Other allosteric modulators of GABA-A receptors
Barbiturates
Barbiturates are allosteric agonists of GABA-A receptors and prolong, by sensitizing the receptor to GABA, periods during which chloride channels are open. In large doses, they could increase the duration of opening of the channels even in the absence of GABA.
Barbiturates were very much used as hypnotics, in particular those with short action such as amobarbital, secobarbital and butobarbital. They are not used any more as hypnotics because their effect, indisputable at the beginning of treatment, disappeared in a few days and, at discontinuation, there was an aggravation of insomnia. They had, moreover, two disadvantages: severe poisoning if taken in high doses and enzyme induction.
Phenobarbital is used as an antiepileptic, particularly in generalized tonic-clonic seizures and in partial secondarily generalised tonic-clonic seizures. There is also an injectable preparation used for the treatment of status epilepticus.
The half-life of phenobarbital is about 80 hours; its effective plasma concentrations range between 15 and 25 mg/L and Its steady- state is obtained within two or three weeks after starting treatment.
Phenobarbital has two principal disadvantages:
- It is an enzyme inducer, but in epileptics this induction is permanent and thus more easily controllable.
- It decreases attention capacity, particularly in children, especially when plasma concentrations are too high.
Primidone is a drug which in the body is converted into two active metabolites, phenylethylmalonamide and phenobarbital. It is used as an antiepileptic and in treatment of essential tremor.
Two barbiturates, thiopental and methohexital have an immediate effect of short duration, which is explained by their liposolubility, responsible for their fast penetration into brain, followed by redistribution in the body. They are used as general anesthetics.
Etomidate
Etomidate is an allosteric gabamimetic, inducing GABA mimetic effect by activating receptors different from those of benzodiazepines but inducing the same effects. Moreover, it inhibits GABA reuptake.
Etomidate is an hypnotic ofrapid onset and short duration. It is used by intravenous route for anesthetic induction and anesthesia, as potentialisator of inhalational anesthetic agents and, with higher doses, in perfusion, as an hypnotic agent for anesthesia of average duration. It can elicit sometimes violent myoclonus, prevented by administration of a benzodiazepine or a curarizing drug.
Bromide
Bromide has a sedating effect that can be explained by its entry into cells through GABA-A receptor channels when its extracellular concentration is high enough, for example after intake of calcium bromogalactogluconate. Sustained intake of bromide- this drug has been often used in self medication - can induce poisoning with neuropsychiatric disturbances such as drowsiness, slurred speech, memory impairment, tremors, delirium and sometimes cutaneous eruptions. This often ignored poisoning, particularly in the elderly, is detected by plasma bromide determination.
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