Lorazepam

Generic Name: Lorazepam
Drug Class: Benzodiazepine
Pharmacological Class: Sedative-hypnotic; anxiolytic; anticonvulsant
ATC Code: N05BA06
Regulatory Status: Prescription-only; Schedule IV controlled substance (varies by country)
Common Brand Names: Ativan, Temesta, Loraz, Lorans, Tavor (region-dependent)

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Mechanism of Action

Lorazepam is a short-to-intermediate acting benzodiazepine that exerts its effects by binding to specific sites on the gamma-aminobutyric acid A (GABA_A) receptor complex in the central nervous system. It enhances the effect of GABA, the primary inhibitory neurotransmitter, by increasing the frequency of chloride channel opening, leading to hyperpolarization of neurons and decreased excitability.

This modulation of GABAergic neurotransmission produces:

• Anxiolytic effects (relieves anxiety)

• Sedative-hypnotic action (induces sleep)

• Anticonvulsant properties

• Muscle relaxant effects

• Amnesic effects (impairment of short-term memory)

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Therapeutic Indications

1. Anxiety Disorders

   • Generalized anxiety disorder (GAD)

   • Panic attacks

   • Short-term relief of severe anxiety (acute settings)

2. Insomnia (short-term, especially when related to anxiety or situational stress)

3. Status Epilepticus

   • Preferred agent for rapid termination of seizures (IV route)

4. Preoperative Sedation (Anxiolysis/Amnesia)

   • Used before surgical or diagnostic procedures

5. Alcohol Withdrawal Syndrome

   • Controls agitation, seizures, and delirium tremens

6. Chemotherapy-Induced Nausea and Vomiting (CINV)

   • Adjunct to antiemetics to control anticipatory nausea

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Formulations and Routes of Administration

• Oral tablets: 0.5 mg, 1 mg, 2 mg

• Oral solution (sublingual/oral drops): Available in some regions

• Injectable solution (IV/IM): 2 mg/mL, 4 mg/mL

• Sublingual tablets: Market-dependent

Routes of Administration:

• Oral (PO) – most common for anxiety and insomnia

• Intravenous (IV) – rapid control in status epilepticus or preoperative sedation

• Intramuscular (IM) – when IV access unavailable

• Sublingual (SL) – for rapid effect, avoids first-pass metabolism

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Dosing Guidelines

General Adult Dosing:

1. Anxiety:

   • 1–3 mg/day in divided doses (2–3 times daily)

   • Maximum: 10 mg/day (short-term use only)

2. Insomnia:

   • 1–2 mg at bedtime

3. Status Epilepticus (IV):

   • 4 mg slow IV push (2 mg/min); may repeat in 10–15 min if seizure persists

   • Pediatric: 0.05–0.1 mg/kg IV (max single dose 4 mg)

4. Preoperative Sedation (IV/IM):

   • Adults: 0.05 mg/kg up to 4 mg 1 hour before surgery

5. Alcohol Withdrawal:

   • 2–4 mg orally every 6–12 hours initially; taper based on response

Elderly and Debilitated Patients:

• Start at lower doses (0.5–1 mg/day)

• Monitor for sedation, ataxia, and cognitive impairment

Pediatric Use:

• Approved IV in status epilepticus

• Oral use not typically first-line for anxiety due to dependency risk

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Pharmacokinetics

• Absorption: Rapid and complete orally; peak in 2 hours (oral)

• Distribution: Highly lipophilic; wide tissue distribution

• Protein Binding: ~85%

• Metabolism: Hepatic via conjugation (not via CYP450 system); forms inactive glucuronides

• Half-life: 10–20 hours (prolonged in elderly/hepatic dysfunction)

• Onset of Action:

  • Oral: 15–60 minutes

  • IV: 1–5 minutes

  • IM: 15–30 minutes

• Duration of Action: 6–12 hours (depends on dose and route)

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Contraindications

• Hypersensitivity to lorazepam or benzodiazepines

• Acute narrow-angle glaucoma

• Severe respiratory insufficiency (unless for seizure control)

• Myasthenia gravis

• Sleep apnea syndrome (oral formulation)

