A typical maintenance dose of perampanel for patients 12 years of age and older is 4, 6, or 8 mg/d. Higher doses may be needed in patients who are receiving CYP3A4-inducing antiseizure drugs. Perampanel use is often associated with behavioral adverse reactions including aggression, hostility, irritability, and anger. The frequency of these adverse effects increases in a dose-dependent fashion, and they occur more often in younger patients and in those with learning disabilities or dementia. Alcohol use may exacerbate the level of anger. Other common adverse effects are dizziness, somnolence, and headache. Falls are more common at higher doses.
Perampanel has a long half-life, typically ranging from 70 to 110 hours, which permits once-daily dosing. Because of the long half-life, steady state is not achieved for 2–3 weeks; the prescriber should make dosage changes no more frequently than at 2-week (or longer) intervals. The kinetics are linear in the dose range of 2–12 mg/d. The half-life is prolonged in moderate hepatic failure. Absorption is rapid and the drug is fully bioavailable. Although food slows the rate of absorption, the extent is not affected. Perampanel is 95% bound to plasma proteins. The drug is extensively metabolized via initial oxidation by CYP3A4 and subsequent glucuronidation.
The most significant drug interactions with perampanel are with potent CYP3A4 inducer antiseizure drugs such as carbamazepine, oxcarbazepine, and phenytoin. Concomitant use with such agents increases the clearance of perampanel by 50–70%, which may require the use of higher perampanel doses. Of somewhat lesser concern is the potential for strong CYP3A4 inhibitors to increase the levels of perampanel. Perampanel may decrease the effectiveness of levonorgestrel-containing hormonal contraceptives.
In 1903, chemists in Germany discovered that lipophilic derivatives of barbituric acid induced sleep in dogs. Phenobarbital was introduced into the clinical market in 1912 as a sleeping aid; it was serendipitously found to be useful in the treatment of epilepsy. In comparison with anesthetic barbiturates such as pentobarbital, phenobarbital is preferred in the chronic treatment of epilepsy because it is less sedative at antiseizure doses. Intravenous pentobarbital, however, is frequently used to induce general anesthesia in the treatment of drug-refractory status epilepticus. Phenobarbital is the oldest of the currently available antiseizure drugs; however, the drug is no longer a first choice in the developed world because of its sedative properties and many drug interactions. It is still useful for neonatal seizures.
Four barbituric acid derivatives were once used for epilepsy: phenobarbital, mephobarbital, metharbital, and primidone. Only phenobarbital and primidone remain in common use.
Mechanism of Action (see also Chapter 22)
Barbiturates such as phenobarbital act as positive allosteric modulators of GABAA receptors at low concentrations (see Figure 22–6); at higher concentrations, the drugs directly activate GABAA receptors. In contrast to benzodiazepines, which augment the frequency of GABAA receptor chloride channel opening, barbiturates increase the mean open duration of the channel without altering either channel conductance or opening frequency. Phenobarbital also exerts other actions on synaptic function and intrinsic neuronal excitability mechanisms; some of these could be relevant to its clinical antiseizure activity, including block of AMPA receptors or voltage-activated calcium channels.