Mechanism of Action of Diazepam

Mechanism of Action of Diazepam

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Introduction

Diazepam is a long-acting benzodiazepine widely used for its anxiolytic, sedative–hypnotic, anticonvulsant, muscle relaxant, and amnestic properties. It acts on the central nervous system by enhancing inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). Diazepam is a high-yield drug in pharmacology, psychiatry, neurology, anesthesia, and emergency medicine examinations due to its rapid onset, multiple indications, and characteristic mechanism of action.

MOA of diazepam
Diazepam pharmacology
Diazepam Mechanism of Action Flowchart
Stepwise mechanism of action of diazepam

Mechanism of Action (Step-wise)

Diazepam enhances inhibitory neurotransmission by modulating the GABA-A receptor–chloride channel complex.

Step-wise mechanism:

  1. GABA-A Receptor Complex
    The GABA-A receptor is a ligand-gated chloride ion channel located on postsynaptic neuronal membranes.
  2. Binding Site of Diazepam
    Diazepam binds to a specific allosteric site on the GABA-A receptor, distinct from the GABA binding site.
  3. Allosteric Modulation
    Binding of diazepam increases the affinity of the GABA-A receptor for endogenous GABA.
  4. Increased Frequency of Chloride Channel Opening
    In the presence of GABA, diazepam increases the frequency (not duration) of chloride channel opening.
  5. Chloride Ion Influx
    Increased chloride influx leads to hyperpolarization of the postsynaptic neuron.
  6. Reduced Neuronal Excitability
    Hyperpolarization makes neurons less likely to fire action potentials.
  7. Central Nervous System Depression
    The net result is anxiolytic, sedative, anticonvulsant, and muscle relaxant effects.

Pharmacokinetics

  • Absorption: Rapid and complete oral absorption
  • Distribution: Highly lipophilic; widely distributed; crosses blood–brain barrier and placenta
  • Protein binding: High
  • Metabolism: Hepatic metabolism via CYP2C19 and CYP3A4
  • Active metabolites: Desmethyldiazepam, oxazepam, temazepam
  • Elimination: Renal excretion of metabolites
  • Half-life: Long (20–50 hours; metabolites longer)

Because of active metabolites, diazepam has a prolonged duration of action.

Clinical Uses

Diazepam is used in multiple neurologic and psychiatric conditions:

  • Anxiety disorders
  • Acute alcohol withdrawal
  • Status epilepticus (IV)
  • Muscle spasm and spasticity
  • Premedication before procedures
  • Sedation and anxiolysis
  • Tetanus (adjunct therapy)

Adverse Effects

Adverse effects are related to CNS depression:

  • Central nervous system:
    • Sedation
    • Drowsiness
    • Ataxia
    • Confusion (especially in elderly)
  • Respiratory depression (high doses or IV use)
  • Dependence and tolerance with long-term use
  • Anterograde amnesia

Abrupt discontinuation after prolonged use can precipitate withdrawal symptoms and seizures.

Comparative Analysis (must include a table + explanation)

Comparison of GABAergic Sedative-Hypnotics

FeatureDiazepamBarbituratesZ-drugs
ReceptorGABA-AGABA-AGABA-A
Channel effect↑ Frequency↑ Duration↑ Frequency
Therapeutic indexHighLowHigh
Respiratory depressionRare aloneCommonRare
Dependence riskModerateHighLow

Explanation:
Diazepam is safer than barbiturates because it enhances GABA action without directly opening chloride channels. Unlike Z-drugs, diazepam has broad anticonvulsant and muscle relaxant properties.

MCQs (10–15)

  1. Diazepam acts by binding to which receptor?
    a) GABA-B
    b) NMDA
    c) GABA-A
    d) Dopamine D₂

Answer: c) GABA-A

  1. Diazepam increases which property of the chloride channel?
    a) Conductance
    b) Duration of opening
    c) Frequency of opening
    d) Number of channels

Answer: c) Frequency of opening

  1. Diazepam requires the presence of which neurotransmitter to act?
    a) Dopamine
    b) Serotonin
    c) GABA
    d) Acetylcholine

Answer: c) GABA

  1. Diazepam produces CNS depression by causing:
    a) Neuronal depolarization
    b) Sodium influx
    c) Neuronal hyperpolarization
    d) Calcium channel opening

Answer: c) Neuronal hyperpolarization

  1. Diazepam is most useful in:
    a) Chronic psychosis
    b) Status epilepticus
    c) Parkinson disease
    d) Myasthenia gravis

Answer: b) Status epilepticus

  1. Diazepam is metabolized in the liver to:
    a) Inactive metabolites only
    b) Active metabolites
    c) Toxic metabolites
    d) Water-soluble metabolites only

Answer: b) Active metabolites

  1. A major advantage of diazepam over barbiturates is:
    a) Faster onset
    b) Lower efficacy
    c) Higher safety margin
    d) No sedation

Answer: c) Higher safety margin

  1. Long-term use of diazepam may cause:
    a) Agranulocytosis
    b) Dependence
    c) Nephrotoxicity
    d) Ototoxicity

Answer: b) Dependence

  1. Diazepam is contraindicated in:
    a) Anxiety
    b) Status epilepticus
    c) Severe respiratory depression
    d) Muscle spasm

Answer: c) Severe respiratory depression

  1. Diazepam differs from barbiturates by:
    a) Acting without GABA
    b) Directly opening chloride channels
    c) Increasing frequency, not duration, of channel opening
    d) Blocking sodium channels

Answer: c) Increasing frequency, not duration, of channel opening

FAQs (minimum 5)

  1. What is the primary mechanism of diazepam?
    Allosteric enhancement of GABA-A receptor–mediated chloride influx.
  2. Why is diazepam safer than barbiturates?
    It does not directly open chloride channels and requires GABA to act.
  3. Does diazepam cause muscle relaxation?
    Yes, by suppressing polysynaptic spinal reflexes.
  4. Why does diazepam have a long duration of action?
    Due to formation of active metabolites.
  5. Can diazepam cause dependence?
    Yes, especially with long-term or high-dose use.
  6. Is diazepam useful in seizures?
    Yes, particularly in acute seizure management.

References

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