Colestipol is an oral prescription cholesterol-lowering drug that is not absorbed from the intestine into the body. It is commonly used to lower bad cholesterol (LDL-C) in people with high cholesterol. Colestipol may also be used for other conditions as determined by your healthcare provider. This article will discuss the mechanism of action of colestipol, its uses, potential side effects, and important considerations for its use.
How Colestipol Works: The Mechanism of Action
Colestipol works by binding bile acid and increasing its removal from your body. Bile acid is a liquid substance your liver produces that helps with food digestion. Because bile acid is made from cholesterol, your body will use cholesterol to replace the bile acid that was removed. As a result, your cholesterol levels will also decrease.
Cholesterol is the major, and probably the sole precursor of bile acids. During normal digestion, bile acids are secreted via the bile from the liver and gall bladder into the intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating absorption. A major portion of the bile acids secreted is reabsorbed from the intestines and returned via the portal circulation to the liver, thus completing the enterohepatic cycle. Only very small amounts of bile acids are found in normal serum.
Colestipol hydrochloride binds bile acids in the intestine forming a complex that is excreted in the feces. This nonsystemic action results in a partial removal of the bile acids from the enterohepatic circulation, preventing their reabsorption. Since colestipol hydrochloride is an anion exchange resin, the chloride anions of the resin can be replaced by other anions, usually those with a greater affinity for the resin than the chloride ion.
The increased fecal loss of bile acids due to colestipol hydrochloride administration leads to an increased oxidation of cholesterol to bile acids. This results in an increase in the number of low-density lipoprotein (LDL) receptors, increased hepatic uptake of LDL and a decrease in beta lipoprotein or LDL serum levels, and a decrease in serum cholesterol levels. Although colestipol hydrochloride produces an increase in the hepatic synthesis of cholesterol in man, serum cholesterol levels fall.
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There is evidence to show that this fall in cholesterol is secondary to an increased rate of clearance of cholesterol-rich lipoproteins (beta or low-density lipoproteins) from the plasma. Serum triglyceride levels may increase or remain unchanged in colestipol hydrochloride treated patients.
The decline in serum cholesterol levels with colestipol hydrochloride treatment is usually evident by one month. When colestipol hydrochloride is discontinued, serum cholesterol levels usually return to baseline levels within one month. Periodic determinations of serum cholesterol levels as outlined in the National Cholesterol Education Program (NCEP) guidelines, should be done to confirm a favorable initial and long-term response.
Indications and Uses of Colestipol
Colestipol is an antihyperlipidemic drug approved by the United States Food and Drug Administration (FDA) as an adjunctive therapy to lower elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia unresponsive to dietary modifications alone. The drug can be used as monotherapy or in conjunction with a statin, niacin, or ezetimibe. The drug is adjunctive to dietary modifications and exercise.
COLESTID Tablets are indicated as adjunctive therapy to diet for the reduction of elevated serum total and LDL-C in patients with primary hypercholesterolemia (elevated LDL-C) who do not respond adequately to diet. Generally, COLESTID Tablets have no clinically significant effect on serum triglycerides, but with their use, triglyceride levels may be raised in some patients.
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Treatment should begin and continue with dietary therapy (see NCEP guidelines). A minimum of six months of intensive dietary therapy and counseling should be carried out prior to initiation of drug therapy. Shorter periods may be considered in patients with severe elevations of LDL-C or with definite CHD.
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According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C is to be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy.
Colestipol may be used in the treatment of heterozygous familial hypercholesterolemia. Although colestipol is effective, it is poorly tolerated due to gastrointestinal adverse effects. Colestipol may be used in combination with a statin. A trial in children with familial hypercholesterolemia treated with colestipol found a 19.5% reduction in LDL-C levels after 8 weeks of therapy.
Colestipol is used off-label to treat cholestatic pruritus and irritable bowel syndrome. Pruritus associated with cholestasis, particularly in primary sclerosing cholangitis, may be treated with colestipol. Colestipol may be better tolerated compared to therapy with cholestyramine. The American Association for the Study of Liver Diseases endorses bile acid sequestrants such as colestipol for cholestatic pruritus in primary biliary cholangitis. These agents are positively charged resins that work by binding to negatively charged anions, including bile acids. Although clinical trials proving efficacy are limited, they have a long track record of clinical use. Patients may prefer colestipol and colesevelam, which are available in tablet forms.
A prospective, controlled trial with 92 patients demonstrated the effectiveness of colestipol as an adjunct therapy to methimazole for treating hyperthyroidism. Greater efficacy was seen in severe cases of thyrotoxicosis.
In a study of 141 patients evaluating the role of bile acids in the pathogenesis of irritable bowel syndrome (IBS), treatment with colestipol improved IBS symptoms (IBS severity scoring system 220 ± 109 vs 277 ± 106). As such, colestipol may be used to treat bile acid diarrhea. However, colestipol is often discontinued due to poor tolerability.
