Lorazepam

Usage

Lorazepam is prescribed for the short-term management of moderate to severe anxiety, insomnia associated with anxiety, and as a pre-operative medication. It’s also used in emergency situations like status epilepticus. It is classified as a benzodiazepine, an anxiolytic, sedative, and anticonvulsant. Lorazepam enhances the effect of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle-relaxant properties.

Alternate Names

The international nonproprietary name (INN) is lorazepam. Brand names include Ativan and Loreev XR.

How It Works

Pharmacodynamics: Lorazepam binds to benzodiazepine receptors on GABA-A receptors in the central nervous system. This binding enhances GABA’s inhibitory effects, leading to decreased neuronal excitability.

Pharmacokinetics:

• Absorption: Lorazepam is well-absorbed orally, reaching peak plasma concentrations in 1-2 hours. Intramuscular (IM) administration has an onset of action within 15-30 minutes, whereas intravenous (IV) administration has a rapid onset within 1-3 minutes.
• Metabolism: Lorazepam is primarily metabolized in the liver through glucuronidation to an inactive metabolite, lorazepam glucuronide. It does not involve the CYP450 enzyme system to a large extent.
• Elimination: Lorazepam is mainly excreted through the kidneys as lorazepam glucuronide. It has a half-life of approximately 10-20 hours.

Mode of Action: Lorazepam potentiates GABAergic neurotransmission by increasing the frequency of chloride channel opening, leading to hyperpolarization of neurons and reduced neuronal firing.

Dosage

Standard Dosage

Adults:

• Anxiety: 2-6 mg/day orally, divided into 2-3 doses. Initiate therapy with 1-2 mg/day and titrate based on patient response.
• Insomnia: 2-4 mg orally as a single dose at bedtime.
• Pre-operative medication: 2-4 mg orally the night before or 1-2 hours before the procedure.

Children:

• Pre-operative medication (5-11 years): 0.05 mg/kg (max 2.5 mg) at least one hour before the operation. Children aged 12-17 years may receive 1-4 mg either the night before or at least one hour before the procedure, or both
• Other indications: Safety and efficacy not established in children under 12 years for anxiety and under 5 years for surgical procedures. Dosages for other indications should be determined by the physician.

Special Cases:

• Elderly Patients: Initial dose of 1-2 mg/day, divided into 2 doses. Titrate cautiously based on response and tolerance.
• Patients with Renal Impairment: Dose reduction may be necessary.
• Patients with Hepatic Dysfunction: Dose reduction may be necessary, especially in severe hepatic dysfunction where it is contraindicated.
• Patients with Comorbid Conditions: Careful assessment and dose adjustment may be required.

Clinical Use Cases

• Intubation: Dosage should be individualized as needed.
• Surgical Procedures: 2-4 mg orally the night before or 1-2 hours pre-operatively. IV administration might be used in specific cases.
• Mechanical Ventilation: Dosage as needed.
• Intensive Care Unit (ICU) Use: 0.02 to 0.04 mg/kg IV loading dose, followed by 0.01 to 0.1 mg/kg/h continuous infusion, or intermittent doses as needed.
• Emergency Situations:
  • Status epilepticus: 4 mg IV at 2 mg/minute. A second dose can be administered if seizures persist.

Dosage Adjustments

Dosage adjustments are required for elderly patients, those with renal/hepatic dysfunction, and those with comorbid conditions. Individualized dosing is crucial. Genetic polymorphisms affecting drug metabolism should also be considered.

Side Effects

Common Side Effects:

Drowsiness, dizziness, weakness, ataxia, confusion, amnesia, disinhibition, headache, nausea, vomiting, constipation, blurred vision, changes in libido.

Rare but Serious Side Effects:

Respiratory depression, allergic reactions, suicidal thoughts, paradoxical reactions (e.g., agitation, aggression), hallucinations.

Long-Term Effects:

Cognitive impairment, dependence, withdrawal symptoms upon discontinuation.

Adverse Drug Reactions (ADR):

Severe allergic reactions, severe respiratory depression, angioedema, Stevens-Johnson syndrome.