• Children <6 months (oral), unless for seizures

• Severe hepatic insufficiency (precaution due to prolonged sedation)

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Warnings and Precautions

1. Dependence and Withdrawal:

   • Risk increases with prolonged use (>2–4 weeks), high doses

   • Abrupt discontinuation can cause rebound anxiety, insomnia, seizures

2. Tolerance:

   • May develop to sedative and hypnotic effects

3. Respiratory Depression:

   • Especially when combined with opioids, alcohol, or in patients with sleep apnea/COPD

4. Cognitive and Psychomotor Impairment:

   • Affects driving, operating machinery, decision-making

5. Paradoxical Reactions:

   • Rare agitation, aggression, disinhibition (more in children/elderly)

6. Elderly Patients:

   • Increased sensitivity; higher risk of falls, confusion

7. Pregnancy and Lactation:

   • Pregnancy: Category D (positive human fetal risk); risk of neonatal withdrawal and floppy infant syndrome

   • Lactation: Excreted in breast milk; sedation and poor feeding in infant possible

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Adverse Effects

Common (>1%):

• Drowsiness

• Dizziness

• Fatigue

• Weakness

• Ataxia

• Cognitive impairment

• Confusion

Less Common:

• Depression, blurred vision

• Hypotension (IV route)

• Respiratory depression (IV or overdose)

Rare/Severe:

• Respiratory failure

• Seizures (on withdrawal)

• Anaphylaxis, angioedema

• Hepatic dysfunction (rare)

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Drug Interactions

Potentiated CNS Depression With:

• Alcohol

• Opioids (morphine, oxycodone) → synergistic risk of respiratory depression and death

• Antipsychotics

• Sedating antihistamines (e.g., diphenhydramine)

• Barbiturates

• Antidepressants (TCAs, SSRIs)

• Anticonvulsants (valproate increases lorazepam levels)

Reduced Effectiveness With:

• Theophylline and caffeine (may antagonize sedative effects)

Pharmacokinetic Considerations:

• Lorazepam does not undergo CYP450 metabolism → fewer metabolic interactions than diazepam or alprazolam

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Overdose Management

Symptoms:

• Profound sedation

• Hypotension

• Ataxia

• Respiratory depression

• Coma

Treatment:

• Supportive care

• Flumazenil (benzodiazepine antagonist) in controlled settings – use cautiously due to seizure risk, especially with chronic users or mixed overdose

• Monitor respiratory and cardiovascular function

• Activated charcoal may be used if ingestion is recent

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Dependence, Tolerance, and Withdrawal

• Physical dependence: Can occur after several weeks of use

• Withdrawal symptoms: Anxiety, insomnia, tremors, sweating, confusion, seizures

• Tapering: Reduce dose gradually over weeks (especially if used >2 weeks)

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Monitoring Parameters

• Sedation level

• Respiratory rate (especially IV or IM)

• Vital signs

• Mental status (confusion, depression)

• Signs of misuse, tolerance, or dependence

• Liver function (if used long-term)

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Comparison with Other Benzodiazepines

Property	Lorazepam	Diazepam	Alprazolam	Clonazepam
Duration	Intermediate	Long	Short-intermediate	Long
Onset (oral)	15–60 min	15–30 min	30–60 min	20–60 min
Half-life	10–20 hrs	20–50 hrs	12–15 hrs	20–60 hrs
Metabolism	Conjugation	CYP450	CYP3A4	CYP3A4
Ideal use	Anxiety, seizures, pre-op sedation	Seizures, alcohol withdrawal	Panic disorder	Seizures, panic disorder

Patient Counseling Points

• Do not operate heavy machinery or drive until you know how it affects you

• Avoid alcohol and other CNS depressants

• Use only as prescribed; do not share or increase dose without medical advice

• Risk of dependence with long-term use

• Do not stop suddenly if used for more than 2 weeks; consult provider for taper

• Store in a secure place, away from children and potential misuse

• Notify provider if pregnant, planning pregnancy, or breastfeeding

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Storage

• Store at room temperature (20–25°C)

• Protect from light and moisture

• Injection formulations must be stored under specific conditions (usually 2–8°C); avoid freezing