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Bile acid sequestering agents (Resins): The liver uses cholesterol to produce bile acids, which are used in the digestive process. The bile acid sequestrants bind to these acids, reducing their supply. In turn, this stimulates the liver to produce more bile acids, which uses more cholesterol. Unfortunately, the resins can increase triglyceride levels. When the statins are not sufficient to lower high cholesterol, these drugs can be added. Their use is often limited by side effects, which are primarily gastrointestinal. They can include nausea, bloating, cramping, and an increase in liver enzymes.

Cholestyramine (questran ®)

Cholesterol is probably the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestines. A major portion of the bile acids is absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation. Only very small amounts of bile acids are found in normal serum.

Cholestyramine resin adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by preventing their absorption.

The increased fecal loss of bile acids due to cholestyramine resin administration leads to an increased oxidation of cholesterol to bile acids, a decrease in beta lipoprotein or low density lipoprotein plasma levels and a decrease in serum cholesterol levels. Although in man, cholestyramine resin produces an increase in hepatic synthesis of cholesterol, plasma cholesterol levels fall.

In patients with partial biliary obstruction, the reduction of serum bile acid levels by cholestyramine resin reduces excess bile acids deposited in the dermal tissue with resultant decrease in pruritus.

1) Cholestyramine for Oral Suspension USP Light powder is indicated as adjunctive therapy to diet for the reduction of elevated serum cholesterol in patients with primary hypercholesterolemia (elevated low density lipoprotein [LDL] cholesterol) who do not respond adequately to diet. Cholestyramine for Oral Suspension USP Light powder may be useful to lower LDL cholesterol in patients who also have hypertriglyceridemia, but it is not indicated where hypertriglyceridemia is the abnormality of most concern.

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 specific for the type of hyperlipoproteinemia determined prior to initiation of drug therapy. Excess body weight may be an important factor and caloric restriction for weight normalization should be addressed prior to drug therapy in the overweight.

Prior to initiating therapy with cholestyramine resin, 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). For individuals with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = Total cholesterol - [(TG/5) + HDL-C]

For TG levels > 400 mg/dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases cholestyramine resin may not be indicated.

Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm initial and adequate long-term response. A favorable trend in cholesterol reduction should occur during the first month of cholestyramine resin therapy. The therapy should be continued to sustain cholesterol reduction. If adequate cholesterol reduction is not attained, increasing the dosage of cholestyramine resin or adding other lipid-lowering agents in combination with cholestyramine resin should be considered.

Since the goal of treatment is to lower LDL-C, the NCEP4 recommends that LDL-C levels be used to initiate and assess treatment response. If LDL-C levels are not available then Total-C alone may be used to monitor long-term therapy. A lipoprotein analysis (including LDL-C determination) should be carried out once a year.

Cholestyramine resin monotherapy has been demonstrated to retard the rate of progression and increase the rate of regression of coronary atherosclerosis.

2) Cholestyramine for Oral Suspension USP Light powder, is indicated for the relief of pruritus associated with partial biliary obstruction. Cholestyramine resin has been shown to have a variable effect on serum cholesterol in these patients. Patients with primary biliary cirrhosis may exhibit an elevated cholesterol as part of their disease.

Oral (dosages are expressed in terms of anhydrous resin):
Children: 240 mg/kg/day in 3 divided doses; need to titrate dose depending on indication

Adults: 4 g 1-2 times/day to a maximum of 24 g/day and 6 doses/day

Mix powder with water or other fluid prior to administration; not to be taken in dry form. Suspension should not be sipped or held in mouth for prolonged periods (may cause tooth discoloration or enamel decay).

Powder for oral suspension: 4 g of resin/5.7 g of powder (5.7 g packets, 240 g can) [light formulation]; 4 g of resin/9 g of powder (9 g packets, 378 g can)

Prevalite®: 4 g of resin/5.5 g of powder (5.5 g packets, 231 g can) [contains phenylalanine 14.1 mg/5.5 g; orange flavor]

Questran®: 4 g of resin/9 g of powder (9 g packets, 378 g can)

Questran® Light: 4 g of resin/5 g of powder (5 g packets, 210 g can) [contains phenylalanine 16.8 g/5 g]

Colesevelam (welchol ®) 

1.1 Primary Hyperlipidemia
WELCHOL is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).

WELCHOL is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
a. LDL-C remains ≥ 190 mg/dL or
b. LDL-C remains ≥ 160 mg/dL and

there is a positive family history of premature cardiovascular disease or
two or more other CVD risk factors are present in the pediatric patient.
Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate.

In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are < 100 mg/dL. An LDL-C goal of < 70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is > 200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C.

1.2 Type 2 Diabetes Mellitus
WELCHOL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus .

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted.

1.3 Important Limitations of Use
WELCHOL should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.
WELCHOL has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones.
WELCHOL has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls.

Mechanism of Action
Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in WELCHOL, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

Type 2 Diabetes Mellitus: The mechanism by which WELCHOL improves glycemic control is unknown.

Dosing (Adults): (usual): Oral:
Monotherapy: 3 tablets twice daily with meals or 6 tablets once daily with a meal; maximum dose: 7 tablets/day

Combination therapy with an HMG-CoA reductase inhibitor: 4 to 6 tablets daily; maximum dose: 6 tablets/day

[Supplied: 625 mg tablet ]

Colestipol (colestid ®) 

Dosing (Adults): Recommended dose (Maintenance) -
(Tablets): 2 to 16 grams/day given once or in divided doses. The starting dose should be 2 grams once or twice daily. Dosage increases of 2 grams, once or twice daily should occur at 1 or 2 month intervals. If the desired therapeutic effect is not obtained at a dose of 2 to 16 grams/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.
Adult (usual): powder: 5-30 g orally (mixed with liquid) once daily or in divided doses.

Colestipol tablets must be taken one at a time and be promptly swallowed whole, using plenty of water or other appropriate liquid. Do not cut, crush, or chew the tablets. Patients should take other drugs at least one hour before or four hours after colestipol tablets to minimize possible interference with their absorption.

[Supplied: 1 gram coated tablet. 5 grams/dose granules for oral suspension. ]



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Bile Acid Sequestrants