Naloxegol (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; PEGylated naloxol; trade names Movantik and Moventig) is a

peripherally acting μ-opioid receptor antagonist Peripherally acting μ-opioid receptor antagonists (PAMORAs) are a class of chemical compounds that are used to reverse adverse effects caused by opioids interacting with receptors outside the central nervous system (CNS), mainly those located in ...

developed by AstraZeneca, licensed from

Nektar Therapeutics Nektar Therapeutics (Nektar) is an American biopharmaceutical company. The company was founded in 1990 and is based in San Francisco, California. The company develops new drug candidates by applying its proprietary PEGylation and advanced polymer ...

, for the treatment of

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

-induced

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

. It was approved in 2014 in adult patients with chronic, non-cancer pain. Doses of 25 mg were found safe and well tolerated for 52 weeks. When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia. The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting and headache. Patients often describe the above side effects to be similar to an instant withdrawal state brought on quickly rather than the 24 hours it may take to occur naturally. As a pure opioid antagonist Naloxegol has no potential for abuse. Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids. It was officially decontrolled on 23 January 2015. It was reclassified as a

prescription drug A prescription drug (also prescription medication or prescription medicine) is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription. The rea ...

after the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

and

DEA The Drug Enforcement Administration (DEA; ) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within the U.S. It is the lead agency for domestic enf ...

concluded that the impermeability of the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

to this compound made it non-habit-forming, and so without the potential for

abuse Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...

Medical use

Naloxegol is indicated for the treatment of

opioid-induced constipation Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

(OIC) in patients with chronic non-cancer pain. It is recommended that any maintenance laxative be discontinued before starting naloxegol or be held for at least 3 days. Naloxegol should be taken on an empty stomach at least two hours after the last meal.

Side effects

The most common side effects for naloxegol include: *

Abdominal pain Abdominal pain, also known as a stomach ache, is a symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...

Diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

Flatulence Flatulence, in humans, is the expulsion of gas from the intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swallowed environm ...

Vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

Headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

Pharmacodynamic properties

Naloxegol inhibits opioid binding in

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

s in the gastrointestinal tract, thus decreasing the constipating effects (slowing of gastrointestinal motility and transit,

hypertonicity In chemical biology, tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially-permeable cell membrane. Tonicity depends on the relative concentration of selective membrane- ...

, increased fluid reabsorption) associated with

s. If naloxegol is coadministered with other opioid antagonists, there is a potential for additive effect and increased risk of opioid withdrawal.

Mechanism of action

Chemically, naloxegol is a

pegylated PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...

(polyethylene glycol-modified)

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...

of α-

naloxol Naloxol is an opioid antagonist closely related to naloxone. It exists in two isomeric forms, α-naloxol and β-naloxol. α-naloxol is a human metabolite of naloxone. Synthetically, α-naloxol can be prepared from naloxone by reduction of the ...

. Specifically, the 6-α-hydroxyl group of α-

is connected via an

ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...

linkage to the free

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...

of a monomethoxy-terminated n=7

oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...

of PEG, shown extending at the lower left of the molecule image at right. The "n=7" defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the "monomethoxy" indicates that the terminal hydroxyl group of the PEG is "capped" with a methyl group.Technically, the molecule that is attached via the ether link is ''O''-methyl-heptaethylene glycol hat is, methoxyheptaethylene glycol, CH₃OCH₂CH₂O(CH₂CH₂O)₅CH₂CH₂OH molecular weight 340.4, CAS number 4437-01-8. See The pegylation of the 6-α- hydroxyl side chain of

prevents the drug from crossing the

(BBB). As such, it can be considered the antithesis of the peripherally-acting opiate loperamide which is utilized as an opiate-targeting anti-diarrheal agent that does not cause traditional opiate side-effects due to its inability to accumulate in the central nervous system in normal subjects.

References

{{Opioid receptor modulators Allyl compounds Daiichi Sankyo 4,5-Epoxymorphinans AstraZeneca brands Mu-opioid receptor antagonists Peripherally selective drugs Synthetic opioids

Medical use

Side effects

Pharmacodynamic properties

Mechanism of action

See also

References