Lorazepam

BRAND NAMES

ATIVAN: Ativan 1 mg Tablet is used to treat anxiety disorders, including panic attacks, social phobias, obsessive-compulsive disorder (OCD), and generalized anxiety disorder (characterized by excessive concern or restlessness). Additionally, it is utilized to temporarily relieve anxiety.

MECHANISM OF ACTION:

Lorazepam binds to benzodiazepine receptors on GABA-A ligand-gated chloride channel neurons throughout the CNS. This medicine boosts GABA's inhibitory actions, increasing the conductance of chloride ions in the cell. As a result, a shift in chloride ions causes hyperpolarization and stability of the cellular plasma membrane. Inhibitory action in the amygdala is advantageous in anxiety disorders, whereas inhibitory activity in the cerebral cortex is beneficial in seizure disorders.

PHARMACOKINETICS:

Absorption: Lorazepam absorbs easily after oral administration. Peak concentrations are achieved two hours after oral dosing. Lorazepam’s bioavailability is around 90%. Furthermore, lorazepam passes quickly through the brain via passive diffusion.

Distribution: Lorazepam exhibits an amount distribution of 1.3 L/kg and interacts with over 90% of plasma proteins. The medication passes across the blood-brain barrier via passive diffusion.

Metabolism: Lorazepam conjugates in the liver and is recirculated enterohepatically. Lorazepam glucuronide is an inactive metabolite. The medicine is glucuronidated directly without initially being metabolized by cytochrome p450. As a result, lorazepam can be safely supplied to people with hepatic impairment, with no effect on its pharmacokinetics.

Excretion: Lorazepam exhibits an elimination half-life of 14±5 hours and a clearance process of 1.1±0.4 mL/min/kg. The medication is mainly eliminated through the urine.

PHARMACODYNAMICS:

Lorazepam is known to have a high affinity for GABA receptors compared to other benzodiazepines, which may explain its strong amnesic effects. Its major pharmacological activities are to boost the effects of the neurotransmitter GABA on the GABAA receptor. Benzodiazepines, such as lorazepam, improve the effects of GABA at the GABAA receptor by increasing the frequency of opening the chloride ion channel on the GABAA receptors, resulting in the therapeutic properties of benzodiazepines. They, however, do not activate GABAA receptors on their own and must be combined with the neurotransmitter GABA. Thus, benzodiazepines boost the actions of the neurotransmitter GABA.

DOSAGE AND ADMINISTRATION

Lorazepam is available in a variety of forms, including oral tablets, oral concentrate solutions, extended-release capsules, and solutions. Lorazepam medication is available in dosages of 0.5 mg, 1 mg, and 2 mg, as well as a 2 mg/mL oral concentration solution. Extended-release capsules are available in dosages of 1 mg, 2 mg, and 3 mg. Lorazepam can also be given intravenously (IV) or intramuscularly (IM), with solutions available in doses of 2 and 4 mg/mL. The beginning of effect is generally 1 to 3 minutes when injected intravenously and 15 to 30 minutes when delivered intramuscularly. 

The majority of patients need an initial dosage of 2 to 3 mg/day, either twice or three times a day, for anxiety. To treat insomnia caused by stress or tension, a daily dosage of 2 to 4 mg can be administered before bedtime. For anxiety, the majority of individuals require an initial dose of 2 to 3 mg per day, usually twice or three times daily. Although the usual range is 2 to 6 mg given in staggered doses, with the maximum amount taken before sleep, the daily dosage can vary from 1 to 10 mg.

CONTRAINDICATION:

Lorazepam is not recommended for individuals who have had allergic responses to lorazepam, any of its components, or other benzodiazepines. The medicine is also not recommended for neonates or premature infants, as well as individuals with significant respiratory impairment (unless during mechanical ventilation), acute narrow-angle glaucoma, sleep apnea, severe respiratory insufficiency, or when delivered intra-arterially.

During the first and third trimesters of pregnancy, lorazepam and other benzodiazepines should not be used as first-line therapies for anxiety or other symptoms of psychiatric disorders. The danger of abuse, overuse, and reliance is very significant with benzodiazepines such as lorazepam. They are therefore not recommended for people who are actively using drugs or illegal substances. Lorazepam and other benzodiazepines, except for patients undergoing AUD detoxification, should not be administered to those who have a history of alcohol dependency or abuse and are not in remission. The likelihood of lethality, including death, increases when alcohol and lorazepam are used together in an overdose. Lorazepam injection formulation contains polyethylene glycol, propylene glycol, or benzyl alcohol; therefore, hypersensitivity to these excipients is a contraindication for administration. Extended-release capsules contain tartrazine; therefore, individuals with a history of allergic reactions should avoid using them.

DRUG INTERACTIONS:

• Lorazepam interacts with other medicines, causing CNS depression. Concurrent use of sedatives, hypnotics, opioids, cough and cold medications, antiepileptics, muscle relaxants, and alcohol may exacerbate lorazepam-induced side effects. When starting treatment with UDP-glucuronosyl transferase (UGT) inhibitors, gradually taper off lorazepam to stop using it.
• Metronidazole should not be given in conjunction with propylene glycol derivatives present in parenteral lorazepam formulations, since this may cause a disulfiram-like response.

SIDE EFFECTS:

Lorazepam, like most benzodiazepines, can cause dose-dependent adverse responses such as central nervous system and respiratory depression. Higher doses of the medication cause additional side effects.

Severe side effects of lorazepam include:

• Respiratory depression and failure
• Seizures
• Suicidality
• Dependency and abuse
• Tachycardia
• Hypotension
• Syncope
• Blood dyscrasias
• Jaundice
• Paradoxical reaction 

Common side effects of lorazepam include:

• Sedation
• Dizziness
• Asthenia
• Ataxia
• Local injection site reaction
• Respiratory depression
• Hypoventilation with IV use
• Hypotension
• Fatigue
• Amnesia

TOXICITY:

When lorazepam is overtaken, it can produce respiratory and CNS depression, which can result in hypotension, ataxia, confusion, coma, excessive sleepiness, muscle weakness, and even death. When benzodiazepines and opioids are used together, there is a risk of mortality, coma, respiratory depression, and extreme drowsiness. Therefore, patients who have insufficient access to alternative treatments should not be prescribed benzodiazepines and opioids combined. According to the indication, lorazepam dosage and duration must be restricted, and patients need to be closely monitored for respiratory depression symptoms. Although lorazepam, like other benzodiazepines, is infrequently linked to high serum ALT, there is a rare case of lorazepam causing clinically noticeable liver impairment. Acute liver injury caused by benzodiazepines usually follows a cholestatic clinical pattern.

Flumazenil is an antidote to benzodiazepine poisoning. Flumazenil competes with benzodiazepines for binding to the GABA-benzodiazepine receptor complex. However, sudden awakening after injection can cause dysphoria, agitation, and other negative consequences. In patients on chronic benzodiazepine therapy, flumazenil's abrupt interruption of benzodiazepine antagonism may cause benzodiazepine withdrawal, including seizures.

STORAGE CONDITIONS:

Store at refrigerator 2 ̊ to 8 ̊ C (36 ̊ to 46 ̊ F).