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Colestipol is successfully used to treat digoxin toxicity. Colestipol interrupts the enterohepatic circulation of digoxin and increases fecal excretion. One case report reported a reduced half-life of 55 hours compared to a predicted half-life of 85.
The clinical trial evaluated colestipol's viability as an oral phosphate binder in hemodialysis patients and reported positive outcomes. The findings suggest the potential for a larger-scale trial to ascertain colestipol's effectiveness as a phosphate binder.
Dosage and Administration
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. 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.
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.
Warnings and Precautions
Prior to initiating therapy with COLESTID Tablets, secondary causes of hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism), should be excluded, and a lipid profile performed to assess total cholesterol, HDL-C, and triglycerides (TG).
Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat absorption and, thus, may reduce absorption of folic acid and fat soluble vitamins such as A, D, and K.
Chronic use of colestipol hydrochloride may be associated with an increased bleeding tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral administration of vitamin K1.
COLESTID Tablets may produce or severely worsen pre-existing constipation. The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction. In patients with pre-existing constipation, the starting dose should be 2 grams once or twice a day. Increased fluid and fiber intake should be encouraged to alleviate constipation and a stool softener may occasionally be indicated. If the initial dose is well tolerated, the dose may be increased as needed by a further 2 to 4 grams/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the desired therapeutic response is not achieved at 2 to 16 grams/day, combination therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. Constipation associated with COLESTID Tablets may aggravate hemorrhoids.
While there have been no reports of hypothyroidism induced in individuals with normal thyroid function, the theoretical possibility exists, particularly in patients with limited thyroid reserve.
Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a possibility that prolonged use may lead to the development of hyperchloremia acidosis.
Drug Interactions
Colestipol binds many different compounds in the gastrointestinal tract, thereby inhibiting their absorption into the body. For example, colestipol can bind with and decrease the oral absorption of carbamazepine (Tegretol), diuretics such as hydrochlorothiazide (found in Dyazide, Maxzide), and furosemide (Lasix), propranolol (Inderal), tetracyclines, and fat-soluble vitamins (vitamins A, D, and K). Colestipol can bind with and inhibit the absorption of thyroid hormones. Colestipol also can bind with ursodiol (Actigall, Urso). Separating the doses of colestipol and these other compounds by several hours should prevent binding with colestipol.
Colestipol binds to vitamin K, a vitamin that is required by the liver to make the factors that allow blood to clot. Colestipol, by reducing the action of vitamin K, may exaggerate the effect of warfarin (Coumadin), reducing the body's ability to form blood clots. This interaction could lead to abnormal bleeding. On the other hand, colestipol can bind with warfarin directly and inhibit the absorption of warfarin.
Colestipol is closely related to cholestyramine. Cholestyramine has been more extensively studied than colestipol. Therefore, several drug interactions have been described with cholestyramine for which data is lacking with colestipol. It would be prudent to assume that similar interactions exist for both drugs and to separate ingestion of colestipol from the other drugs by several hours.
You should take other drugs at least 1 hour before or 4 hours after you take colestipol. This will decrease your risk of drug interactions.
Potential Side Effects
Colestipol can cause a wide range of adverse effects, including constipation, bloating, dyspepsia, and nausea.
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. Patients aged 65 or older and patients using a larger dose of colestipol are more prone to constipation. 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.
Colestipol therapy is reported to cause asymptomatic hepatotoxicity with elevated serum transaminases. 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.
Colestipol can reduce the absorption of beta blockers, fibrates, and ezetimibe.
Contraindications
COLESTID Tablets are contraindicated in those individuals who have shown hypersensitivity to any of their components.
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. 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 should be avoided in patients with complete biliary obstruction.
Special Populations
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.
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.
Breastfeeding considerations: Colestipol, a nonabsorbable resin, does not reach the maternal bloodstream and consequently does not transfer to the infant through breast milk.
Pediatric patients: The adverse event profile of colestipol in patients under 18 has not been established.
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. 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.
Alternatives to Colestipol: Welchol
For patients with high cholesterol levels, specific drugs that modify the amount of lipids in the body can help manage symptoms and reduce risks associated with cardiovascular diseases. Colestipol and Welchol are two such drugs that are commonly prescribed for hypercholesterolemia. These medications work by binding to bile acids in your intestines and preventing them from being reabsorbed into your blood, thereby reducing total cholesterol levels.
Welchol, also known as colesevelam, is a bile acid sequestrant that reduces the level of low-density lipoprotein (LDL) cholesterol in the body. It operates by binding to bile acids in your intestines and preventing them from being reabsorbed into the bloodstream. This reduction in bile acids causes your liver to pull more LDL cholesterol from your blood to produce more bile acids, thereby lowering overall levels of LDL cholesterol.
While both drugs function similarly, there are differences between them that might make one preferable over the other depending on individual circumstances. Colesevelam tends to cause fewer complaints of bloating or constipation than colestipol does.
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