Revision Year: 2022 Publisher: Medochemie Ltd., 1-10 Constantinoupoleos Street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Benzodiazepine derivatives
ATC code: N05BA06
Lorazepam is a benzodiazepine drug with short to medium duration of action. It has all the well known intrinsic benzodiazepine effects: anxiolytic, sedative/hypnotic, anticonvulsant and muscle relaxant, each to a different extent.
Following oral administration lorazepam is rapidly and almost completely absorbed, peak serum levels occurring at 2 hours (range: 0.5–3 h), oral bioavailability 90–93%.
Lorazepam is approximately 85%–91% protein bound, with the free fraction being significantly higher in elderly patients. It penetrates the cerebrospinal fluid, with concentrations being about 5%–28% corresponding plasma levels. It crosses the placental barrier, and plasma levels in neonates approximate maternal serum levels. Distribution half life is 20–25 minutes (range: 10.3–42.7), and volume of distribution is 1.3 L/Kg.
Steady state plasma concentrations are achieved within three days.
Lorazepam is extensively metabolised in the liver, approximately 75%, and undergoes enterohepatic recirculation, chronic dosing has no effect on hepatic hydroxylation capacity. The principal metabolite, inactive, is 3–O–phenolic glucuronide at 75% dose, with smaller amounts of 6–chloro–4–O–chlorophenyl–2, 1–quinazolinone, and the hydroxylated derivative of lorazepam, all of which are inactive.
The principal route of excretion is renal, 88%, with lower amounts excreted in the faeces, 7%. Total body clearance is 1.1 ml/minute/Kg. Lorazepam elimination half life is 12 h and there is minimal risk of excessive accumulation. The elimination half life of the glucuronide inactive metabolite is 12–18 hours.
There is no alteration in the pharmacokinetic parameters in the elderly. Hepatic impairment In severe hepatic impairment the elimination half life of lorazepam is doubled.
Renal impairment results in a decrease in rate of glucuronide metabolite excretion without an increase in the half life of lorazepam.
Acute peroral lorazepam toxicity studies in animals did not reveal any specific sensitiveness (see section 4.9 “Overdose” for acute toxicity in man).
Peroral lorazepam was investigated in rats (80 weeks) and dogs (12 months) in chronic toxicity studies. Histopathological, ophthalmological, and haematological examinations as well as organ functioning tests showed no or only slightly significant changes without biological relevance, even in high doses.
Oesophageal dilation occurred in rats treated with lorazepam for more than one year at a dose of 6 mg/kg/day.
Lorazepam has not been subjected to extensive studies on mutagenic effects; however, tests on lorazepam were negative hitherto. Studies in rats and mice did not indicate any distinct carcinogenic potential after oral lorazepam application.
The effect of lorazepam on embryonal and foetal development and reproduction was examined in rabbits, rats and mice. These studies did not reveal any evidence of teratogenic properties or dysfunction of reproduction of lorazepam.
Experimental studies gave evidence of behavioural disorders of the offspring of maternal animals with long-term exposure to benzodiazepines.
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