Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1  Pharmacodynamic Properties
Pharmacotherapeutic group: Other nervous system drugs, ATC Code: NO7XX06 
Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.

The precise mechanism by which tetrabenazine exerts its effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.

Studies conducted in vitro and in vivo have shown that tetrabenazine is a selective inhibitor of monoamine transportation into pre-synaptic neuronal vesicles, by reversible inhibition of the VMAT2 (vesicular monamine transporter 2), which is principally located in the central nervous system. Studies have shown that α- dihydrotetrabenazine, one of the principal metabolite of tetrabenazine, has a similar affinity and more significant selectivity for VMAT2.

At a synaptic level tetrabenazine and α-dihydrotetrabenazine creates a reversible depletion of monamines in the presynaptic terminals. Within the CNS tetrabenazine and α-dihydrotetrabenazine causes preferential depletion of dopamine from nerve terminals. Neurotransmitter depletion by a single dose of tetrabenazine is reversible and lasts only a few hours.

Pharmacokinetic Properties

5.2     Pharmacokinetic Properties
Tetrabenazine is quickly and mostly absorbed after oral administration. Its absorption is not affected by the taking of food.

After administration of single doses from 12.5 to 50 mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.

Clinical testing has shown that a single oral dose of tetrabenazine undergoes extensive (>75%) absorption from the gastro-intestinal tract. The metabolism of tetrabenazine is complex, initially proceeding via the formation of alpha and beta dihydrotetrabenazine. The majority of the observed metabolites appear to be formed from these dihydrotetrabenazines as a result of O-dealkylation, hydroxylation and conjugation.

No significant build-up has been observed after daily administration. The elimination half-life of dihydrotetrabenazine is approximately five hours.

Tetrabenazine is mostly eliminated in metabolised form in urine (less than 2% of tetrabenazine is excreted in unchanged form).