Elimination benzodiazepines

The launch of benzodiazepines eliminated the risk associated with using barbiturates. The benzodiazepines are well tolerated and produce only low toxicities. However, after extensive use of benzodiazepines in millions of patients, it became apparent that benzodiazepines also produce side effects, although to a considerably lower degree than barbiturates. 

In humans too, sex differences in metabolism exist, but they are small and usually clinically not important. The clearance of benzodiazepines eliminated by metabolic conjugation (temazepam, oxazepam, lorazepam) is, for example, significantly smaller in women than in men. 

The action of triethylamine or 4-methylmorpholine on the imidazole derivatives 1 results in the formation of 4,5-dihydro-l/f-l,2-benzodiazepines 2, which eliminate imidazole on heating with ethanolic sodium ethoxide to give H-, 2-benzodiazepines 3.121 Details for compound 3 (R1 = Ph, R2 = Me) only were reported it was stated that other derivatives were obtained similarly but details were not given. 

Azidoquinoline (4c) can be irradiated in the presence of sodium methoxide to give 2,3-dimethoxy-2,3-dihydro-l//-l,4-benzodiazcpine (7). which undergoes elimination of methanol on heating lo provide 3-methoxy-3//-l,4-benzodiazepine (6c).218... 

Medical use of benzodiazepines has been declining. Prescribing trends show an overall decline in the number of all benzodiazepine prescriptions written, with a market shift to increased prescribing of short elimination half-life agents (lorazepam, alprazolam), compared with long-elimination half-life agents (diazepam, chlordiazepoxide) (Ciraulo et al. 2004). In 2001, alprazolam was the most widely prescribed benzodiazepine (Ciraulo et al. 2004), and it also was the most widely prescribed psychiatric medication in that year for mood and anxiety disorders (Stahl 2002). 

AUC, area under the plasma concentration curve BZ, benzodiazepine Cl, clearance t1/2, elimination half-life. 

AUC, area under the plasma concentration cuive BZ, benzodiazepine Cl, clearance t, elimination half-life Vd, volume of distribution. Data from Benzodiazepines. Fads and Comparisons 4.0 Online. Wolters Kluwer Health, Inc. 2005, http //online.factsandcomparisons.com and Madabushi R, Frank B, DrewelowB, etal. Hyperforinin St. John s wort drug interactions. Fur J Gin Pharmacol 2006 62 225-233. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by microsomal oxidation followed by glucuronide conjugation. 

There is an association between falls and hip fractures and the use of long-elimination half-life benzodiazepines thus, flurazepam and quazepam should be avoided in the elderly. 

Cycloreversion with nitrile oxide formation is known not only in furoxans but also in isoxazolines, 1,2,4-oxadiazoles, furazans, and some other live-membered heterocycles (76). Such process, eliminating nitrile oxide fragment 3-R CeHiC N+Cr ", was observed mass spectrometrically in 3a,4,5,6-tetrahydro-[ 1,2,4 oxadiazolo[4,5-a J [ 1,5 benzodiazepine derivatives 11 (83). 

Since the volume of distribution is increased, the elimination half-life of lipid-soluble drugs is increased. This affects for example medium- and long-acting benzodiazepines as well as i.e. verapamil that can accumulate in the body. 

The effect may wane faster than the plasma elimination curve due to tolerance, for example, benzodiazepines and nitrates. 

The benzodiazepines that have been most commonly marketed as sedative-hypnotics include temazepam (Restoril), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and triazolam (Halcion). Of these five, temazepam is the most easily metabolized and eliminated. Therefore, temazepam is preferred for elderly and medically ill patients to minimize the risk of drug accumulation. 

Q68 Benzodiazepines with a short elimination half-life present a less severe withdrawal after drug discontinuation than drugs with a long elimination half-life. Symptoms of benzodiazepine withdrawal syndrome include anxiety, depression, insomnia and headache. 

The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area)... 

In usual sedative doses, zolpidem preserves deep sleep (stages 3 and 4) and has only minor and inconsistent effects on REM sleep. Compared with the benzodiazepines, zolpidem has relatively weak anxiolytic, anticonvulsant, and skeletal muscle relaxant properties at therapeutic doses. Zolpidem has a rapid onset and a relatively short duration of action. It is well absorbed after oral administration, with approximately 70% bioavail-abUity. It undergoes hydroxylation and oxidation to inactive metabohtes in the fiver. Its elimination half-life is approximately 2.5 hours, which is usually sufficient to provide for a normal 8 hours of sleep without daytime grogginess. 

As mentioned above, oxidative reactions will be rate-limiting in most instances. However, some medications are simply metabolized through conjugation. For example, benzodiazepines such as lorazepam are conjugated and excreted. The rate of conjugative reactions may be increased by OCs accelerating the elimination of these compounds because this reaction is rate-limiting [Yonkers and Hamilton 1995 Stoehr et al. 1984). 

TABLE 5 5. Elimination half-life of benzodiazepines undergoing hydroxy lation... 

The clinical duration of action of benzodiazepines does not correlate witii die elimination half-life. Intramuscular lorazepam is well absorbed. We do not recommend intramuscular chlordiazepoxide or diazepam. Source. Adapted from Teboul and Chouinard 1990. 

At equipotent doses, all benzodiazepines have similar effects. The choice of benzodiazepine is generally based on half-life, rapidity of onset, metabolism, and potency. In patients with moderate to severe hepatic dysfunction, it may be useful to avoid benzodiazepines. All benzodiazepines are metabolized at various levels by the liver, which leads to an increased risk of sedation and confusion in hepatic failure. If it is necessary to prescribe this class of medication, lorazepam and oxazepam are reasonable choices because they are predominantly eliminated by renal excretion. 

The first starting material for building benzodiazepines was prepared inadvertently in a synthesis aimed at the benzodiazoxepine (6-1). The oxime acetamide (6-2) from 2-aminobenzophenone was thus treated with hydrogen chloride in the expectation that the new heterocycle would form by the elimination of water between the oxime and the enol form of the amide. The product mrned out in fact to be the quinazoline A-oxide (6-3), the product from the addition of the nucleophilic oxime nitrogen to the amide carbonyl group. 

Conversion of an amide a thioamide enhances the reactivity of that function since it favors the enol form and provides a better leaving group for addition-elimination reactions (mercaptide vs. hydroxide). Thioamides obtained by treatment of diazepi-none such as (15-1) or (16-1) with phosphorus pentasulhde provide starting materials for further modihcation of the benzodiazepine nucleus. (More recently developed reagents such as Lawesson s Reagent or hw(tricyclohexyltin) sulhde provide more convenient methods for that transformation.) Thus, reaction of the thioamide (15-2) with (9-allylhydroxylamine leads directly to the amidine, probably via an addition-elimination sequence of the thioenol tautomer of (15-2). There is thus obtained the antianxiety agent uldazapam (15-3) [17]. 

First-order kinetics The amount of drug eliminated per unit of time is directly proportional to its concentration. In this state, the mechanisms for biotransformation and elimination are not saturated (e.g., benzodiazepines, tricyclic antidepressants, lithium carbonate). 

Kales A, Soldatos CR, Vela-Bueno A. Clinical comparison of benzodiazepine hypnotics with short and long elimination of half-lives. In Smith DE, Wesson DR, eds. The benzodiazepines. 

Kales A, Soldatos CR, Bixler EO, et al. Early morning insomnia with rapidly eliminated benzodiazepines. Science 1983 220 95-97. 

Ray WA, Griffin MR, Downey M. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 1989 262 3303-3307. 

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