chemistry

Naldemedine

Naldemedine is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Naldemedine rather than just read about it. In short: Naldemedine, sold under the brand name Symproic in the US and Rizmoic in the European Union, is a medication that is used for the treatment of opioid-induced constipation in adults who have previously been treated with a laxative in the European Union, or to treat opioid induced constipation in adults with chronic non-cancer pain in the US. It is a peripherally acting μ-opioid receptor antagonist and was developed b…

Key takeaways

Naldemedine belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Naldemedine to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Naldemedine from memory before moving on to harder problems.

Reference excerpt

Naldemedine, sold under the brand name Symproic in the US and Rizmoic in the European Union, is a medication that is used for the treatment of opioid-induced constipation in adults who have previously been treated with a laxative in the European Union, or to treat opioid induced constipation in adults with chronic non-cancer pain in the US. It is a peripherally acting μ-opioid receptor antagonist and was developed by Shionogi. Clinical studies have found it to possess statistically significant effectiveness for these indications and to be generally well tolerated, with predominantly mild to moderate gastrointestinal side effects. Effects indicative of central opioid withdrawal or impact on the analgesic or miotic effects of co-administered opioids have only been observed in a small number of patients.

Medical uses In the US, naldemedine is approved for the treatment of opioid induced constipation in adults with chronic non-cancer pain, including those who have chronic pain related to prior cancer or its treatment and do not need frequent opioid dosage escalation. In the European Union, naldemedine is also approved for the treatment of opioid induced constipation in adults, but as a second-line therapy after treatment with a laxative.

Contraindications The drug is contraindicated in patients with gastrointestinal obstruction or perforation, or those at risk for these problems.

Side effects Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% under placebo, depending on the study), diarrhea (7% versus 2–3%), nausea (4–6% versus 2–5%), vomiting (3% versus 2%), gastroenteritis (2–3% versus 1%), and opioid withdrawal syndrome (1.5–3.2% versus 0.5–1.5%). The latter was severe but manageable in one patient, and otherwise mild to moderate. Hypersensitivity reactions were rare; they occurred in two patients.

Overdose Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate.

Interactions As naldemedine is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples include itraconazole (which increased naldemedine exposure 2.9-fold in a study), ketoconazole, clarithromycin and grapefruit juice. Conversely, CYP3A4 inducers such as rifampicin and St John's wort decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study. Strong inhibitors of the pump P-glycoprotein such as ciclosporin may increase naldemedine concentrations in the blood plasma.

Pharmacology

Mechanism of action

Naldemedine is a derivative of naltrexone and, like this substance, blocks opioid receptors of the types μ (mu), δ (delta) and κ (kappa). While naltrexone is able to cross the blood–brain barrier and can therefore be used to treat opioid dependence, the large hydrophilic side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in the central nervous system when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs.

Pharmacokinetics After oral intake, naldemedine has an absolute bioavailability in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal. As the area under the curve is not significantly different with or without a meal, the drug can be taken independently of food. Once in the bloodstream, 93 to 94% of the substance is bound to plasma proteins, mainly to albumin. Naldemedine is mainly metabolized by the enzyme CYP3A4 to nor-naldemedine (which makes up about 9–13% of the circulating substance), and to a much lesser extent by UGT1A3 to naldemedine 3-glucuronide. Minor metabolites are the 6-glucuronide, the 7-(R/S)-hydroxy-derivates, and two products formed by enterobacteria through cleaving the oxadiazole ring: naldemedine carboxylic acid and benzamidine. Nor-naldemedine, the glucuronides, and the carboxylic acid are opioid receptor antagonists, but less potent than the original substance.

Naldemedine and its metabolites are excreted via urine and faeces. The part of the molecule "left" of the cleavage line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and carboxylic acid) is found to 20.4% in the urine and to 64.3% in the faeces, while the part "right" to the line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and benzamidine) is found to 57.3% in the urine and to 34.8% in the faeces. This indicates that benzamidine is predominantly excreted in the urine and the carboxylic acid is predominantly excreted in the faeces. The terminal half-life is about 11 hours.

Chemistry Naldemedine is used in form of the tosylate, a white to light tan powder. It is not hygroscopic and has a high water solubility at a physiologic pH.

Society and culture

Commercialization Naldemedine is manufactured by Shionogi Inc., a United States–based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a pharmaceutical company founded in 1878 based in Osaka, Japan. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States. In the US market, Shionogi Inc. has partnered with Purdue Pharma in a joint venture for US commercialization of Symproic. Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders. Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on 12 July 2017. The Drug Enforcement Administration officially removed the Class II scheduling in September 2017.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Naldemedine

Start with the simplest possible case. Write down what Naldemedine claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Naldemedine before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Naldemedine ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Naldemedine

In research: Naldemedine appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Naldemedine in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Naldemedine is common in secondary-school and first-year university syllabi. It links to neighbouring topics 4,5-Epoxymorphinans, Carboxamides, Cyclopropyl compounds, so understanding it makes those chapters shorter.
In everyday life: Look for Naldemedine outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Naldemedine in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Naldemedine means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Naldemedine out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Naldemedine in simple terms?

Why does Naldemedine matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Naldemedine?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Naldemedine.