Flurazepam metabolites

RIA-Specificity The specificity of the antiserum initially is evaluated by cross-reactivity studies involving all the flurazepam metabolites known to be present in plasma. The mono-as well as di-desethylmetabolites exhibited a cross-reactivity of 17 and 3.7% respectively, while other possible competitors cross-reacted less than 1% as shown in Table 32.1. 

The effects of flurazepam and quazepam are long because of active metabolites. 

V-desalkylflurazepam accounts for most of flurazepam s pharmacologic effects. This metabolite may help when daytime anxiety or early morning awakening is present, but daytime sedation with impaired psychomotor performance may occur. 

Table 32.1 Flurazepam and Hapten 3-Hemisiccinyloxyl-flurazepam vis-a-vis the Cross-Reactivity of Metabolites Present in Plasma ...

Evidently, due to the cross-reactivity of both mono- and di-desethyl metabolites, a specific assay of flurazepam could not be developed successfully without first separating it from its metabolites effectively by the help of column chromatography. 

Flurazepam (Dalmane) [C-IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose Adults Beds >15 y. 15-30 mg PO qhs PRN X in elderly Caution [X, /-] Elderly, low albumin, hepatic impair Contra NAG PRG Disp Caps SE Hangover d/t accumulation of metabolites, apnea, anaphylaxis, angioedema, amnesia Interactions T CNS depression W/ antidepressants, antihistamines, opioids, EtOH T effects OF digoxin, phenytoin T effects W/ cimetidine, disulfiram, fluoxetine, iso-niazid, ketoconazole, metoprolol, OCPs, propranolol, SSRIs, valproic acid. 

Prazepam and flurazepam are almost completely converted to active metabolites before they reach the... 

The long half-lives of flurazepam and quazepam are due to their metabolite desalkylflurazepam. 

This non-BZD hypnotic, cyciopyrroione, is indicated for short-term management of insomnia. Zopiclone has a BZD-like profile, a short half-life of 3.5 to 6.5 hours, no active metabolites, minimal rebound effects, and less abuse potential than BZDs. The usual therapeutic dose is oral 7.5 mg administered 30 to 60 minutes before bedtime. Zopiclone has a well-documented capacity to reduce sleep latency, improve quality and duration of sleep, and reduce the frequency of nighttime awakenings. In clinical trials, 7.5 mg doses of zopiclone have been found to be as effective as triazolam 0.5 mg, temazepam 20 mg, flurazepam 15-30 mg, and nitrazepam 5 to 10 mg for the short-term treatment of insomnia (136). 

BZDs with active metabolites and slow elimination, such as diazepam, flurazepam, and quazepam, are well known for producing unwanted daytime sedation (111,... 

Flurazepam 1-2 40-100 Active metabolites with long half-lives... 

Flurazepam and two of its metabolites have demonstrated reversible hydrolysis of the 4,5-azomethine [131]. In acid solution, this reaction may be monitored employing pulse polarography to measure the decrease in concentration of the 4,5-azomethine of the 1,4-benzodiazepine or increase in carbonyl concentration of the open benzophenone (see Fig. 26.10). 

Flurazepam (Dalmane) 0.5-1.0 Long Long elimination half-life because of active metabolites... 

Long-term accumulation of flurazepam and its active metabolites may cause insidious onset of confusion or falls, especially in the elderly... 

The antianxiety effects of chlordiazepoxide (165) were described in 1960 and this compound was followed by diazepam (135). These two drugs have captured 75% of the market for sedatives in the USA. Other benzodiazepines used as antianxiety agents include oxazepam (166 R = H), a metabolite of diazepam that is better tolerated, lorazepam (166 R = Cl) and potassium clorazepate (167). Prazepam is the iV-cyclopropylmethyl analogue of diazepam. The benzodiazepines have other therapeutic applications, many being used for inducing sleep, diazepam and nitrazepam are anticonvulsants and flurazepam (168) is both an antianxiety agent and a potent hypnotic. Thieno- and pyrazolo-1,4-diazepinones isosteric with diazepam have similar pharmacological properties (B-81 Ml 10604). 

