Tiagabine is indicated for the adjunctive treatment of focal seizures, with or without secondary generalization. In adults, the recommended initial dose is 4 mg/d with weekly increments of 4–8 mg/d to total doses of 16–56 mg/d. Initial dosages can be given twice a day, but a change to three times a day is recommended above 30–32 mg/d. Divided doses as often as four times daily are sometimes required. Adverse effects and apparent lack of efficacy limit the use of this drug. Minor adverse events are dose related and include nervousness, dizziness, tremor, difficulty concentrating, and depression. Excessive confusion, somnolence, or ataxia may require discontinuation. Psychosis occurs rarely. The drug can cause seizures in some patients, notably those taking the drug for other indications. Rash is an uncommon idiosyncratic adverse effect.
Tiagabine is 90–100% bioavailable, has linear kinetics, and is highly protein bound. The half-life is 5–8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve (see Chapter 3). To avoid adverse effects, the drug should be taken with food. Hepatic impairment causes a slight decrease in clearance and may necessitate a lower dose. The drug is oxidized in the liver by CYP3A. Elimination is primarily in the feces (60–65%) and urine (25%).
Retigabine (US Adopted Name: ezogabine), a potassium channel opener, is a third-line treatment for focal seizures. Because retigabine causes pigment discoloration of the retina and skin, its use is limited to those who have failed to respond to other agents.
Mechanism of Action
Retigabine is an allosteric opener of KCNQ2-5 (Kv7.2-Kv7.5) voltage-gated potassium channels, which are localized, in part, in axons and nerve terminals. Opening KCNQ potassium channels in presynaptic terminals inhibits the release of various neurotransmitters, including glutamate, which may be responsible for the seizure protection.
Doses of retigabine range from 600 to 1200 mg/d, with 900 mg/d expected to be the most common. The drug is administered in three divided doses, and the dose must be titrated beginning at 300 mg/d. Most adverse effects are dose-related and include dizziness, somnolence, blurred vision, confusion, and dysarthria. Urinary symptoms, including retention, hesitation, and dysuria, believed to be due to effects of the drug on KCNQ potassium channels in detrusor smooth muscle, may occur. They are generally mild and usually do not require drug discontinuation. In 2013, reports began to appear of blue pigmentation, primarily on the skin and lips, but also on the palate, sclera, and conjunctiva. The skin dyspigmentation is due to the presence of coarse melanin granules within dermal cells and not to deposition of the drug within the tissue. The skin discoloration has not been associated with more serious adverse effects but may be of cosmetic significance. In addition, however, retinal pigment abnormalities can occur independent of skin changes. Of particular concern are postmarketing reports of macular abnormalities characterized as vitelliform lesions, such as those seen in macular degeneration or dystrophy. Decreased visual acuity has been reported, but documentation is lacking. Nevertheless, because of the ophthalmologic adverse reactions, regulatory agencies have recommended use of retigabine only in cases where other antiseizure drugs are not adequate or not tolerated.