Macrogol

Macrogol, also known as polyethylene glycol (PEG), is used as a medication to treat constipation in children and adults.[1] It is also used to empty the bowels before a colonoscopy.[1] It is taken by mouth.[1] Benefits usually occur within three days.[2] Generally it is only recommended for up to two weeks.[3] It is also used as an excipient.[4]

Macrogol
Clinical data
Trade namesMiraLax, ClearLax, Golytely, others
Other namesPolyethylene glycol (PEG), PEG 3350, PEG 4000, PEG 6000
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa603032
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
Drug classOsmotic laxative
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNone
ExcretionFaeces (100%)
Identifiers
IUPAC name
  • Poly(oxyethylene)
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaH–(OCH2CH2)n–OH
Molar massVaries
 NY (what is this?)  (verify)

Side effects may include increased bowel gas, abdominal pain, and nausea.[1] Rare but serious side effects may include an abnormal heartbeat, seizures, and kidney problems.[5] Use appears to be safe during pregnancy.[6][1] It is classified as an osmotic laxative.[2] It works by increasing the amount of water in the stool.[3]

Macrogol came into use as a bowel prep in 1980 and was approved for medical use in the United States in 1999.[7][8][9] It is available as a generic medication and over the counter.[1][10] In 2020, it was the 226th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[11][12] Typically it is formulated together with electrolytes.[13]

Medical uses
A polyethylene glycol (PEG) and electrolytes solution used as a laxative used to cleanse the colon before colonoscopy, lower gastrointestinal series, or colon surgery.

Constipation
Macrogol 4000, pharmaceutical quality

Macrogol 3350, often in combination with electrolytes, is used for short-term relief of constipation as well as for long-term use in constipation of various causes, including in multiple sclerosis and Parkinson's disease patients (an often-overlooked non-motor symptom) as well as constipation caused by pharmaceutical drugs such as opioids and anticholinergics. Whole bowel irrigation with macrogol is part of the bowel preparation before surgery or colonoscopy. Limited data also support its use for the treatment of fecal impaction.[14]

In those with chronic constipation it works better than lactulose.[15]

A 2007 comparison showed that people with constipation had a better response to macrogol than to tegaserod.[16] Popular types include: macrogol 3350,[17] macrogol 4000, and macrogol 6000.[18] The number represents the average molecular mass. Combining different molecular masses provides some control over the consistency.[19]

Excipient

Macrogol is used as an excipient in pharmaceutical products.[4] Lower-molecular-weight variants are used as solvents in oral liquids and soft capsules, whereas solid variants are used as ointment bases, tablet binders, film coatings, and lubricants.[19]

For example, PEG-2000 is one of the excipients in the Moderna COVID-19 vaccine.[20][21]

PEGylation

Macrogols are also attached to biopharmaceutical drugs to slow down their degradation in the human body and increase their duration of action, as well as to reduce immunogenicity. This process is called PEGylation.[22][23][24]

Contraindications

Contraindications for macrogol taken orally as a laxative are intestinal perforation, bowel obstruction, ileus, inflammatory bowel diseases, and toxic megacolon.[14]

The doses of macrogol as an excipient are too low to have relevant contraindications.[25]

Allergy to macrogol is rare, and usually appears as an allergy to an increasing number of seemingly unrelated products, including cosmetics, drugs that use it as an excipient, and peri-procedural substances such as ultrasound gel.[26]

Adverse effects

Oral macrogol is generally well tolerated. Possible side effects include headache, bloating, nausea, allergies, and electrolyte imbalance, mainly hypokalaemia (low blood potassium levels) and hyperkalaemia (high blood potassium levels). Hyperkalaemia is not an effect of macrogol itself but of potassium salts which are usually part of macrogol formulations.[14] With excessive use, it can cause diarrhea.

Interactions

The interaction potential is low. Resorption of other pharmaceutical drugs can be reduced because oral macrogol accelerates intestinal passage, but this is seldom clinically relevant. For antiepileptic drugs, such a mechanism has been described in rare cases.[14]

Pharmacology

Mechanism of action as a laxative

Macrogol is an osmotically acting laxative; that is, an inert substance that passes through the gut without being absorbed into the body. It relieves constipation because it causes water to be retained in the bowel instead of being absorbed into the body. This increases the water content and volume of the stools in the bowel, making them softer and easier to pass, as well as improving gut motility.[14][27][28]

Available forms

Macrogol is sold as a non-prescription preparation in the form of powder. When sold for gut cleansing (and as a laxative), it is usually in combination with salts such as sodium bicarbonate, sodium chloride and potassium chloride[29] to help mitigate the possibility of electrolyte imbalance and dehydration. Brand names include SoftLax, Purelax, MiraLax, Laxido, Glycoprep, CosmoCol, Movicol, Cololyt, Osmolax, and others.

