Colesevelam

Last updated
Colesevelam
Colesevelam structure.svg
Clinical data
Trade names Welchol, Cholestagel
AHFS/Drugs.com Monograph
MedlinePlus a699050
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • US: ℞-only
  • EU:Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability N/A
Metabolism Colesevelam is not absorbed and not metabolised.
Elimination half-life N/A (non-systemic drug)
Excretion By intestines only, colesevelam is non-systemic.
Identifiers
  • Allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride
CAS Number
PubChem CID
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C31H67Cl3N4O
Molar mass 618.25 g·mol−1
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Colesevelam is a bile acid sequestrant administered orally. It was developed by GelTex Pharmaceuticals and later acquired by Genzyme. It is marketed in the U.S. by Daiichi Sankyo under the brand name Welchol and elsewhere by Genzyme as Cholestagel. In Canada, it is marketed by Valeant as Lodalis.

Contents

Clinical use

Colesevelam is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia as monotherapy and to improve glycemic control in adults with type 2 diabetes mellitus, [1] including in combination with a statin. The expanded use of colesevelam in adults with type 2 diabetes mellitus is an example of drug repositioning.[ citation needed ]

Colesevelam is one of the bile-acid sequestrants, which along with niacin and the statins, are the three main types of cholesterol-lowering agents. The statins are considered the first-line agents. This is because of the larger body of evidence supporting statins' ability to prevent cardiovascular disease, as well as the prominent side effects from the other two types, including bloating and constipation (bile-acid sequestrants) and skin flushing (niacin). These side effects often lead to low patient compliance. [2]

Colesevelam can be used instead of cholestyramine in symptomatic chronic diarrhea due to bile salt malabsorption (bile acid diarrhea), which can be a primary condition, or secondary to Crohn's disease or the postcholecystectomy syndrome. [3] [4] [5]

Constituents

Colesevelam is a modified polyallylamine. It is made by crosslinking polyallylamine with epichlorohydrin, and then modifying it with bromodecane and (6-bromohexyl)trimethylammonium bromide. The bromide ions are then replaced with chloride ions when the material is washed. [6]

The constituents of the polymer colesevelam shown as subunits that do not exist per se in the final product are:

Colesevelam.png

N-prop-2-enyldecan-1-amine; trimethyl-[6-(prop-2-enylamino)hexyl]azanium; prop-2-en-1-amine; 2-(chloromethyl)oxirane; hydrogen chloride; chloride.

Mechanism of action

Colesevelam is part of a class of drugs known as bile acid sequestrants. 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. [7]

It is not yet known how Colesevelam works to help control blood sugar in people with type 2 diabetes. However, it is clear that the drug works within the digestive tract, since it is not absorbed into the rest of the body.[ citation needed ]

Cholesterol

Since Colesevelam can lower total and LDL cholesterol levels (along with raising HDL), taking it may decrease one's risk of developing certain health problems in the future.

Previous clinical research studies indicate individuals taking 3,800 mg to 4,500 mg of Colesevelam daily were able to:

The combination of Colesevelam with a HMG-CoA reductase inhibitor (known more commonly as a statin) can further lower cholesterol levels. [8]

Side effects

In controlled clinical studies involving approximately 1,400 patients, the following adverse reactions have been reported in patients treated with colesevelam. When reporting to the very common (≥ 1 / 10), common (≥ 1 / 100, 51/10), uncommon (≥ 1 / 1000, 51/100), rare (≥ 1/10.000, 51/1000) and distinction very rarely (51/10.000), including individual cases:[ citation needed ]

The background incidence of flatulence and diarrhea was the same in patients in controlled clinical trials, and higher in the placebo group. Only constipation and dyspepsia were shown to occur in a higher percentage of patients who received Cholestagel, compared to the placebo group. Side effects were generally mild or moderate in severity. In the application of colesevelam in combination with statins, no unexpected frequent side effects occurred. [9]

Related Research Articles

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

Dyslipidemia is an abnormal amount of lipids in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). ASCVD includes coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Cerivastatin</span> Chemical compound

Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin (Lipitor). Cerivastatin was voluntarily withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis.

