Lorazepam - Drug Monograph

Introduction

Lorazepam is a benzodiazepine medication primarily used for the management of anxiety disorders, preoperative sedation, and status epilepticus. As a Schedule IV controlled substance, it possesses sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties. First approved by the FDA in 1977, lorazepam remains widely prescribed despite increased awareness of its potential for dependence and abuse.

Mechanism of Action

Lorazepam enhances the effect of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. It binds to specific sites on the GABA-A receptor complex, facilitating chloride ion channel opening and increasing chloride conductance. This hyperpolarizes neurons and reduces neuronal excitability, resulting in CNS depression. Unlike some benzodiazepines, lorazepam has no active metabolites and does not undergo hepatic oxidation.

Indications

FDA-approved indications:

• Anxiety disorders
• Preoperative sedation (anxiolysis/amnesia)
• Status epilepticus

Off-label uses:

• Alcohol withdrawal syndrome
• Chemotherapy-induced nausea and vomiting
• Acute agitation
• Insomnia (short-term management)

Dosage and Administration

• Anxiety: 2-6 mg/day divided 2-3 times daily
• Insomnia: 2-4 mg at bedtime

• Preoperative sedation: 0.05 mg/kg IM (max 4 mg)
• Status epilepticus: 4 mg IV slow push, may repeat in 10-15 minutes

• Elderly/debilitated patients: Initiate 1-2 mg/day in divided doses
• Hepatic impairment: Reduce dose by 50% or avoid
• Renal impairment: Use with caution (CrCl <30 mL/min)

Pharmacokinetics

• Absorption: Well absorbed orally (90% bioavailability); IM absorption reliable but slower
• Distribution: Vd 1.3 L/kg; 85% protein bound
• Metabolism: Hepatic glucuronidation (UGT enzymes) to inactive metabolites
• Elimination: Renal excretion (88%); half-life 10-20 hours
• Onset of action: Oral: 30-60 minutes; IV: 1-3 minutes

Contraindications

• Known hypersensitivity to benzodiazepines
• Acute narrow-angle glaucoma
• Severe respiratory depression
• Severe hepatic impairment
• Myasthenia gravis
• Sleep apnea syndrome
• Pregnancy (especially first trimester)

Warnings and Precautions

• Concurrent use with opioids may result in profound sedation, respiratory depression, coma, and death
• Risk of abuse, misuse, and addiction

• Paradoxical reactions (agitation, aggression)
• Impaired cognitive and motor performance
• Depression and suicidal ideation
• Withdrawal symptoms with abrupt discontinuation
• Physical and psychological dependence potential
• Elderly patients at increased risk of falls and cognitive impairment

Drug Interactions

• Opioids: Enhanced CNS depression (additive effects)
• Alcohol: Increased impairment and respiratory depression
• Other CNS depressants: Barbiturates, antipsychotics, sedatives
• Valproic acid: May decrease lorazepam clearance
• Probenecid: May prolong lorazepam half-life
• Oral contraceptives: May increase lorazepam clearance

• Limited significance due to lorazepam's high extraction ratio

Adverse Effects

• Sedation (15.9%)
• Dizziness (6.9%)
• Weakness (4.2%)
• Unsteadiness (3.4%)

• Depression
• Headache
• Sleep disturbances
• Amnesia
• Hypotension

• Respiratory depression
• Dependence and withdrawal
• Paradoxical reactions
• Blood dyscrasias
• Hepatic enzyme elevations

Monitoring Parameters

• Efficacy: Anxiety scales, seizure frequency, sedation level
• Safety: Respiratory rate, oxygen saturation (especially with opioids)
• Cognitive function: Regular assessment in elderly
• Signs of misuse/dependence: Especially in high-risk patients
• Liver function tests: Periodically with long-term use
• Withdrawal symptoms: During taper/discontinuation

Patient Education

• Take exactly as prescribed; do not increase dose without consultation
• Avoid alcohol and other CNS depressants
• Do not abruptly stop medication (risk of withdrawal)
• May cause drowsiness - avoid driving or operating machinery
• Use effective contraception; notify provider if pregnant or planning pregnancy
• Store securely to prevent misuse by others
• Report any thoughts of self-harm or worsening depression
• Keep all follow-up appointments for medication monitoring

References

1. FDA Prescribing Information: Lorazepam Tablets, USP 2. American Psychiatric Association. (2010). Practice Guideline for the Treatment of Patients with Panic Disorder 3. Glauser T, et al. (2016). Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults 4. Mayo-Smith MF. (1997). Pharmacological Management of Alcohol Withdrawal 5. Ashton H. (2005). The diagnosis and management of benzodiazepine dependence 6. Greenblatt DJ, et al. (1993). Clinical pharmacokinetics of lorazepam 7. NICE Guidelines: Anxiety disorders (2011) 8. WHO Model List of Essential Medicines, 22nd List (2021)