It is dissolved in water to create a clear and odorless solution which is then drunk. While most consumers find the taste of macrogol itself to be very mild and unobjectionable, the electrolytes contained in formulations for purging and cleansing give the solution an extremely salty and bitter taste.

Polyethylene glycol-electrolyte solution is a prescription product sold under various brand names including Colyte, Gavilyte, Golytely, Nulytely, Moviprep, and Trilyte.[30]

Research

PEGylation
The protein uricase can be PEGylated to form pegloticase, which improves its solubility at physiological pH, increases serum half-life and reduces immunogenicity without compromising activity. Upper images show the whole tetramer, lower images show one of the lysines that is PEGylated. (PDB: 1uox​ PEG-uricase model from reference[31])
Main article: PEGylation

When attached to various biopharmaceutical medications (which are proteins), macrogol results in a slowed clearance of the carried protein from the blood. This makes for a longer-acting medicinal effect and reduces toxicity, and it allows for longer dosing intervals. It also reduces the proteins' immunogenicity. Examples for PEGylated proteins include peginterferon alfa-2a and -2b, which are used to treat hepatitis C, pegfilgrastim, which is used to treat neutropenia, and pegloticase for the treatment of gout.[14]

Nerves and spinal cords

There is evidence demonstrating PEG-induced repair of specific nerve cells in animal models:

  • It has been shown that macrogol can improve healing of spinal injuries in dogs.[32]
  • One of the earlier findings is that macrogol can aid in nerve repair in earthworms.[33]
  • The subcutaneous injection of macrogol 2000 in guinea pigs after spinal cord injury leads to rapid recovery through molecular repair of nerve membranes.[34] The effectiveness of this treatment to prevent paraplegia in humans after an accident is not known yet.
  • Macrogol is being used in the repair of motor neurons damaged in crush or laceration incidents in vivo and in vitro. When coupled with melatonin, 75% of damaged sciatic nerves were rendered viable.[35]

Cancer prevention
  • High-molecular-weight macrogol (e.g., 8000 g/mol) has been shown to be a dietary preventive agent against colorectal cancer in animal models.[36]
  • The Chemoprevention Database shows macrogol is the most effective known agent for the suppression of chemical carcinogenesis in rats. Cancer prevention applications in humans, however, have not yet been tested in clinical trials.[37]

