Benzodiazepines: Action and Uses

• Benzodiazepines (BZDs) are categorized by duration: short, intermediate, and long-acting.

Duration of Action

• Short-acting BZDs include midazolam (2–6h) and triazolam (2–6h).
• Lorazepam (6–24h) is an intermediate-acting BZD.
• Clonazepam (>24h) is a long-acting BZD.

Mechanism of Action

• BZDs bind between the alpha-1 and gamma-2 subunits on the GABA-A receptor.
• GABA binds to GABA receptors, opening chloride channels.
• Chloride influx causes hyperpolarization, hindering neuron depolarization.
• BZDs boost the frequency of chloride channel opening when GABA is present, amplifying inhibitory signals.
• BZDs function as positive allosteric modulators on GABA-A receptors.

Indications

• BZDs treat anxiety disorders, insomnia, status epilepticus, night terrors, withdrawal, anesthesia, and muscle spasms.
• They address generalized anxiety disorder, panic attacks, and short-term insomnia.
• Lorazepam and diazepam are used for status epilepticus.
• Chlordiazepoxide and diazepam manage alcohol withdrawal/delirium tremens.
• Diazepam is a treatment for muscle spasticity.
• Midazolam induces preoperative sedation.
• BZDs, when combined with antipsychotics, can treat acute agitation or mania.

Side Effects

• Common side effects include sedation, confusion, CNS depression, paradoxical stimulation, anterograde amnesia, respiratory depression, and coma.
• Cognitive impairment, muscle weakness, ataxia, and falls are other side effects, especially in the elderly.
• Prolonged use can lead to dependence and tolerance.

Contraindications

• BZDs are not advised in cases of respiratory depression, myasthenia gravis, pregnancy/breastfeeding, and severe liver impairment.
• Caution is needed with elderly patients because of increased fall and confusion risks.
• Pregnancy is contraindicated due to teratogenic effects like cleft palate and floppy infant syndrome.
• Substance abuse history is a contraindication because of dependence risk.
• Use with caution in patients with severe respiratory insufficiency or sleep apnea.
• Lorazepam, oxazepam, and temazepam (LOT) are safer choices in hepatic impairment.

Overdose Antidote

• Flumazenil is the antidote for BZD overdose with an initial dose of 0.2 mg.
• Maximum dose of Flumazenil per cycle is 1 mg because it may cause seizures/arrhythmias.

Common Benzodiazepines

• Short-acting BZDs (t½ < 6 hrs): triazolam, midazolam
• Intermediate-acting BZDs (t½ 6–24 hrs): lorazepam, temazepam, oxazepam, alprazolam
• Long-acting BZDs (t½ > 24 hrs): diazepam, clonazepam, chlordiazepoxide, flurazepam

Mnemonic

• "TOM and AL’s Long Cool Dudes" aids recall of drug categories
• Triazolam, Oxazepam, Midazolam: short/intermediate
• Alprazolam, Lorazepam: intermediate
• Long-acting: Clonazepam, Diazepam
• LOT drugs (safe in liver disease, metabolized via conjugation): Lorazepam, Oxazepam, Temazepam

Mechanism of Action (Detailed)

• BZDs are positive allosteric modulators of the GABA-A receptor.
• They bind at the interface between the α and γ subunits on the GABA-A receptor complex.
• Binding increases the frequency of chloride (Cl⁻) channel opening in the presence of GABA; GABA is required.
• Increased Cl⁻ influx leads to hyperpolarization of the neuron, decreasing excitability.
• They enhance GABA’s inhibitory effect but do not mimic it, making them safer than barbiturates in overdose.

Subunit Specific Effects:

• The GABA-A receptor is a pentamer (5 subunits), typically 2α, 2β, 1γ.
• α1 subunits are related to sedation, amnesia, and anticonvulsant effects.
• α2 and α3 subunits are related to anxiolysis and muscle relaxation.
• α5 subunits are related to cognition, learning, and memory.

Receptor Binding Summary

• BZDs do not affect GABA-B receptors, which are metabotropic; instead, they act only on ionotropic GABA-A receptors.
• BZDs do not open Cl⁻ channels alone; GABA must be present.
• Synergistic effects occur with alcohol, opioids, and barbiturates.