Mechanism of Action of Lorazepam
Lorazepam activates γ-aminobutyric acid A (GABA-A) neuronal receptors in the brain, enhancing the activity of the inhibitory neurotransmitter GABA and thereby reducing central nervous system excitability. 1
Core Pharmacologic Mechanism
- Lorazepam does not directly activate GABA-A receptors but requires GABA to be present, acting as a positive allosteric modulator that potentiates GABA-mediated neural inhibition 1, 2
- The drug has non-selective affinity for GABA-A receptors, interacting with multiple receptor subunits (α1, α2, α3, and α5) 3
- This receptor activation results in increased chloride ion conductance, hyperpolarizing neurons and reducing their excitability 2
Clinical Effects Resulting from GABA-A Activation
The GABA-A receptor modulation produces multiple therapeutic effects:
- Anxiolytic effects - reduction of anxiety through enhanced inhibitory neurotransmission 1, 4
- Sedative and hypnotic effects - dose-dependent central nervous system depression 1, 4
- Amnestic effects - anterograde amnesia that extends beyond sedative effects 1
- Anticonvulsant activity - suppression of seizure activity through enhanced inhibition 1, 2
- Muscle relaxation - centrally mediated reduction in muscle tone 2
Important Mechanistic Distinctions
- Lorazepam has no analgesic activity despite its other CNS effects 1
- The drug undergoes direct glucuronidation with no active metabolites, making its effects more predictable than other benzodiazepines like diazepam or midazolam 1, 3, 2
- Lorazepam is more potent than midazolam, which is more potent than diazepam at GABA-A receptors 1
Cardiovascular and Respiratory Effects
Beyond central GABA-A receptor effects, lorazepam causes:
- Dose-dependent respiratory depression, particularly when combined with opioids or other CNS depressants 1, 3
- Systemic hypotension through decreased systemic vascular resistance 4, 2
- Modest increase in heart rate as a compensatory response to reduced vascular resistance 2