preventing their reabsorption, which helps reduce the accumulation of bile salts contributing to itching.[19]
One study describes how cholestyramine can be used to treat hyperphosphatemia in patients on hemodialysis.[20]
Mechanism of Action
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Mechanism of Action
Cholestyramine is a large cationic exchange resin polymer that is insoluble in water. As metabolites of cholesterol, bile acids are normally reabsorbed in the jejunum and ileum efficiently. Excretion is increased up to 10-fold when cholestyramine is given, resulting in the enhanced conversion of cholesterol to bile acids in the liver via 7a-hydroxylation, which is controlled by negative feedback provided by bile acids. Increased LDL and IDL cholesterol uptake from plasma results from the upregulation of the LDL receptors, particularly in the liver. Therefore, the bile acid resins, including cholestyramine, are ineffective in patients with homozygous familial hypercholesterolemia with no functioning receptors.
Decreased activation of the farnesoid X receptor (FXR) by bile acids may result in a modest increase in plasma triglycerides but can also improve glucose metabolism in patients with diabetes.[21] 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 primarily 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 is deconjugated in the intestine, and free hormones are reabsorbed. During thyrotoxicosis, there is increased enterohepatic circulation of thyroid hormone. Cholestyramine decreases the reabsorption of thyroid hormone from enterohepatic circulation.[13][14]
Pharmacokinetics
Absorption: Cholestyramine is not absorbed from the gastrointestinal tract.
Metabolism: Anion exchange resins, such as cholestyramine, bind bile acids in the intestine and reduce the enterohepatic circulation of bile acids, leading to accelerated conversion of cholesterol to bile acids. Small heterodimer partner (SHP) is a key molecule regulating bile acid synthesis and plays a role in cholesterol metabolism in the liver.[22][1]
Distribution: Cholestyramine is limited to the gastrointestinal tract, shows prolonged gastric retention through mucoadhesion, and is distributed throughout the stomach.[23]
Elimination: Cholestyramine is excreted in feces.
Administration
Available Dosage Forms and Strengths
Cholestyramine is available as an oral formulation packet containing 4 g of granules per dose and an oral powder containing 4 g per dose.
Adult Dosage
Dyslipidemia: The reduction in LDL cholesterol by cholestyramine resin is dose-dependent. A dose of 8 to 12 g of cholestyramine is associated with a 12% to 18% reduction in LDL cholesterol. A therapy length of 2 weeks is adequate to attain maximal LDL cholesterol reduction. A maximal dose of cholestyramine (24 g) may reduce LDL cholesterol by up to 25%. However, this will also lead to gastrointestinal side effects, which are often not well-tolerated.[24]
Pruritus: For patients with pruritus associated with cholestasis, cholestyramine should ideally be taken with breakfast. Symptoms of pruritus are less frequent in the morning, and 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 g dose may be given after breakfast. Additional doses can be taken with meals 2 or 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 that can potentially mix with cholestyramine, leading to diminished efficacy. The maintenance dose is usually 4 g daily, but the effective dose for treating cholestasis ranges from 4 to 16 g daily.
Although cholestyramine lowers serum bile acid levels by inhibiting the reabsorption of bile acids from the small bowel, other bile acid sequestrants, such as colesevelam, do not relieve pruritus in cholestasis. Thus, binding of other pruritogens and stimulating the release of other endogenous anti-opioid agents, such as cholecystokinin, might explain why cholestyramine is effective in relieving pruritus in other non-cholestatic disorders, such as polycythemia versus uremia.
Specific Patient Populations
Hepatic impairment: No dose adjustment is required.
Renal impairment: Patients with renal impairment and volume depletion are at risk of hyperchloremic metabolic acidosis; use with caution.[25]
Pregnancy considerations: According to the National Lipid Association guidelines, bile acid sequestrants can be administered to pregnant women.[3]
Breastfeeding considerations: Cholestyramine is a non-absorbable resin. Due to its inability to penetrate the maternal bloodstream, it does not pass to the infant through breast milk. Therefore, its use during lactation is deemed acceptable.[26]
Pediatric patients: As per NLA guidelines, statins and bile acid sequestrants are treatments known to be effective and safe for children and adolescents. However, poor palatability often hinders adherence in these patients.[3][27]
Older patients: Please refer to adult dosing. Concurrent drugs should be given as described in the Interactions section.
