Colestipol

Mechanism of Action

Colestipol is a large basic anion-exchange resin copolymer that is nonabsorbable and insoluble in water.[18] The primary mechanism of action is the formation of insoluble complexes with bile acids in the small intestine that are subsequently excreted in the feces. Bile acids emulsify and solubilize lipids in the intestinal lumen as part of normal digestion. The rate-limiting step in bile acid synthesis involves hydroxylation of the steroid nucleus of cholesterol by cholesterol 7-alpha-hydroxylase.[19] Data show that 95% of bile acids are recycled via enterohepatic circulation to the liver, while 5% are excreted in the feces.[19]

Increased fecal excretion of bile acids reduces the total bile acid pool available for enterohepatic circulation. As a result, upregulation of cholesterol 7-alpha-hydroxylase leads to increased conversion of cholesterol into bile acids, reducing total serum cholesterol levels. Further upregulation of hepatic low-density lipoprotein receptors (LDLR) to replenish intrahepatic cholesterol stores available for bile acid synthesis leads to increased uptake of LDL-C and an overall reduction in plasma LDL cholesterol (LDL-C) levels.

In cases of thyrotoxicosis, enterohepatic circulation of thyroid hormones, including thyroxine (T4) and triiodothyronine (T3), increases.[13] Interaction between positively charged nitrogen atoms of colestipol with negatively charged iodothyronines leads to increased fecal excretion of iodothyronines.[13]

According to a systematic review, colestipol is suggested for moderate to severe cholestatic pruritus. The mechanism of colestipol in cholestatic pruritus is by binding to bile acids within the small intestine, preventing reabsorption and facilitating elimination via feces.[20]

Pharmacokinetics 

Absorption: Colestipol demonstrates negligible solubility in water despite its hydrophilic nature and is not hydrolyzed by digestive enzymes. The high molecular weight polymer present in colestipol appears to render it nonabsorbable. The primary effects of bile acid sequestrants like colestipol are restricted to the intestine.[21]

Distribution: In humans, less than 0.17% of a single dose labeled with ^14C-colestipol is excreted in the urine after 60 days of consistent administration at 20 g daily. This low percentage suggests minimal systemic distribution or absorption of colestipol hydrochloride within the body.

Metabolism: The binding of bile acids to colestipol creates an insoluble compound that cannot be reabsorbed and is excreted in the feces.

Elimination: Bile acids ordinarily undergo extensive (>95%) enterohepatic recirculation, are secreted in bile, act as fat-solubilizing compounds in the upper intestine, and are reabsorbed in the distal small bowel. However, colestipol disrupts this cycle, resulting in the excretion of colestipol-bound bile acids in the feces.[1] Colestipol is minimally excreted in the urine and predominantly in feces due to its nonabsorbable nature.

Administration

Available Dosage Forms and Strengths

Colestipol is available to patients in 2 forms—oral tablet or granular form as a powdered suspension. The powdered suspension is also available in a flavored form to improve palatability. However, the flavored suspension is taken cautiously in patients with phenylketonuria, as it contains phenylalanine.

Colestipol is available in various formulations and doses, including granules in a bottle containing 5 g of the medication and flavored granules in packets, each containing 5 g of the substance. Furthermore, the oral form is available in tablets with a dosage of 1 g per tablet.

Adult Dosage

Patients with phenylketonuria must consult their clinician before initiating therapy with a flavored colestipol suspension. Powdered suspensions of colestipol should be mixed with water or other fluids before ingestion to prevent inhalation or esophageal distress. Other medications, such as fat-soluble vitamins, should be ingested 1 hour before or 4 hours after the administration of colestipol.[22]

Colestipol tablets are recommended in 2 to 16 g daily. Therapy should be initiated at a dosage of 2 g/d. Colestipol powdered suspension is recommended in a dosage of 1 to 6 packets per day. One packet contains 5 g of colestipol.

Specific Patient Populations

Hepatic impairment: There is no dosage adjustment information for hepatic impairment for colestipol in the product labeling.

Renal impairment: There is no dosage adjustment information for renal impairment for colestipol in the product labeling.

