Product Details

A drug formerly used as an antipsychotic but now used primarily in the symptomatic treatment of various hyperkinetic disorders. It is a monoamine depletor and used as symptomatic treatment of chorea associated with Huntington's disease.

Indication

Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia

Associated Conditions

• Gilles de la Tourette's Syndrome
• Hemiballismus
• Huntington's Disease (HD)
• Tardive Dyskinesia
• Senile chorea

Pharmacodynamics

Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

Mechanism of action

Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).

Absorption

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients;
Tmax, oral = 69 min in HD or tardive dyskinesia patients

Volume of distribution

Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.

Protein binding

Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%.

Metabolism

Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.

• Tetrabenazine
   
  alpha-dihydrotetrabenazine
• Tetrabenazine
   
  b-dihydrotetrabenazine

Route of elimination

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose.

Half life

α-HTBZ = 7 hours; β-HTBZ = 5 hours; 9-desmethyl-β-DHTBZ = 12 hours.

Clearance

IV, 1.67 L/min in HD or tardive dyskinesia patients

Toxicity

Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg

Affected organisms

• Humans and other mammals

SOURCE:DRUGBANK