Pharmacology - Lorazepam (Ativan)

[Jatelka]

Lorazepam is 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.

It’s chemical formula is C15H10Cl2N2O2 and it’s molecular weight is: 321.16



It is a nearly white powder almost insoluble in water.

Pharmacokinetics

It is readily absorbed after oral administration with an absolute bioavailability of 90% percent. Peak plasma levels occur at 2 hours and the peak level from a 2 mg dose is approximately 20 ng/mL.

The half-life is about 12 hours and for the major metabolite, lorazepam glucuronide, about 18 hours. It is approximately 85% bound to plasma proteins. It is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is excreted in urine. Lorazepam glucuronide has no demonstrable activity.

Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics. However, in one study, total body clearance of lorazepam decreased by 20% in subjects of 60 to 84 years of age.

Indications

Short-term relief of the symptoms of anxiety. The effectiveness in long-term use (ie: greater than 4 months) has not been assessed by systematic clinical studies.

Usual therapeutic dose is 2 to 6 mg/day in divided doses. For anxiety, usual initial initial dose is 1mg two to three times a day.

For insomnia, usual starting dose is 2mg at bed-time.

Adverse Effects

As with all benzodiazepines, adverse effects are are dose dependent, with more severe effects occurring with high doses.

In a 3500 patients treated for anxiety, the most frequent adverse reaction was sedation (15.9%), followed by dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%).

Other adverse reactions to lorazepam include fatigue, drowsiness, amnesia, confusion, disorientation, unmasking of depression, disinhibition, euphoria, suicidal ideation/attempt, ataxia, extrapyramidal symptoms, tremor, vertigo visual disturbance, dysarthria/slurred speech, change in libido, decreased orgasm, headache, GI disturbance, change in appetite, deranged liver function tests, hypersensitivity reactions, anaphylactis, alopecia, rashes, hyponatremia, low blood counts and hypothermia.

Paradoxical reactions, including anxiety, excitation, agitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, and hallucinations may occur.

Pre-existing depression may emerge or worsen during use of lorazepam.

Clinically Significant Drug Interactions

Lorazepam produces increased CNS-depressant effects when administered with other CNS depressants, including 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 sodium valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when co-administered with valproate.

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

The effects of probenecid and valproate are thought to be due to inhibition of glucuronidation.

Administration of theophylline or aminophylline reduces the effect of lorazepam

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

Withdrawal symptoms (e.g. rebound insomnia) can appear after as little as one week. Lorazepam should not be discontinued suddenly.

Symptoms reported following discontinuation include headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization, depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise, and physical contact/perceptual changes, involuntary movements, nausea, vomiting, diarrhoea, loss of appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memoryloss, and hyperthermia.

Convulsions/seizures may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

There is evidence that tolerance develops to the sedative effects of benzodiazepines.

Cautions and Precautions

Compromised respiratory function

Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam.

Paradoxical reactions are more likely to occur in children and the elderly.

Renal and Hepatic Insufficiency

Oesophageal dilation occurred in rats treated with lorazepam for more than one year at 6 mg/kg/day (approximately 6 times the maximum human therapeutic dose). The effect was reversible only when the treatment was withdrawn within two months of first observation of the phenomenon. The clinical significance of this is unknown.

Essential Laboratory Tests

Periodic blood counts and liver-function tests are recommended for patients on long-term therapy.

Carcinogenesis And Mutagenesis

No evidence of carcinogenic potential was demonstrated in rats during an 18-month study. No studies regarding mutagenesis have been performed.

Pregnancy and Lactation

Reproductive studies in animals showed skeletal abnormalities that did not occur in control groups. At doses of 40 mg/kg there was increased foetal loss.

Lorazepam crosses the placenta and infants of mothers who took benzodiazepines preceding delivery have been reported to have withdrawal symptoms during the postnatal period.

Lorazepam is excreted in breast milk

Overdose

All the usual benzodiazepine effects.

[Colby]

very good info Thank you