The bile acid sequestrants are a group of resins used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic agents, although they may be used for purposes other than lowering cholesterol. They are used in the treatment of chronic diarrhea due to bile acid malabsorption.

<span class="mw-page-title-main">Malabsorption</span> Medical condition

Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety of anaemias.

<span class="mw-page-title-main">Stanol ester</span> Class of chemical compounds

Stanol esters is a heterogeneous group of chemical compounds known to reduce the level of low-density lipoprotein (LDL) cholesterol in blood when ingested, though to a much lesser degree than prescription drugs such as statins. The starting material is phytosterols from plants. These are first hydrogenated to give a plant stanol which is then esterified with a mixture of fatty acids also derived from plants. Plant stanol esters are found naturally occurring in small quantities in fruits, vegetables, nuts, seeds, cereals, legumes, and vegetable oils.

Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Colestyramine</span> Pharmaceutical drug

Colestyramine (INN) or cholestyramine (USAN) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

<span class="mw-page-title-main">Fenofibrate</span> Drug of the fibrate class, mainly used to reduce cholesterol levels

Fenofibrate, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes.

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

Postcholecystectomy syndrome (PCS) describes the presence of abdominal symptoms after a cholecystectomy.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">Lubiprostone</span> Medication used for constipation

Lubiprostone, sold under the brand name Amitiza among others, is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company.

<span class="mw-page-title-main">Colestipol</span> Chemical compound

Colestipol is a bile acid sequestrant used to lower blood cholesterol, specifically low-density lipoprotein (LDL). It is also used to reduce stool volume and frequency, and in the treatment of chronic diarrhea.

Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt diarrhea or bile salt malabsorption. It can result from malabsorption secondary to gastrointestinal disease, or be a primary disorder, associated with excessive bile acid production. Treatment with bile acid sequestrants is often effective. It is recognised as a disability in the United Kingdom under the Equality Act 2010

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

Bempedoic acid/ezetimibe, sold under the brand name Nexlizet among others, is a fixed-dose combination medication used for the treatment of high cholesterol. It is a combination of bempedoic acid and ezetimibe.

References

  1. Fonseca, V. A.; Rosenstock, J.; Wang, A. C.; Truitt, K. E.; Jones, M. R. (2008). "Colesevelam HCl Improves Glycemic Control and Reduces LDL Cholesterol in Patients with Inadequately Controlled Type 2 Diabetes on Sulfonylurea-Based Therapy". Diabetes Care. 31 (8): 1479–1484. doi:10.2337/dc08-0283. PMC   2494667 . PMID   18458145.
  2. Principles and Practice of Endocrinology and Metabolism, 2000, ed. Becker, chapter 163
  3. Puleston, J; Morgan, H; Andreyev, J (2005). "New treatment for bile salt malabsorption". Gut. 54 (3): 441–442. doi:10.1136/gut.2004.054486. PMC   1774391 . PMID   15711000.
  4. Wedlake, L; Thomas, K; Lalji, A; Anagnostopoulos, C; Andreyev, HJ (2009). "Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective chart review and patient questionnaire". Clinical Therapeutics. 31 (11): 2549–58. doi:10.1016/j.clinthera.2009.11.027. PMID   20109999.
  5. Beigel F, Teich N, Howaldt S, Lammert F, Maul J, Breiteneicher S, Rust C, Göke B, Brand S, Ochsenkühn T (November 2014). "Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized, double-blind, placebo-controlled study". J Crohns Colitis. 8 (11): 1471–9. doi: 10.1016/j.crohns.2014.05.009 . PMID   24953836.
  6. US Patent 5,607,669
  7. RxList: Welchol
  8. eMedTV: WelChol
  9. Consumer information for cholestagel Archived 2011-07-19 at the Wayback Machine , March 2009 (in German)