Lorazepam

Generic Name: Lorazepam

Lorazepam is a benzodiazepine with anxiolytic, anti-anxiety, anticonvulsant, anti-emetic and sedative properties. Lorazepam enhances the effect of the inhibitory neurotransmitter gamma-aminobutyric acid on the GABA receptors by binding to a site that is distinct from the GABA binding site in the central nervous system. This leads to an increase in chloride channel opening events, a facilitation of chloride ion conductance, membrane hyperpolarization, and eventually inhibition of the transmission of nerve signals, thereby decreasing nervous excitation.

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Dr. Anirban Deep Banerjee

Lorazepam is a benzodiazepine. Benzodiazepines are drugs which reduce the nerve activity in the brain and spinal cord. Although their exact mechanism of action is not completely understood, it is believed that benzodiazepines, such as lorazepam, enhance the effects of gamma-aminobutyric acid by binding with its receptors in the brain. Gamma-aminobutyric acid, also known as GABA is a neurotransmitter (a chemical in the brain) which is responsible for decreasing stimulation in the brain, promoting relaxation, and preparing the body for sleep. Other examples of benzodiazepines are alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium).

Anxiety

Lorazepam has anxiety-reducing effects and its best-known indication is the short-term management of severe anxiety. In the US, the FDA advises against use of benzodiazepines such as lorazepam for longer than four weeks. It is fast acting, and useful in treating fast onset panic anxiety.

Lorazepam can effectively reduce agitation and induce sleep, and the duration of effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, especially in the presence of severe anxiety or night terrors. It has a fairly short duration of action.

Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after seven days' use of lorazepam.

Seizures

Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is more effective than diazepam and intravenous phenytoin in the treatment of status epilepticus and has a lower risk of continuing seizure that might require additional medication. However, phenobarbital has a superior success rate compared to lorazepam and other drugs, at least in the elderly.

Lorazepam's anticonvulsant properties and pharmacokinetic profile, make intravenous use reliable for terminating acute seizures, but induces prolonged sedation. Oral benzodiazepines, including lorazepam are occasionally used as long-term prophylactic treatment of resistant absence seizures; because of gradual tolerance to their anti-seizure effects, benzodiazepines such as lorazepam are not considered first-line therapies.

Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome. In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism.

Sedation

Lorazepam is sometimes used for individuals receiving mechanical ventilation. However, in critically ill people, propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam is discouraged.

Its relative effectiveness in preventing new memory formation, along with its ability to reduce agitation and anxiety, makes lorazepam useful as premedication. It is given before a general anesthetic to reduce the amount of anesthetic required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Lorazepam by mouth is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures. Lorazepam is sometimes used as an alternative to midazolam in palliative sedation. In intensive care unitslorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia.

Agitation

Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals, but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function. However, adverse effects such as behavioral disinhibition may make benzodiazepines inappropriate for some acutely psychotic patients. Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.

Other

Catatonia with inability to speak is responsive to lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or overly rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment. As lorazepam can have paradoxical effects, haloperidol is sometimes given at the same time.

It is sometimes used in chemotherapy in addition to medications used to treat nausea and vomiting, i.e. nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick. It is also used as adjunct therapy for cyclic vomiting syndrome.

The most common side effects associated with Ativan are:

  • Sedation
  • Dizziness
  • Weakness
  • Unsteadiness

Other side effects include:

  • A feeling of depression
  • Amnesia
  • Loss of orientation
  • Headaches
  • Sleep disturbances
  • Low blood pressure (hypotension)
  • Impotence (electrical dysfunction, ED)
  • Changes in appetitie
  • Sleep aphea

Possible serious side effects include:

  • Extrapyramidal symptoms
  • Respiratory depression
  • Suicidal ideation/attempt
  • Seizures
  • Depression

tablet: Schedule IV

  • 0.5mg
  • 1mg
  • 2mg

oral concentrate: Schedule IV

  • 2mg/mL

injectable solution: Schedule IV

  • 2mg/mL
  • 4mg/mL

Anxiety Disorders

Initial: 2-3 mg PO q8-12hr PRN; not to exceed 10 mg/day

Maintenance: 2-6 mg/day PO divided q8-12hr

Short-Term Treatment of Insomnia

2-4 mg PO qHS

Preoperative Sedation, Anxiety Relief, & Anterograde Amnesia

0.05 mg/kg IM for 1 dose; 2 hours before surgery; not to exceed 4 mg (2 mg/dose in elderly), OR 

