Mechanism of Action (MOA)
Tetrabenazine works presynaptically to reduce the overall supply of monoamines, including dopamine10
The precise mechanism by which Xenazine® (tetrabenazine) exerts its antichorea effects
is unknown, but it is believed to be related to its effect as a reversible depletor of
monoamines from nerve terminals.10
Dialing back dopamine2
The loss of inhibitory inputs of the medium-sized projection spiny neurons in the brain
striatum is believed to be the underlying cause of involuntary movement characteristic of
the disease.2 Based on studies in mouse models, dialing back the dopamine input
into the striatum may be a possible strategy for affecting chorea.3
- The presynaptic release of dopamine is partially regulated by vesicular monoamine transporter 2 (VMAT2).4,5
- VMAT2 transports and concentrates monoamines, including dopamine, in presynaptic storage vesicles.4,5
- Dopamine stored in synaptic vesicles is protected from degradation by monoamine oxidase (MAO). Therefore,
the activity of VMAT2 determines the amount of cytosolic dopamine available for synaptic release.6
- To date, 5 dopamine receptor subtypes have been classified (D1 through D5); they are divided into 2
subclasses – namely D1-like (D1 and D5) and D2-like (D2, D3, and D4) dopamine receptors.7
- Dopamine binds to its receptors on the postsynaptic neuron to either trigger or inhibit neuronal
excitation, depending on the receptor subtypes.7,8
- The excessive stimulation of dopamine triggers involuntary and uncontrollable body movements typical of the chorea in HD.9
- Tetrabenazine reversibly binds to VMAT2 and reduces uptake of dopamine into synaptic vesicles10
- There are no conclusive studies in humans, but it is hypothesized that tetrabenazine:
- Provides greater selectivity for dopamine than for other monoamines12
- Selectively reduces dopaminergic activity12
- Tetrabenazine interacts with VMAT at a site distinct from that of substrate binding.6
- Tetrabenazine has no affinity for the monoamine transporters on the synaptic membrane.11
- The dopamine pool in the cytosol is rapidly metabolized and depleted from synaptic release.6
- Tetrabenazine inhibition of VMAT2 results in an overall reduction in synaptic monoamines, including dopamine.10
Xenazine is also contraindicated in patients who have impaired hepatic function or are taking monoamine oxidase inhibitors (MAOIs) or reserpine.
Xenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.
At least 20 days should elapse after stopping reserpine before starting Xenazine.
Xenazine® (tetrabenazine) has a
Short Half-life (t1/2)10
Tetrabenazine is hepatically metabolized and effects on monoamine
depletion are due primarily to actions of 2 major metabolites
α-HTBZ and β-HTBZ are metabolized principally by CYP2D6
Patients who are poor metabolizers of CYP2D6 should not be given any daily doses greater than 50 mg
- "FDA Approves First Drug for Treatment of Chorea in Huntington's Disease", FDA News Release, August 15, 2008: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116936.htm. Updated April 15, 2013. Accessed August 17, 2015.
- Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur
J Neurosci. 2008; 27:2803-2820.
- Cyr M, Sotnikova TD, Gainetdinov RR, Caron MG. Dopamine enhances motor and neuropathological
consequences of polyglutamine expanded huntington. FASEBJ. 2006; 20:2541-2543.
- Henry JP, Sagne C, Bedet C, Gasnier B.The vesicular monoamine transporter: from
chromaffin granule to brain. Neurochem Int. 1998;32:227-246.
- Zheng G, Dwoskin LP, Crooks PA. Vesicular monoamine transporter 2: role as a novel
target for drug development. AAPS J. 2006; 8:E682-E692.
- Guillot TS, Miller GW. Protective actions of the vesicular monoamine transporter2
(VMAT2) in monoaminergic neurons. Mol Neurobiol. 2009;39:149-170.
- Werkman TR, Glennon JC, Wadman WJ, McCreary AC. Dopamine receptor pharmacology:
interactions with serotonin receptors and significance for the aetiology and treatment
of schizophrenia. CNS Neurol Disord Drug Targets. 2006;5:3-23.
- Calabresi P,Centonze D,Gubellini P,et al. Synaptic transmission in the striatum:
from plasticity to neurodegeneration. Prog Neurobiol. 2000; 61:231-265.
- Joel D,Weiner I. The connections of the primate subthalmic nucleus: indirect pathways
and the open-interconnected scheme of basal ganglia-thalamocortical circuitry. Brain
Res Brain Res Rev. 1997;23:62-78.
- Xenazine [package insert]. Deerfield, IL: Lundbeck; June 2015.
- Rostene W, Boja JW, Scherman D, Carroll FI, Kuhar MJ. Dopamine transport: pharmacological
distinction between the synaptic membrane and the vesicular transporter in rat striatum.
Eur J Pharmacol. 1992; 218:175-177.
- Pettibone DJ, Totaro JA, Pflueger B. Tetrabenazine-induced depletion of brain monoamines:
characterization and interaction with selected antidepressants. Eur J Pharmacol. 1984;102:425-430.