Retigabine

Key takeaways

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

Reference excerpt

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017. Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including tinnitus, migraine and neuropathic pain. The manufacturer withdrew retigabine from clinical use in 2017 due to declining use, after the addition of a black box warning regarding side effects was added to the drug in 2013.

Adverse effects The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. The most common adverse effects were drowsiness, dizziness, tinnitus and vertigo, confusion, and slurred speech. Less common side effects included tremor, memory loss, gait disturbances, and double vision. In 2013, FDA warned the public that the drug can cause blue skin discoloration and eye abnormalities, characterized by pigment changes in the retina. It was not known whether those changes were reversible at the time. The FDA added a black-box warning to the drug about these issues. Psychiatric symptoms and difficulty urinating were also reported, with most cases occurring in the first 2 months of treatment. The manufacturer stopped manufacturing retigabine in 2017 due to declining use.

Interactions Retigabine appears to be free of drug interactions with most commonly used anticonvulsants. It may increase metabolism of lamotrigine (Lamictal), whereas phenytoin (Dilantin) and carbamazepine (CBZ, Tegretol) increase the clearance of retigabine. Concomitant use of retigabine and digoxin may increase serum concentration of the latter. In vitro studies suggest that the main metabolite of retigabine acts as a P-glycoprotein inhibitor, and may thus increase absorption and reduce elimination of digoxin.

Pharmacology

Mechanism of action Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action markedly different from that of any current anticonvulsants. This mechanism of action is similar to that of the chemically similar flupirtine, which is used mainly for its analgesic properties. The term "channel opener" refers to a shift in the voltage dependence for channel opening towards more negative potentials. This means that KCNQ/Kv7 channels open at more negative potentials in the presence of Retigabine. Recently, it has also been shown that Retigabine stabilizes the open Kv7.2/7.3 channel, making deactivation slower with little change in voltage dependence. This effect of Retigabine is observed at concentrations below 10 micromolar. A similar effect is observed on the homomeric Kv7.2 channel.

Pharmacokinetics Retigabine is quickly absorbed, and reaches maximum plasma concentrations between half an hour and 2 hours after a single oral dose. It has a moderately high oral bioavailability (50–60%), a high volume of distribution (6.2 L/kg), and a terminal half-life of 8 to 11 hours. Retigabine requires thrice-daily dosing due to its short half-life. Retigabine is metabolized in the liver, by N-glucuronidation and acetylation. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.

Chemistry

Analogues Retigabine is a bioisostere of flupirtine in which the pyridine ring has been replaced with a phenyl ring. Azetukalner (encukalner), pynegabine, and fluoxakalner are also analogues of flupirtine and retigabine.

History Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinical setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal models of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling of the amygdala, pentylenetetrazol, kainate, NMDA, and picrotoxin. Researchers hoped this wide-ranging activity would translate to studies in humans as well.

Clinical trials In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment. A Phase II trial meant to assess the safety and efficacy of retigabine for treating postherpetic neuralgia was completed in 2009, but failed to meet its primary endpoint. Preliminary results were reported by Valeant as "inconclusive".

Regulatory approval The U.S. Food and Drug Administration accepted Valeant's New Drug Application for retigabine on December 30, 2009. The FDA Peripheral and Central Nervous System Drugs Advisory Committee met on August 11, 2010, to discuss the process and unanimously recommended approval of Potiga for the intended indication (add-on treatment of partial seizures in adults). However, the possibility of urinary retention as an adverse effect was considered a significant concern, and the panel's members recommended that some sort of monitoring strategy be used to identify patients at risk of bladder dysfunction. Potiga was approved by the FDA on June 10, 2010, but did not become available on the U.S. market until it had been scheduled by the Drug Enforcement Administration. In December 2011, the U.S. Drug Enforcement Administration (DEA) placed the substance into Schedule V of the Controlled Substances Act (CSA), the category for substances with a comparatively low potential for abuse. This became effective 15 December 2011.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Retigabine

Start with the simplest possible case. Write down what Retigabine 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 Retigabine 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 Retigabine 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 Retigabine

In research: Retigabine 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 Retigabine 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: Retigabine is common in secondary-school and first-year university syllabi. It links to neighbouring topics 4-Fluorophenyl compounds, Anticonvulsants, Carbamates, so understanding it makes those chapters shorter.
In everyday life: Look for Retigabine 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.

How to study Retigabine in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Retigabine 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 Retigabine out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Retigabine in simple terms?

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline.

Why does Retigabine 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 Retigabine?

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 Retigabine.