0.044 mg/kg IV for 1 dose; 15-20 minutes before surgery; not to exceed 4 mg (2 mg/dose in elderly)

Status Epilepticus

Usual 4 mg/dose slow IV at 2 mg/min

If seizure persists after 5-10 min, administer 4 mg IV again

Anxiolytic/Sedation in ICU (Off-label)

Intubated and mechanically ventilated patients

  • 0.02-0.04 mg/kg loading dose IV
  • 0.02-0.06 mg/kg intermittent IV q2-6hr PRN, OR 
  • 0.01-0.1 mg/kg/hr continuous IV; not to exceed 10 mg/hr

Chemotherapy-Induced Nausea/Vomiting (Off-label)

0.5-2 mg PO/IV q6hr; PRN thereafter

Chronic Insomnia (Off-label)

2-4 mg PO qHS

Dosing Considerations

IV: Monitor respirations q5-15min and before each repeated IV dose

Dosing Modifications

Renal impairment

  • PO: Dose adjustment not necessary
  • IV/IM: Use with caution in mild-to-moderate impairment; not recommended in severe impairment or renal failure
  • IV/IM (prolonged periods or high doses): Monitor; risk of propylene glycol toxicity

Hepatic impairment

  • PO: No dose adjustment recommended in mild-to-moderate impairment; use with caution (may require lower dose) in severe impairment
  • IV/IM: Use with caution in mild-to-moderate impairment; not recomended in severe impairment of hepatic failure

Pediatric

Dosage Forms & Strengths

tablet: Schedule IV

  • 0.5mg
  • 1mg
  • 2mg

oral concentrate: Schedule IV

  • 2mg/mL

injectable solution: Schedule IV

  • 2mg/mL
  • 4mg/mL

Status Epilepticus (Off-label)

Infants and children: 0.05-0.1 mg/kg IV over 2-5 minutes; not to exceed 4 mg/dose; may repeat q10-15min PRN 

Alternatively, 0.1 mg/kg at slow IV rate not to exceed rate of 2 mg/min; not to exceed dose of 4 mg

Adolescents: 4 mg slow IV; if seizure persists after 10-15 minutes, administer 4 mg IV again

Anxiolytic/Sedation/Agitation (Off-label)

Children: 0.05 mg/kg/dose PO q4-8hr; not to exceed 2 mg/dose 

Chemotherapy-Induced Nausea/Vomiting (Off-label)

Children >2 years: 0.025-0.05 mg/kg/dose IV q6hr PRN; not to exceed 2 mg/dose 

Dosing Considerations

IV: Monitor respirations q5-15min and before each repeated IV dose

Geriatric

Preferred agent in elderly because short-acting and has inactive metabolite

Anxiety disorders

Lower initial dose recommended; 1-2 mg PO divided q8-12hr

Insomnia

Lower initial dose recommended; 0.5-1 mg PO qHS, increase PRN

To avoid oversedation, initial daily dose should not exceed 2 mg

Dosing considerations

When higher dose indicated, increase evening dose before daytime doses

Overdosage

In postmarketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and/or other drugs. Therefore, in the management of overdosage, it should be borne in mind that multiple agents may have been taken.

The benzodiazepines, including Ativan (lorazepam), produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics.

Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest.

Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate.

Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid.

The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

Lorazepam and Xanax are both effective in treating anxiety for a short time. But they also have many other uses, which are specific to each drug. Additionally, the side effects of each drug are similar, but not exactly the same.

To help decide the drug that’s best for you, your doctor will consider the condition you have as well as your medical history and the other drugs you take. It’s not always clear why one medication works better for some people than for others. If the drug you end up using doesn’t work out, your doctor may change the dose or try other benzodiazepine medications that may help.

Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. Ativan (lorazepam) is not recommended for use in patients with a primary depressive disorder or psychosis.

Use of benzodiazepines, including lorazepam, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression.

Use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. As with all patients on CNS-depressant drugs, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles and that their tolerance for alcohol and other CNS depressants will be diminished.

Physical And Psychological Dependence

The use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence. The risk of dependence increases with higher doses and longer term use and is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving lorazepam or other psychotropic agents.

In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided and a gradual dosage-tapering schedule followed after extended therapy.

Pregnancy

Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.

Nursing Mothers

Lorazepam has been detected in human breast milk; therefore, it should not be administered to breastfeeding women, unless the expected benefit to the woman outweighs the potential risk to the infant.

Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability).

Geriatric Use

Clinical studies of Ativan generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age

Age does not appear to have a significant effect on lorazepam kinetics

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