Mechanism of Action of Tetrabenazine

Introduction

Tetrabenazine is a centrally acting vesicular monoamine transporter 2 (VMAT2) inhibitor used primarily to manage hyperkinetic movement disorders. It is especially effective in reducing chorea associated with Huntington’s disease. By depleting monoamines such as dopamine from nerve terminals, it helps in restoring neurochemical balance in the basal ganglia.

Mechanism of Action (Stepwise Points)

1. Selective VMAT2 Inhibition: Tetrabenazine binds reversibly to VMAT2 in presynaptic neurons.
2. Reduced Monoamine Storage: It prevents dopamine, norepinephrine, and serotonin from entering synaptic vesicles.
3. Increased Cytosolic Breakdown: Monoamines remain in the cytoplasm and are degraded by monoamine oxidase (MAO), particularly MAO-B for dopamine.
4. Synaptic Dopamine Depletion: The depletion leads to diminished dopaminergic neurotransmission.
5. Symptom Relief: Reduced dopamine transmission alleviates chorea and other hyperkinetic movements.

Pharmacokinetics

• Absorption: Rapid oral absorption; bioavailability is low due to first-pass metabolism.
• Metabolism: Extensively metabolized in the liver to active metabolites α-HTBZ and β-HTBZ.
• Half-life: Parent compound ~6 hours; active metabolites ~4–8 hours.
• Excretion: Primarily via urine; minor fecal elimination.
• Protein Binding: Moderate binding to plasma proteins.

Clinical Uses

• Chorea associated with Huntington’s disease
• Tardive dyskinesia
• Tourette syndrome (off-label)
• Hemiballismus (off-label)

Adverse Effects

• Sedation and Fatigue
• Depression and Suicidality
• Parkinsonism (bradykinesia, rigidity)
• Insomnia
• Orthostatic hypotension
• Nausea

Comparative Analysis

Feature	Tetrabenazine	Deutetrabenazine	Valbenazine
Target	VMAT2	VMAT2	VMAT2
Duration of Action	Short	Longer than tetrabenazine	Longest
Dosing Frequency	Multiple times/day	Twice daily	Once daily
CNS Penetration	High	Moderate	Moderate
Approved Indications	Chorea (HD)	Chorea, Tardive dyskinesia	Tardive dyskinesia
Side Effects	Depression, sedation	Less depression, sedation	Least CNS effects

Explanation: Tetrabenazine was the first VMAT2 inhibitor, with high CNS activity but greater psychiatric risks. Deutetrabenazine and valbenazine offer improved pharmacokinetics and tolerability.

Multiple Choice Questions (MCQs)

1. Tetrabenazine primarily inhibits which transporter?
   a) DAT
   b) SERT
   c) VMAT2
   d) NET
2. Tetrabenazine leads to reduced levels of which neurotransmitter most significantly?
   a) GABA
   b) Dopamine
   c) Glutamate
   d) Acetylcholine
3. Which disorder is FDA-approved for tetrabenazine use?
   a) Parkinson’s disease
   b) Epilepsy
   c) Huntington’s chorea
   d) ALS
4. What is the major psychiatric side effect of tetrabenazine?
   a) Euphoria
   b) Mania
   c) Depression
   d) Hallucinations
5. Tetrabenazine is metabolized in the liver to:
   a) Dopamine
   b) α-HTBZ and β-HTBZ
   c) Levodopa
   d) Serotonin
6. Which is NOT a common adverse effect of tetrabenazine?
   a) Fatigue
   b) Seizures
   c) Insomnia
   d) Parkinsonism
7. VMAT2 is responsible for transporting monoamines into:
   a) Nucleus
   b) Synaptic vesicles
   c) Axon hillock
   d) Mitochondria
8. Compared to tetrabenazine, deutetrabenazine has:
   a) Shorter half-life
   b) Fewer side effects
   c) Higher toxicity
   d) No CNS penetration
9. Which monoamine is most involved in chorea pathophysiology?
   a) Serotonin
   b) Dopamine
   c) Histamine
   d) GABA
10. What is the route of administration for tetrabenazine?
    a) Intramuscular
    b) Oral
    c) Subcutaneous
    d) Intravenous

FAQs

Q1: Can tetrabenazine be used in depression?
A1: No. In fact, it can exacerbate depression and should be used cautiously in such patients.

Q2: Is tetrabenazine a dopamine antagonist?
A2: No. It depletes presynaptic dopamine by inhibiting its vesicular storage, not by receptor antagonism.

Q3: What makes deutetrabenazine safer than tetrabenazine?
A3: Deutetrabenazine has deuterium-substitution, prolonging half-life and reducing peak-trough fluctuations, thereby minimizing side effects.

Q4: Does tetrabenazine require dose titration?
A4: Yes. Dosing should be started low and gradually increased based on response and tolerability.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition
• KD Tripathi, Essentials of Medical Pharmacology, 7th Edition
• Pharmacological Screening Methods & Toxicology by Avanapu Srinivasa Rao
• Biopharmaceutics & Pharmacokinetics by Thakur Publication

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