Contraindications

• Hypersensitivity to benzodiazepines.
• Acute narrow-angle glaucoma.
• Severe respiratory insufficiency.
• Sleep apnea.
• Myasthenia gravis.
• Severe hepatic impairment.

Drug Interactions

Lorazepam interacts with several medications, including:

• CNS depressants: Opioids, alcohol, barbiturates, antihistamines, other benzodiazepines – increased sedation and respiratory depression.
• CYP450 inhibitors/inducers: Although Lorazepam’s metabolism does not rely heavily on the CYP450 system, certain interactions may occur.
• Other: Valproic acid, antidepressants – increased lorazepam levels.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D - There is positive evidence of human fetal risk. Use only if potential benefit justifies risk to the fetus.
• Breastfeeding: Lorazepam is excreted in breast milk. Monitor infants for drowsiness, poor feeding, and weight gain. Consider alternative options if possible.

Drug Profile Summary

• Mechanism of Action: Enhances GABAergic neurotransmission.
• Side Effects: Drowsiness, dizziness, ataxia, respiratory depression (rare).
• Contraindications: Hypersensitivity to benzodiazepines, severe respiratory insufficiency, sleep apnea, acute narrow-angle glaucoma, severe hepatic impairment.
• Drug Interactions: CNS depressants, some antidepressants.
• Pregnancy & Breastfeeding: Use with caution; potential risks to the fetus and nursing infant.
• Dosage: Varies depending on indication and patient factors; individualized dosing is essential.
• Monitoring Parameters: Respiratory rate, mental status, vital signs.

Popular Combinations

Lorazepam may be combined with other medications, such as analgesics for pre-operative sedation, depending on the specific clinical scenario. However, due to the increased risk of respiratory depression, combining lorazepam with other CNS depressants is generally avoided.

Precautions

• General Precautions: Evaluate for pre-existing medical conditions, including respiratory, hepatic, and renal impairment.
• Specific Populations: Use cautiously in pregnant women, breastfeeding mothers, children, and the elderly.
• Lifestyle Considerations: Avoid alcohol and other CNS depressants. Caution patients about operating machinery or driving.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Lorazepam?

A: Dosage varies based on indication and patient specifics. Adults: anxiety (2-6 mg/day divided), insomnia (2-4 mg at bedtime), pre-op (2-4 mg). Elderly/impaired function: lower initial dose (1-2 mg/day). Pediatric dosing requires careful consideration, with pre-op doses calculated by weight.

Q2: How long can a patient take Lorazepam?

A: Short-term use is recommended, typically 2-4 weeks. Long-term use can lead to dependence and withdrawal symptoms.

Q3: What are the signs of Lorazepam overdose?

A: Excessive drowsiness, confusion, respiratory depression, coma.

Q4: Can Lorazepam be used in patients with respiratory problems?

A: Use cautiously in patients with mild to moderate respiratory impairment. Contraindicated in severe respiratory insufficiency and sleep apnea.

Q5: Does Lorazepam interact with alcohol?

A: Yes, concurrent use with alcohol can potentiate CNS depression, leading to increased sedation and respiratory depression.

Q6: What are the withdrawal symptoms of Lorazepam?

A: Anxiety, insomnia, tremors, seizures, hallucinations. Taper the dose gradually to minimize withdrawal symptoms.

Q7: Can Lorazepam be used during pregnancy?

A: It should be used with caution during pregnancy due to potential risks to the fetus. Discuss risks and benefits with the patient.

Q8: What should be monitored while a patient is on Lorazepam?

A: Monitor respiratory rate, mental status, and vital signs. Assess for signs of dependence and adverse effects.

Q9: How should Lorazepam be administered?

A: Lorazepam can be administered orally, IM, or IV. IV administration should be performed slowly to minimize the risk of adverse reactions.

Q10: Can lorazepam be crushed or chewed?

A: Tablets can be broken along the score line if needed to adjust the dose, but it’s generally recommended to swallow tablets whole. Crushing or chewing is generally not recommended unless directed by a physician, as it can alter the drug’s release profile.