lorazepam

benzodiazepine· Brands: Ativan, Lorivan, TemestaIMIVPOSL

Mechanism of action

Lorazepam is a benzodiazepine that binds to the benzodiazepine site on the gamma-aminobutyric acid type A (GABA-A) receptor, enhancing the inhibitory effect of GABA. This increases the frequency of chloride channel opening, hyperpolarising the neuronal membrane and reducing neuronal excitability in the central nervous system.

Pharmacokinetics

Lorazepam is well absorbed after oral administration, with an absolute bioavailability of approximately 90%. Peak plasma concentrations occur within 1 to 2 hours. It is widely distributed and is highly protein bound (85 to 91%). Lorazepam is metabolised in the liver by conjugation to glucuronide, which is inactive and excreted in urine. The elimination half-life is about 9 to 16 hours, with metabolites having a shorter half-life. Onset of action is 5 to 20 minutes after intravenous administration, 30 minutes after intramuscular injection, and 1 to 2 hours orally. It crosses the placenta and enters breast milk.

Indications & dosing

Short-term management of anxiety

Short-term use; lowest effective dose.

adult · PO: 0.5–1 mg every 6-8 h PRN · Short-term use; lowest effective dose.

Short-term management of insomnia

Use for 2-4 weeks maximum; tolerance limits long-term use.

adult · PO: 1–2 mg at bedtime · Use for 2-4 weeks maximum; tolerance limits long-term use.

Status epilepticus

Give IV slowly; may repeat once after 10 minutes if seizures persist.

adult · IV: 4 mg single dose · Give IV slowly; may repeat once after 10 minutes if seizures persist.

Preoperative sedation

Usually given 1-2 hours before procedure.

adult · PO: 2 mg single dose · Usually given 1-2 hours before procedure.

Alcohol withdrawal

Taper gradually to avoid withdrawal seizures.

adult · PO: 2–4 mg every 6-8 h · Taper gradually to avoid withdrawal seizures.

Contraindications & precautions

Hypersensitivity to lorazepam or other benzodiazepines · Risk of anaphylaxis or severe allergic reaction.
Severe respiratory insufficiency · Benzodiazepines can cause respiratory depression.
Sleep apnoea · May worsen apnoeic episodes.
Myasthenia gravis · Muscle weakness may be exacerbated.
Pregnancy, especially first trimester · Potential teratogenicity; use only if benefit outweighs risk.
Breast-feeding · Lorazepam is excreted in breast milk; monitor infant.
Severe hepatic impairment · Reduce dose; risk of encephalopathy.
Acute narrow-angle glaucoma · May increase intraocular pressure.
Avoid alcohol and other CNS depressants, as they increase sedative effects.
Discontinue gradually to reduce risk of withdrawal, seizures, and rebound anxiety.
Use with caution in the elderly, as they are more susceptible to cognitive impairment and falls.
Use with caution in hepatic impairment; consider dose reduction or avoidance in severe disease.
Advise patients against driving or operating machinery until effects are known.
Use with caution in patients with a history of substance misuse or addictive disorders.

Adverse effects

Sedation and drowsiness
Dizziness
Ataxia
Amnesia (anterograde)
Respiratory depressionserious
Paradoxical agitation or hostility
Dependence and withdrawal reactionsserious
Falls and fractures (especially in elderly)serious

Renal & hepatic adjustment

eGFR 0+: No dose adjustment required. Use caution in severe renal impairment (eGFR < 30 mL/min) and monitor for excessive sedation.
Hepatic impairment (mild): Use with caution; consider a lower initial dose and titrate slowly.
Hepatic impairment (moderate): Reduce the dose and titrate slowly; monitor for excessive sedation and respiratory depression.
Hepatic impairment (severe): Avoid use; risk of precipitating hepatic encephalopathy. If considered essential, use the lowest possible dose with close monitoring. (avoid)

Monitoring, pregnancy & toxicity

Respiratory rate · During initiation and with dose changes; more frequently in elderly or with concurrent CNS depressants.
Sedation level · Before each dose or at least daily in hospitalised patients.
Blood pressure · Monitor for hypotension, especially during parenteral administration.
Mental status · Monitor for paradoxical agitation or disinhibition.
Signs of dependence or withdrawal · In long-term use, assess regularly.
Pregnancy: Not recommended in pregnancy unless potential benefit outweighs risk. Avoid in the first trimester and near term. If used, prescribe the lowest effective dose for the shortest duration.
Toxicity: CNS and respiratory depression (drowsiness, confusion, ataxia, hypoventilation, coma) · Supportive care: monitor airway, breathing, circulation, and vital signs. Provide oxygen and ventilatory support if needed.
Toxicity: Hypotension · Fluids and vasopressors as required. Monitor blood pressure.
Toxicity: Benzodiazepine toxicity reversal with flumazenil · Consider flumazenil as a specific antagonist in severe cases. Use with caution in patients with concurrent benzodiazepine dependence, seizures, or tricyclic antidepressant overdose as it may precipitate withdrawal or seizures.
Toxicity: Dependence and withdrawal on sudden cessation · Not an acute toxicity, but in long-term use, reduce dose gradually to avoid withdrawal seizures.

Antidotes & reversal

Flumazenil · Use with caution; re-sedation and seizure risk.

Clinical notes

Lorazepam is used for the short-term relief of anxiety, for premedication before surgery, as an anticonvulsant in status epilepticus, and for sedation in intensive care. Caution is required in patients with respiratory depression, severe hepatic impairment, or myasthenia gravis. Prolonged use can lead to tolerance and dependence, with withdrawal symptoms on discontinuation. Abrupt withdrawal can be dangerous; the dose should be tapered gradually. Lorazepam is not recommended in pregnancy or breastfeeding unless the potential benefit outweighs the risk. Paradoxical agitation may occur in the elderly and children. It is a controlled substance in many countries.

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BNF; local formulary