Mechanism of Action of Austedo
Austedo (deutetrabenazine) works as a reversible inhibitor of vesicular monoamine transporter 2 (VMAT2), which depletes monoamines including dopamine, serotonin, norepinephrine, and histamine from nerve terminals by blocking their uptake into synaptic vesicles. 1
How Deutetrabenazine Works
The active drug deutetrabenazine is rapidly metabolized in the liver to two major circulating metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-HTBZ. These metabolites are the primary active compounds responsible for the therapeutic effect, not the parent drug itself 1.
The VMAT2 Inhibition Process
- VMAT2 is a protein transporter located on synaptic vesicles within nerve terminals
- Under normal conditions, VMAT2 pumps monoamine neurotransmitters (dopamine, serotonin, norepinephrine, histamine) from the nerve terminal cytoplasm into storage vesicles
- The α-HTBZ and β-HTBZ metabolites reversibly bind to and block VMAT2, preventing monoamines from being packaged into vesicles
- This results in depletion of monoamine stores available for release into the synapse
- The effect is reversible, distinguishing it from reserpine which binds irreversibly to VMAT2 1
Clinical Relevance
While the precise mechanism by which this monoamine depletion treats chorea in Huntington's disease and tardive dyskinesia remains unknown, it is believed that reducing dopamine availability in the striatum (the brain region with highest VMAT2 binding) 1 dampens the excessive involuntary movements characteristic of these conditions.
Important Pharmacological Note
The drug reaches peak brain concentrations within 3-4 hours, with highest binding in the striatum and lowest in the cortex 1. This regional selectivity likely contributes to its therapeutic effects on movement disorders while the reversible nature of VMAT2 inhibition provides a safety advantage over older irreversible agents.
Note: The question appears to confuse Austedo with dextromethorphan/quinidine. Austedo contains deutetrabenazine, not dextromethorphan/quinidine. Dextromethorphan/quinidine is a completely different medication (brand name Nuedexta) used for pseudobulbar affect, which works through NMDA receptor antagonism and sigma-1 receptor agonism 2, 3.