The mixed-function oxidase system also oxidizes carbon atoms adjacent (i.e.. a) to carbonyl and imino (C = N) func-linnalitics. An important class of drugs undergoing this type of oxidation is the benzodiazepines. For example, diazepam IValiumI, flurazepam (Dalmane), and nimetazepam are oxi-Ji/ed to their corresponding 3-hydroxy metabolites. 

Flurazepam Hydtrothloride. U5P. Flurdzepam hydrochloride. 7-chloro-1 -12-(dieihylamino)ethyl -5-(2-fluoro-phenyD-l, 3-dihydro-2A/-1. 4-benzodia7.pin-2-one dihydro-chloridc (Dalmanc). is notable as a benzodiazepine marketed almost exclusively for use in insomnia. Metabolism or the dialkyl aminoalkyl side chain is extensive. A major metabolite is A -dealkyl flurazepam. which has a very long half-life and persists for several days after administration. 

Benzodiazepines with the shortest efimination half-life (tm) generally have the shortest duration of action. In some cases, an active metabolite may have a ty2 longer than the parent drug and thus contributes to a longer duration of action. For instance, flurazepam has a ty2 of 2 to 3 hours, but its active metabolite, desalkylflurazepam, has a ty2 of 50 to... 

The choice of a particular benzodiazepine is based on its pharmacokinetic profile. When used as a single dose, the extent of distribution and elimination half-life is important in predicting the duration of action. However, after multiple dosing, the elimination half-life and formation of active metabolites determine the extent of drug accumulation and resultant clinical effects." The benzodiazepine pharmacokinetic profiles are summarized in Table 71-4. The onset of action depends on the rate of absorption. Flurazepam and triazolam are absorbed rapidly. Temazepam is less lipophilic and has a slower onset of effect. Sedation after flurazepam, estazolam, and quazepam occurs within 1 to 2 hours after ingestion." Triazolam is redistributed quickly because of its high lipophilicity and thus has a short duration of effect." Estazolam and temazepam are intermediate in their duration of action. The therapeutic effects of flurazepam and quazepam are long in comparison because of the active metabolites. 

A-DAF accounts for most flurazepam pharmacologic effects. Quazepam and one of its metabolites, 2-oxo-quazepam, have elimination half-lives of 39 hours." Quazepam s oxo-quazepam metabolite is metabolized to A-DAF. If oxidation of A-DAE is impaired its half-life becomes prolonged, and complications of drug accumulation may result with repeated dosing however, tolerance may develop to these effects. A-DAE may be useful when daytime anxiety or early morning awakening are complaints, but daytime sedation and impaired psychomotor performance may complicate therapy. ... 

Extracted metabolites, desipramine, fluvoxamine, imipramine, maprotiline, nortriptyline Noninterfering chlordiazepoxide, clobazam, clozapine, diazepam, flurazepam, fluspiri-lene, haloperidol, nitrazepam, oxazepam, perazine, pimozide, spiroperidol, trifluperidol Interfering clomipramine, doxepin... 

Wong, S.H.Y. McHugh, S.L. Dolan, J. Cohen, K.A. Tricyclic antidepressant analysis by reversed-phase liquid chromatography using phenyl columns. J.Liq.Chromatogr., 1986, 9, 2511-2538 [also acetaminophen, amobarbital, amoxapine, barbital, chlordiazepoxide, chlorpromazine, cimetidine, clomipramine, codeine, desipramine, desmethyldoxepin, diazepam, doxepin, fluphenazine, flurazepam, glutethimide, hydroxyamoxapine, imipramine, lorazepam, maprotiline, meperidine, metabolites, nortriptyline, oxazepam, pentobarbital, perphenazine, phenobarbital, phenytoin, propoxyphene, protriptyline, secobarbital, thioridazine, trazodone]... 

Noggle, FT., Jr. Clark, C.R. DeRuiter, J. Liquid chromatographic separation of some common benzodiazepines and their metabolites. J.Liq.Chromatogr., 1990, 13, 4005-4021 [also alprazolam, bromazepam, chlordiazepoxide, clobazam, clorazepate, demoxepam, diazepam, estazolam, fludiazepam, fiunitrazepam, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordiazepam, oxazepam, prazepam, temazepam, triazolam]... 

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