Pregnancy considerations: Colestipol is safe since it is not systemically absorbed. However, colestipol may induce the malabsorption of fat-soluble vitamins (A, D, E, and K), which is hazardous to the mother and child. Therefore, the benefits of drug therapy should be weighed against the risks before the initiation of treatment.[23]

As per the NLA guidelines, most women diagnosed with hypercholesterolemia are advised against drug therapy during pregnancy. However, those with atherosclerotic cardiovascular disease or homozygous familial hypercholesterolemia may require pharmacotherapy. Bile acid sequestrants are considered reasonable therapeutic options during pregnancy.[7]

Breastfeeding considerations: Colestipol, a nonabsorbable resin, does not reach the maternal bloodstream and consequently does not transfer to the infant through breast milk. Accordingly, colestipol is considered safe during lactation.[24]

Pediatric patients: The adverse event profile of colestipol in patients under 18 has not been established. However, colestipol has been used safely in pediatric patients with familial hypercholesterolemia.[4] According to the NLA guidelines, statins and bile acid sequestrants can be considered for children and adolescents.[6]

Older patients: The gastrointestinal adverse effects of colestipol, such as constipation, may be more pronounced in patients over the age of 60.[25]

Adverse Effects

Adverse Drug Reactions

• Most adverse effects caused by colestipol therapy are related to the gastrointestinal system. Colestipol can cause a wide range of adverse effects, including constipation, bloating, dyspepsia, and nausea.[26]

• Constipation is the most common adverse drug reaction and ranges in severity from mild cases to severe cases. The reaction is often a cause of poor compliance and discontinuation of therapy.[27] Patients aged 65 or older and patients using a larger dose of colestipol are more prone to constipation.[25] Constipation may be alleviated with increased fluid and fiber intake, as well as the use of stool softeners. Colestipol may aggravate preexisting hemorrhoids.

• The usage of colestipol in powdered suspension form may cause decreased palatability. Flavored suspensions of colestipol are used to improve palatability. 

• Non-gastrointestinal adverse effects are infrequently reported. These include infrequent occurrences of cardiovascular symptoms such as angina, musculoskeletal symptoms such as joint pains and arthritis, and neurologic symptoms such as migraine headaches. 

• Colestipol may cause transient elevations in alkaline phosphatase levels, although the clinical significance is unknown.[25]

• Colestipol therapy is reported to cause asymptomatic hepatotoxicity with elevated serum transaminases. However, the mechanism by which colestipol causes hepatotoxicity is unknown.[28]

• Colestipol may cause hyperchloremic metabolic acidosis.

Drug-Drug Interactions

• Colestipol may induce malabsorption of fat-soluble vitamins (vitamins A, D, E, and K). Patients with preexisting deficiencies of these vitamins should consult their clinician before commencing therapy with colestipol. These vitamins should be taken 4 hours after colestipol.[22]

• Colestipol can reduce the absorption of beta blockers, fibrates, and ezetimibe.[21]

• Colestipol may reduce the absorption of many drugs if they are given concomitantly with colestipol. Anionic drugs such as warfarin, thiazide diuretics, propanolol, levothyroxine, and digitalis should be given 1 hour before or 4 hours after colestipol.[22]

Contraindications

Colestipol should not be used in patients with known hypersensitivity to the drug or its components.

Warning and Precautions

• Colestipol should be avoided for use in patients with disorders that cause decreased intestinal motility, in patients with a recent history of abdominal surgery, and patients with a history of recent episodes of intestinal obstruction.[22] 

• Colestipol is contraindicated in patients undergoing therapy with mycophenolic acid. As colestipol binds to bile acids, it reduces the absorption of mycophenolic acid and may reduce the efficacy. 

• Colestipol causes elevated triglyceride levels. Lyons et al demonstrated an 8.9% rise in triglyceride levels in patients treated with colestipol.[28] Colestipol should be avoided in patients with triglyceride levels above 400 mg/dL. It may be used in patients with serum levels below 200 mg/dL of triglyceride.[22] Therefore, as a precaution, clinicians should reserve this drug for use in patients with hypercholesterolemia without associated hypertriglyceridemia.[18] 

• Colestipol is a bile acid sequestrant. As a large anion exchange resin, it may bind numerous intestine molecules. Of note, colestipol may bind to free triiodothyronine (T3), resulting in increased fecal excretion of T3 and reduced enterohepatic circulation.[29] As a result, colestipol therapy may worsen symptoms in patients with preexisting hypothyroidism. Therefore, patients on colestipol therapy should consider consulting their clinician before commencing treatment. 

