Lorazepam metabolite

In the presence of cirrhosis or other liver impairment, lorazepam or oxazepam should be utilized for detoxification. These two benzodiazepines have no active hepatic metabolites and are generally considered safer choices for patients with liver damage. Once the starting point for the taper is determined, the dose is decreased by 10-20% per day. It is important to note that this rate of taper is much faster than that used for patients treated chronically with benzodiazepines who are discontinuing their anxiolytic in order to determine if it is still needed for control of symptoms. In that case, the rate of decrease is 10-20% per week. Should the patient display... 

The use of polysaccharide-based CSPs instead of protein-based CSPs often increases the peak efficiency and facilifafes faster separafions. Papini ef al. [159] recently developed a method for the enantioseparation of lorazepam and on a Chiralpak OD-R column and an enzymatic hydrolysis was used to determine the amount of the glucoronide metabolite of lorazepam present. The separation was performed in 7 min with an LOQ of 1 and 10 ng/mL for lorazepam in plasma and urine, respectively. Another relatively fast separation for chiral analysis was published by Lausecker and Eischer [188]. They developed a method for determination of the drug candidate R483 within... 

Eight BDZs among the most frequently encountered in forensic toxicology (clonazepam, desal-kylflurazepam, diazepam, flunitrazepam, lorazepam, midazolam, nordiazepam and oxazepam) were determined in whole blood after solvent extraction with butyl chloride and fast isocratic separation using a C18 (100 x 4.6 mm x 5 (tm) column [61]. The mobile phase was composed of phosphate buffer (35mM, pH 2.1) and acetonitrile (70 30, v/v) and the flow rate was 2mL/min. Within less than 4 min of analysis time, the analytes could be successfully determined starting from therapeutic concentrations. Using HPLC coupled with APCI-MS-MS, Rivera et al. [62] set up a method for the detection of 18 BDZ and metabolites after butyl chloride extraction at alkaline pH in 0.5mL... 

Knowing the structure of a particular BZ drug can help predict the metabolic pathway for that drug. For example, oxazepam, lorazepam, and temazepam are all 3-OH BZs and are directly conjugated (Chouinard et ah, 1999). Temazepam is partly demethylated to oxazepam, but otherwise these drugs have no active metabolites (Bellantuono et ah, 1980). 

Anticipatory nausea Lorazepam 0.04-0.08 mg/kg Lack of active metabolites Galloway and Yaster, 2000... 

Unlike oxidized BZDs, conjugated BZDs (e.g., lorazepam, lormetazepam, oxazepam, and temazepam) do not have active metabolites. Only the parent compounds account for clinical activity. 

Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. However, such depressant actions of the benzodiazepines are usually reversible with flumazenil. 

The rates of oral absorption of benzodiazepines differ depending on a number of factors, including lipophilicity. Oral absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Oxazepam, lorazepam, and temazepam are absorbed from the gut at slower rates than other benzodiazepines. The bioavailability of several benzodiazepines, including chlordiazepoxide and diazepam, may be unreliable after intramuscular injection. Most of the barbiturates and other older sedative-hypnotics are absorbed rapidly into the blood following their oral administration. 

The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relationship to the time course of pharmacologic effects. Those benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have shorter half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22-1. 

The pharmacokinetic properties of the benzodiazepines in part determine their clinical use. In general, the drugs are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg. The onset of action is very rapid. Total body clearances of the parent drug and its metabolites are low, corresponding to half-lives of 20-40 hours. 

Diazepam is a benzodiazepine. Diazepam is more reliably absorbed following oral rather than intramuscular admininstration. This may be due to precipitation in the muscle. Diazepam appears to undergo enterohepatic recirculation with a second plasma peak occurring 4-6 hours after initial administration. This may be associated with re-sedation. Diazepam is oxidised in the liver to active metabolites including desmethyldiazepam (nordiazepam), which has a half-life of over 100 hours. Benzodiazepine oxidation may be impaired in patients with liver disease and in some elderly patients. Metabolism of benzodiazepines such as oxazepam and lorazepam is not impaired in the elderly and in those with liver dysfunction. 

Use only drugs with no active metabolites (lorazepam, oxazepam). 

Benzodiazepine (BZ) intoxication is manifested as slurred speech, poor coordination, swaying, drowsiness, hypotension, nystagmus, and confusion. Signs and symptoms of BZ withdrawal are similar to those of alcohol withdrawal, including muscle pain, anxiety, restlessness, confusion, irritability, haJlucinations, delirium, seizures, and cardiovascular collapse. Withdrawal from short-acting BZs (e.g., oxazepam, lorazepam, alprazolam) has an onset within 12 to 24 hours of the last dose. Diazepam, chlordiazep-oxide, and clorazepate have elimination half-lives (or active metabolites with elimination half-lives) of 24 to greater than 100 hours. So, withdrawal may be delayed for several days after their discontinuation. Sedative-hypnotic dependence is summarized in Table 73-2. 

BZDs PROTEASE INHIBITORS t adverse effects, e.g. prolonged sedation Inhibition of CYP3A4-mediated metabolism of BZDs and buspirone Watch closely for t sedation 4 dose of sedative as necessaiy. Some recommend considering substituting long-acting for shorter-acting BZDs with less active metabolites (e.g. lorazepam for diazepam)... 

After chronic administration of diazepam, i.e. at steady state, plasma concentrations of desmethyidiazepam (the major metabolite in blood) are similar to those of diazepam. The hydroxylated metabolites of the benzodiazepines, together with benzodiazepines which have an hydroxyl group at the C3 position (e.g. lorazepam), are conjugated with glucuronic acid and it is these derivatives which account for the major fraction of the dose excreted in the urine. 

Disposition in the Body. Readily absorbed after oral administration bioavailability about 95%. About 75% of a dose is excreted in the urine as the inactive glucuronide conjugate within 5 days (up to about 50% in the first 24 hours) and 14% is excreted as conjugates of minor metabolites which include ring-hydroxyl-ation products and quinazoline derivatives only negligible amounts are excreted as free lorazepam about 7% of a dose is eliminated in the faeces. 

Because of its short half-life and inactive metabolites, lorazepam may be a preferred benzodiazepine in some patients with liver disease... 

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). 

---