OXAZEPAM

Absorption

Following oral administration, peak plasma levels (Cmax) averaged 450 mg/mL and occurred approximately 3 hours (Tmax) after dosing.

Toxicity

The oral LD50 in rats and mice is >8000 mg/kg and 1540 mg/kg, respectively.
Symptoms of oxazepam overdose are likely to be consistent with its adverse effect profile and range from mild to severe, sometimes fatal, CNS depression. Treatment should include gastric decontamination, via lavage or induced vomiting, followed by symptomatic and supportive measures. The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to non-pharmacological management, but may increase the risk of seizure in long-term benzodiazepine users and in cyclic antidepressant overdose.

Chemical properties

Off-White Solid

Originator

Serax,Wyeth,US,1965

The Uses of OXAZEPAM

Anxiolytic; muscle relaxant (skeletal); anticonvulsant; ligand for the GABAA receptor benzodiazepine modulatory site. Controlled substance (depressant).

Indications

Oxazepam is indicated for the management of anxiety disorders and for the short-term relief of symptoms of anxiety. It may also be used in the management of alcohol withdrawal symptoms.

Background

Oxazepam is an intermediate-acting, 3-hydroxybenzodiazepine used in the treatment of alcohol withdrawal and anxiety disorders. Oxazepam, like related 3-hydroxybenzodiazepine lorazepam, is considered less susceptible to pharmacokinetic variability based on patient-specific factors (e.g. age, liver disease) - this feature is advantageous as compared to other benzodiazepines, and is likely owing in part to oxazepam's relatively simple metabolism. It is an active metabolite of both diazepam and temazepam and undergoes very little biotransformation following absorption, making it unlikely to participate in pharmacokinetic interactions.

Definition

ChEBI: A 1,4-benzodiazepinone that is 1,3-dihydro-2H-1,4-benzodiazepin-2-one substituted by a chloro group at position 7, a hydroxy group at position 3 and phenyl group at position 5.

Manufacturing Process

(A) Suspend 10 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2one 4-oxide in 150 ml of acetic anhydride and warm on a steam bath with stirring until all the solid has dissolved. Cool and filter off crystalline, analytically pure 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4benzodiazepin-2-one, melting point 242°C to 243°C.
(B) Add to a suspension of 3.4 g of 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl2H-1,4-benzodiazepin-2-one in 80 ml of alcohol.6 ml of 4 N sodium hydroxide. Allow to stand after complete solution takes place to precipitate a solid. Redissolve the solid by the addition of 80 ml of water. Acidify the solution with acetic acid to give white crystals. Recrystallize from ethanol to obtain 7chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, melting point 203°C to 204°C.

brand name

Serax (Alpharma); Zaxopam (Quantum Pharmics).

Therapeutic Function

Tranquilizer

General Description

Odorless creamy-white to pale-yellow powder or white crystalline solid. Bitter taste. pH (2% aqueous suspension) 4.8-7.

General Description

Oxazepam, 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazpin-2-one (Serax), isan active metabolite of both chlordiazepoxide and diazepamand can be considered a prototype for the 3-hydroxy benzo-diazepines. It is much more polar than diazepam. Oxazepam is rapidlyinactivated to glucuronidated metabolites that are excretedin the urine. Thus, the half-life of oxazepam is about 4 to 8hours, and it is marketed as a short-acting anxiolytic. As aresult, its cumulative effects with chronic therapy are muchless than with long-acting benzodiazepine such as chlordiazepoxideand diazepam.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

OXAZEPAM is stable in light and is non hygroscopic. OXAZEPAM is stable in neutral solution. OXAZEPAM is hydrolyzed by acids and bases.

Fire Hazard

Flash point data for OXAZEPAM are not available; however, OXAZEPAM is probably combustible.

Pharmacokinetics

Benzodiazepines, including oxazepam, exert their sedative and anxiolytic effects by potentiating the effects of endogenous GABA, the primary inhibitory neurotransmitter in the CNS. Compared to other benzodiazepines, it has relatively low potency and a moderate duration of action. Oxazepam should be administered with caution to patients for whom a drop in blood pressure may lead to cardiac complications as, in rare cases, it may cause hypotension.

Pharmacokinetics

The half-life of oxazepam is approximately 4 to 8 hours, and cumulative effects with chronic therapy are much less than with long-acting benzodiazepines, such as chlordiazepoxide and diazepam. Lorazepam is the 2′-chloro derivative of oxazepam and has a similarly short half-life (2–6 hours) and pharmacological activity.

Clinical Use

Oxazepam

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism possibly increased by rifampicin.
Antipsychotics: enhanced sedative effects; risk of serious adverse effects in combination with clozapine.
Antivirals: possibly increased concentration with ritonavir.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.
Ulcer-healing drugs: metabolism inhibited by cimetidine.

Metabolism

Oxazepam has a single major inactive metabolite, a glucuronide conjugate. The glucuronidation of the S-isomer is catalyzed by UGT2B15. The glucuronidation of the R-isomer is catalyzed by UGT2B7 and UGT1A9.

Metabolism

Oxazepam is an active metabolite of both chlordiazepoxide and diazepam and is marketed separately, as a shortacting anxiolytic agent. Oxazepam is rapidly inactivated to glucuronidated metabolites that are excreted in the urine.