• Colestipol should be avoided in patients with complete biliary obstruction.[22]

• Chronic use of colestipol may cause an increased risk of bleeding due to hypoprothrombinemia resulting from vitamin K deficiency. However, this condition can be promptly treated with parenteral vitamin K1 and prevented from recurring by administering oral vitamin K1.

Monitoring

Periodic monitoring of serum lipoproteins is recommended in patients taking colestipol to assess treatment response and dosage modifications. As colestipol is known to cause constipation of varying severity and may cause intestinal obstruction, monitoring of constipation at 4- to 6-week intervals is recommended. Worsening constipation or failure to meet therapeutic goals may require combination therapy or replacement with alternate therapy. 

Clinicians should regularly monitor patients with preexisting fat-soluble vitamin deficiencies (A, D, E, and K) when on colestipol therapy. Colestipol may impede the absorption of fat-soluble vitamins by acting as a bile acid sequestrant.[30] If any of these vitamins are deficient, signs should be recognized, and treatment should be promptly started. As colestipol may cause hyperchloremic metabolic acidosis, signs of hyperchloremic acidosis may ensue. These include headaches, seizures, increased respiratory rate, and arrhythmias. Patients on warfarin therapy should have their International Normalized Ratio (INR) monitored regularly as the absorption is affected by colestipol.[21]

Toxicity

Signs and Symptoms of Overdose

No reports of toxicity associated with colestipol therapy have been reported other than the adverse events described above. Colestipol is relatively safe as it is not absorbed systemically and does not cause severe adverse effects. In the event of an overdose, the primary concern is the potential obstruction of the gastrointestinal tract. 

Management of Overdose

Treatment decisions in overdose are influenced by the location and severity of any potential obstruction, along with the assessment of normal gut motility.

Recommendations

Patients often report poor tolerability to colestipol due to the many gastrointestinal adverse effects and poor palatability.[31] Therefore, healthcare professionals should consider this and modify treatment by offering a different drug formulation.

Enhancing Healthcare Team Outcomes

Colestipol is a bile acid sequestrant that may be offered to patients to treat various conditions, such as hypercholesterolemia or pruritus associated with chronic liver disease. Colestipol is less commonly prescribed in the current age due to poor compliance with use and poor tolerability. Still, colestipol is highly effective in managing hypercholesterolemia and pruritus. Therefore, healthcare professionals treating these conditions should be familiar with the properties. This familiarity may enable them to offer patients an improved quality of life.

Clinicians initiating colestipol for hypercholesterolemia should review and consider atherosclerotic cardiovascular disease risk factors. As per the NLA, it is advisable to consult or refer children with familial hypercholesterolemia to a lipid specialist.[32] Nurses should be aware of colestipol's most commonly encountered adverse effects to develop strategies to monitor their occurrence and report them to clinicians. The pharmacist should serve as the main point of contact for those members of the interprofessional team seeking advice on the dosage and administration of colestipol, checking for drug interactions, risk mitigation of adverse effects, and giving clear instructions to patients on how to use the drug. 

A study investigated the effectiveness of the multidisciplinary lipid clinic in enhancing guideline-based care for lipid disorders within the healthcare system. Though a modest referral rate from active cardiology and primary care providers, the clinic attended to 83 patients, significantly improving the diagnosis and management of conditions such as familial hypercholesterolemia and dyslipidemia. The impact included increased use of evidence-based therapies, decreased lipid levels, and adaptive measures like transitioning to telehealth for sustained capacity. These results underscore the potential of the multidisciplinary lipid clinic to enhance patient outcomes.[33] Coordination between all interprofessional healthcare team members, including clinicians, specialists, pharmacists, and nurses, is crucial in enhancing outcomes associated with colestipol therapy.