Adverse Effects
The various adverse effects associated with cholestyramine resin administration are discussed below.[25][28][29][30][29][28]
- Dyspepsia and bloating: can be decreased if cholestyramine is wholly suspended in liquid several hours before ingestion
- Constipation: preventable with adequate water and fiber intake
- Decreased palatability: due to a gritty sensation from drinking the powdered cholestyramine solution
- Hyperchloremic metabolic acidosis: Cholestyramine is generally considered safe since it is not systemically absorbed. However, in rare instances, such as in patients with renal insufficiency and patients receiving aldosterone antagonists such as spironolactone, it is known to cause hyperchloremic metabolic acidosis. Cholestyramine is a cationic resin that exchanges chloride anions for bile acids in the lumen of the small intestine, resulting in the fecal excretion of bile acids. The chloride and bicarbonate anti-porter present at the apical brush border of the duodenum causes increased chloride absorption and bicarbonate secretion, 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.
- Crystal deposition and small bowel perforation: infrequent adverse effects associated with cholestyramine administration
- Colitis: One case report describes cholestyramine-induced colitis
Drug-Drug Interactions
Cholestyramine can interfere with the absorption of many medications such as digitalis glycosides, propranolol, thiazides, warfarin, tetracycline, iron salts, statins (eg, 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.[31]
The American Thyroid Association has stated that cholestyramine can interfere with the absorption of levothyroxine.[32]
Contraindications
Cholestyramine is contraindicated in cases of severe hypertriglyceridemia and complete biliary obstruction.[28]
Warning and Precautions
- Phenylketonuria: Some cholestyramine formulations may contain phenylalanine. This medication should not be administered to patients with phenylketonuria.
- Bleeding risk: High cholestyramine doses may cause vitamin K deficiency and increase fetal hemorrhage risk. Clinicians should supplement vitamin K if PT is prolonged. Frequent PT/INR monitoring may be needed for women receiving cholestyramine.[33]
Monitoring
Clinicians should monitor patients for gastrointestinal adverse effects and signs of vitamin malabsorption. Periodic monitoring of the lipid panel is required. Monitoring for severe hypertriglyceridemia is essential when the patient's fasting triglyceride level is ≥300 mg/dL.[4] The ASCVD risk profile for individual patients can be calculated based on risk factors for the consideration of statins.[34] Interference with the absorption of fat-soluble vitamins like vitamin K can impact clotting factors; monitor PT/INR. Supplementation of fat-soluble vitamins is required.
Toxicity
Signs and Symptoms of Overdose
Long-term administration of high doses of cholestyramine can cause toxicity and gastrointestinal obstruction.
Management of Overdose
First, the location and extent of the obstruction should be identified. Treatment is initiated with IV fluids. Perforation may require surgical intervention.[29] The prognosis is good with proper treatment.
Enhancing Healthcare Team Outcomes
Cholestyramine has been available for over half a century. Most clinicians are not aware of its usefulness as a therapeutic agent for the treatment of both hypercholesterolemia and pruritus. Clinicians providing care to patients with chronic pruritus should be familiar with this agent as it can significantly improve quality of life. Primary caregivers, nurse practitioners, internists, and other clinicians who treat patients with liver failure may find the drug useful for managing pruritus. Nurses can provide patient counseling regarding potential adverse events and dosing and serve as a primary contact point between the patient and the prescribing clinician. 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. Healthcare professionals who want to use the drug should consult the pharmacist for more practical details such as dosage and duration.[35][36] An interprofessional team approach and cordial communication between physicians, advanced practice providers, pharmacists, and nurses are important to decrease adverse effects and improve outcomes related to cholestyramine therapy.
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