Other

References
  1. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 57–58. ISBN 9780857113382.
  2. "DailyMed - polyethylene glycol 3350 powder, for solution". dailymed.nlm.nih.gov. Retrieved 19 April 2019.
  3. "Polyethylene Glycol 3350: MedlinePlus Drug Information". medlineplus.gov. Retrieved 19 April 2019.
  4. "Macrogol as Excipient". Biesterfeld AG. Retrieved 10 June 2022.
  5. "PEG-3350 and Electrolytes for Oral Solution" (PDF). FDA. Retrieved 19 April 2019.
  6. "Polyethylene glycol 3350 Use During Pregnancy". Drugs.com. Retrieved 19 April 2019.
  7. Townsend, Courtney M.; Beauchamp, R. Daniel; Evers, B. Mark; Mattox, Kenneth L. (2016). Sabiston Textbook of Surgery E-Book: The Biological Basis of Modern Surgical Practice. Elsevier Health Sciences. p. 1325. ISBN 9780323401630.
  8. "Prescription Polyethylene Glycol 3350; Denial of a Hearing and Order Withdrawing Approval of Abbreviated New Drug Applications". Federal Register. 2 April 2018. Retrieved 19 April 2019.
  9. Ginsberg, Gregory G.; Kochman, Michael L.; Norton, Ian D.; Gostout, Christopher J. (2011). Clinical Gastrointestinal Endoscopy E-Book: Expert Consult - Online and Print. Elsevier Health Sciences. p. 87. ISBN 9781437735703.
  10. "Polyethylene glycol 3350 Uses, Side Effects & Warnings". Drugs.com. Retrieved 19 April 2019.
  11. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  12. "Polyethylene Glycol 3350 - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  13. Aronson, Jeffrey K. (2015). Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. Elsevier. p. 567. ISBN 9780444537164.
  14. Haberfeld, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  15. Lee-Robichaud, H; Thomas, K; Morgan, J; Nelson, RL (7 July 2010). "Lactulose versus Polyethylene Glycol for Chronic Constipation". The Cochrane Database of Systematic Reviews (7): CD007570. doi:10.1002/14651858.CD007570.pub2. PMID 20614462.
  16. Di Palma, Jack A.; Cleveland, Mark vB.; McGowan, John; Herrera, Jorge L. (2007). "A Randomized, Multicenter Comparison of Polyethylene Glycol Laxative and Tegaserod in Treatment of Patients With Chronic Constipation". The American Journal of Gastroenterology. 102 (9): 1964–71. doi:10.1111/j.1572-0241.2007.01365.x. PMID 17573794. S2CID 32055676.
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  18. Hyry H, Vuorio A, Varjonen E, Skyttä J, Mäkinen-Kiljunen S (2006). "Two cases of anaphylaxis to macrogol 6000 after ingestion of drug tablets". Allergy. 61 (8): 1021. doi:10.1111/j.1398-9995.2006.01083.x. PMID 16867059. S2CID 36543393.
  19. Smolinske, Susan C. (1992). Handbook of Food, Drug, and Cosmetic Excipients. p. 287. ISBN 9780849335853.
  20. "Pfizer–BioNTech COVID-19 Vaccine Standing Orders for Administering Vaccine to Persons 12 Years of Age and Older" (PDF). Centers for Disease Control and Prevention (CDC). Archived (PDF) from the original on 2 March 2021. Retrieved 5 March 2021.
  21. "What Ingredients are in the COVID-19 Vaccine?" (PDF). Connecticut Department of Public Health.
  22. Veronese, FM; Harris, JM (2002). "Introduction and overview of peptide and protein pegylation". Advanced Drug Delivery Reviews. 54 (4): 453–6. doi:10.1016/S0169-409X(02)00020-0. PMID 12052707.
  23. "Things About PEGylation Technology and Biopharmaceuticals You Should Know". Biochempeg. Retrieved 10 January 2020.
  24. Porfiryeva, N. N.; Moustafine, R. I.; Khutoryanskiy, V. V. (1 January 2020). "PEGylated Systems in Pharmaceutics". Polymer Science, Series C. 62 (1): 62–74. doi:10.1134/S181123822001004X. ISSN 1555-614X. S2CID 226664780.
  25. "Compound Macrogol Oral Powder Sugar Free. - Summary of Product Characteristics (SmPC) - (emc)". www.medicines.org.uk. Retrieved 10 January 2020.
  26. Wenande, E.; Garvey, L. H. (1 July 2016). "Immediate-type hypersensitivity to polyethylene glycols: a review". Clinical & Experimental Allergy. 46 (7): 907–922. doi:10.1111/cea.12760. ISSN 1365-2222. PMID 27196817. S2CID 1247758.
  27. Mutschler, Ernst (2013). Arzneimittelwirkungen (in German) (10 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 608. ISBN 978-3-8047-2898-1.
  28. Chaussade, S (1999). "Mechanisms of action of low doses of polyethylene glycol in the treatment of functional constipation". Italian Journal of Gastroenterology and Hepatology. 31 Suppl 3: S242–4. PMID 10726227.
  29. [eg. Laxido package insert]
  30. "Polyethylene Glycol-Electrolyte Solution (Professional Patient Advice)". Drugs.com. 20 February 2020. Retrieved 8 June 2020.
  31. Sherman, MR; Saifer, MG; Perez-Ruiz, F (3 January 2008). "PEG-uricase in the management of treatment-resistant gout and hyperuricemia". Advanced Drug Delivery Reviews. 60 (1): 59–68. doi:10.1016/j.addr.2007.06.011. PMID 17826865.
  32. Bowman, Lee (4 December 2004). "Study on dogs yields hope in human paralysis treatment". seattlepi.com.
  33. Krause, T. L.; Bittner, G. D. (1990). "Rapid morphological fusion of severed myelinated axons by polyethylene glycol". PNAS. 87 (4): 1471–1475. Bibcode:1990PNAS...87.1471K. doi:10.1073/pnas.87.4.1471. PMC 53497. PMID 2304913.
  34. Borgens, R. B.; Bohnert, D (2001). "Rapid recovery from spinal cord injury after subcutaneously administered polyethylene glycol". Journal of Neuroscience Research. 66 (6): 1179–1186. doi:10.1002/jnr.1254. PMID 11746451. S2CID 11902183.
  35. Stavisky, R. C.; Britt, J. M.; Zuzek, A; Truong, E; Bittner, G. D. (2005). "Melatonin enhances the in vitro and in vivo repair of severed rat sciatic axons". Neuroscience Letters. 376 (2): 98–101. doi:10.1016/j.neulet.2004.11.033. PMID 15698928. S2CID 24634247.
  36. Corpet, D. E.; Parnaud, G; Delverdier, M; Peiffer, G; Taché, S (2000). "Consistent and Fast Inhibition of Colon Carcinogenesis by Polyethylene Glycol in Mice and Rats Given Various Carcinogens". Cancer Research. 60 (12): 3160–3164. PMID 10866305.
  37. Chemoprevention Database. Inra.fr. Retrieved on 30 November 2012.
  38. Lo, M. M.; Tsong, T. Y.; Conrad, M. K.; Strittmatter, S. M.; Hester, L. D.; Snyder, S. H. (1984). "Monoclonal antibody production by receptor-mediated electrically induced cell fusion". Nature. 310 (5980): 792–4. Bibcode:1984Natur.310..792L. doi:10.1038/310792a0. PMID 6088990. S2CID 4357934.
  • "Macrogol". Drug Information Portal. U.S. National Library of Medicine.
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