Retigabine

Retigabine is an Antiepileptic drug belonging to the potassium channel opener.

Retigabine is used in the treatment of Partial-onset seizures.

Retigabine is rapidly absorbed and distributed, with an absolute oral bioavailability of 60%. Retigabine is metabolized exclusively via phase II hepatic N-glucuronidation and acetylation. N-glucuronidation is the primary metabolic pathway of the two and forms two major N-glucuronide metabolites.It is excreted via Urine (85%, 36% of total dose as unchanged drug, 18% of total dose as NAMR) and feces (14%, 3% of total dose as unchanged drug)

The Tmax of Retigabine was about 0.5 to 2 hours.

The common side effects are dizziness, drowsiness, headache, weakness, Nausea, strong irregular heartbeat, swelling, and dizziness upon standing.

Retigabine is available in dosage forms, such as tablets.

Retigabine is available in Europe, Japan, China, and India.

Retigabine binds the KCNQ (Kv7.2-7.5) voltage-gated potassium channels, thereby stabilizing the channels in the open formation and enhancing the M-current. As a result, neuronal excitability is regulated, and epileptiform activity is suppressed. In addition, Retigabine may also exert therapeutic effects through the augmentation of GABA-mediated currents.

Retigabine is available in the form of dosage forms, such as tablets.

Retigabine tablets were taken orally with or without food.

Retigabine is used in the treatment of Partial-onset seizures.

Retigabine is a first-in-class anticonvulsant that works by activating KCNQ2/3 channels. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability.

Retigabine is approved for its use in the following clinical indications:

Partial-onset seizures: As adjunctive treatment for partial-onset seizures in patients ≥18 years who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity

Retigabine is available in various dosage strengths: 50 mg, 100 mg, 200 mg, 300 mg, 400 mg.

Retigabine is available in the form of dosage forms, such as tablets.

• Dose Adjustment in Kidney Patients

● CrCl ≥50 mL/minute: No dosage adjustment necessary.

● CrCl <50 mL/minute: Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 200 mg 3 times daily (600 mg per day).

● ESRD requiring hemodialysis: Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 200 mg 3 times daily (600 mg per day).

● Note: Immediately following hemodialysis a single supplemental dose is recommended; if break through seizures occur toward the end of hemodialysis, an additional supplemental dose may be considered at the start of subsequent dialysis sessions.

• Dose Adjustment in Hepatic Impairment Patient

● Mild impairment (Child-Pugh 5 to 6): No dosage adjustment necessary.

● Moderate impairment (Child-Pugh 7 to 9): Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 250 mg 3 times daily (750 mg per day).

● Severe impairment (Child-Pugh >9): Initial: 50 mg 3 times daily; may increase at weekly intervals in increment of ≤150 mg per day to a maximum dose of 200 mg 3 times daily (600 mg per day).

Retigabine is approved for the treatment of Partial seizure.

Eat Stimulants such as tea, coffee, chocolate, sugar, sweets, soft drinks, excess salt, spices and animal proteins may trigger seizures by suddenly changing the body’s metabolism. Some parents have reported that allergic reactions to certain foods (e.g. white flour) also seem to trigger seizures in their children.

Concerns related to adverse effects:

• CNS effects: Dose-related dizziness and somnolence (generally mild-to-moderate) have been reported; effects generally occur during dose titration and appear to diminish with continued use. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Dermatologic effects: Skin discoloration has been reported; typically blue in color (but may also be gray-blue or brown) and is predominantly located on or around the lips, nail beds of the fingers or toes, face and legs; discoloration of the palate, sclera, and conjunctiva may also occur. Skin discoloration developed in ~10% of patients, generally after ≥2 years of treatment and at higher doses (≥900 mg). If detected, consider other treatment options or discontinue use.
• Neuropsychiatric disorders: Dose-related neuropsychiatric disorders, including confusion, psychotic symptoms, and hallucinations, have been reported, generally within the first 8 weeks of treatment; some patients required hospitalization. Symptoms resolved in most patients within 7 days of discontinuation of therapy. The risk appears to be greatest with rapid titration at greater than the recommended doses.

Consumption of grapefruit juice is not recommended during treatment with this medicine due to the increased risk of severe side effects.

The adverse reactions related to molecule Retigabine can be categorized as

● Common Adverse effects: Abnormal gait, confusion, dizziness, fatigue, headache, nausea, somnolence, speech disorder, tremor, urinary tract infection, and blurred vision.

● Less Common adverse effects: tremor, memory loss, gait disturbances, and double vision.

• May prolong the effect of some anesthesia (e.g. thiopental Na).
• Additive effects w/ drugs that prolong QT interval including class Ia/III antiarrhythmics (e.g. quinidine, amiodarone), some antipsychotic agents (e.g. chlorpromazine), and some antimicrobial agents (e.g. clarithromycin).
• Reduced plasma levels w/ phenytoin or carbamazepine.

Symptoms: Agitation, aggressive behavior, irritability; cardiac arrhythmia (cardiac arrest/asystole or ventricular tachycardia) may occur.

Management: Supportive treatment. Ensure an adequate airway, ventilation and oxygenation.

Pharmacodynamics:

Retigabine activates specific voltage-gated K channels in the brain known as the KCNQ (Kv7.2-7.5) family of ion channels, thereby stabilising the K channels in open formation, enhancing the M-type current and exerting a hyperpolarising effect on neuronal cells, resulting to stabilisation of the resting membrane potential and suppression of seizure activity.

Pharmacokinetics:

• Absorption: Readily absorbed. Bioavailability: Approx 60%. Time to peak plasma concentration: Approx 0.5-2 hr.
• Distribution: Well distributed in the body. Volume of distribution: 2-3 L/kg. Plasma protein binding: Approx 80%.
• Metabolism: Extensively metabolised, mainly via glucuronidation by the uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) to form inactive N-glucuronides (major metabolites); also undergoes acetylation by N-acetyltransferase 2 (NAT2) to form an active, but less potent, N-acetyl metabolite (NAMR) that is subsequently glucuronidated.
• Excretion: Via Urine, approx 85% (36% as unchanged drug, 18% as NAMR, and 24% as N-glucuronides); faeces (approx 14%, w/ 3% as unchanged drug). Elimination half-life: Approx 6-11 hr

1. https://go.drugbank.com/drugs/DB09235
2. https://www.apollopharmacy.in/salt/RETIGABINE
3. https://pubchem.ncbi.nlm.nih.gov/compound/Retigabine #section=MeSH-Pharmacological-Classification
4. https://www.medplusmart.com/product/efnocar-40mg-tab_efno0001