Lorazepam pharmacokinetics

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Caille G, Spenard J, Lacasse Y, et al Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses. Biopharm Drug Dispos 4 31—42, 1983... 

Greenblatt DJ, DivollM, Harmatz JS, et al Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci 71 248-252, 1982... 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

Blin, O., Jacquet, A., Callamand, S., Jouve, E., Habib, M., Gayraud, D., Durand, A., Bruguerolle, B., and Pisano, P., Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers, Br. J. Clin. Pharmacol., 48, 510-512, 1999. 

Benzodiazepines have similar pharmacological properties and are used in anxiety and insomnia. The choice of which benzodiazepine to use usually lies with the pharmacodynamic and pharmacokinetic properties, which vary across the class. For example, diazepam, flurazepam and nitrazepam have a prolonged duration of action whereas lorazepam and temazepam have a shorter duration of action. 

Oxycodone/Lorazepam/Ethanol Multiple oral doses of pregabalin were coadministered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with those drugs. 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

The pharmacokinetic profile is different with different compounds. Diazepam after oral administration is completely and rapidly absorbed from the proximal small intestine. Oxazepam is least rapidly absorbed while lorazepam is an intermediately absorbed between these two. They are metabolised in liver by dealkylation and hydroxylation and excreted in urine as glu-curonide conjugates. They cross the placental barrier and are secreted in milk. 

Knowing the differential pharmacokinetics for a class of drugs allows the clinician to choose specific members to either achieve a faster onset or a delayed offset of action (13, 14, 17, 18). For example, lorazepam is rapidly absorbed from the gastrointestinal tract into the systemic circulation and from there distributed into the brain. In contrast, oxazepam, the most polar BZD, is slowly absorbed from the gastrointestinal tract. Even after oxazepam is in the systemic circulation, it slowly enters tissue compartments, including the brain, during the distribution phase. Unlike lorazepam, oxazepam is not available in either the intramuscular or intravenous formulations. Thus, lorazepam would be preferable to achieve acute control of alcohol withdrawal (e.g., delirium tremens), whereas oxazepam would better stabilize a dependency-prone patient on sedative-hypnotics, because it does not cause the euphoria seen with the more rapidly absorbed members of this class. 

Lorazepam. Lorazepam has been increasingly studied for control of psychotic aggressivity ( 157,158, 159,160, 161,162, 163,164, 165,166 and 167). One reason is that, of all the BZDs available in parenteral form, lorazepam has a pharmacokinetic profile (quick, reliable absorption) that makes it particularly suitable for this type of use. Open, retrospective, and controlled studies indicate that oral or parenteral lorazepam added to an antipsychotic controls disruptive behavior safely and effectively for most patients. The combination may also permit an overall reduction of the antipsychotic dose, although this assumption requires further study ( 162, 164, 166). 

A BZD s pharmacokinetics may play a role in the occurrence, in part accounting for the increase in its incidence after the advent of short-acting BZD anxiolytics and hypnotics (e.g., lorazepam, alprazolam, and triazolam). 

Saano, V., Hansen, P.P., and Paronen, P., Interactions and comparative effects of zoplicone, diazepam and lorazepam on psychomotor performance and on elimination pharmacokinetics in healthy volunteers, Pharmacol. Toxicol., 70, 135, 1992. 

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. 

A thorough review of the pharmacokinetics of haloperidol, with special emphasis on interactions, has been published (58). The interactions include one with lorazepam. 

In a separate study, pharmacokinetic-pharmacodynamic modeling of the psychomotor and amnesic effects of a single oral dose of lorazepam 2 mg was investigated in 12 healthy volunteers in a randomized, double-blind, placebo-controlled, two-way, crossover study using the following tasks choice reaction time, immediate and delayed cued recall of paired words, and immediate and delayed free recall and recognition of pictures (12). The delayed recall trials were more impaired than the immediate recall trials similar observations were made with the recognition versus recall tasks. 

The pharmacokinetics of intranasal lorazepam compared with oral administration have been evaluated in 11 volunteers in a randomized, crossover study (20). Lorazepam had favorable pharmacokinetics for intranasal administration compared with standard methods. Intranasal delivery could provide an alternative non-invasive delivery route for lorazepam. 

Blin O, Jacquet A, Callamand S, Jouve E, Habib M, Gayraud D, Durand A, Bruguerolle B, Pisano P. Pharmacokinetic-pharmacodynamic analysis of amnesic effects of lorazepam in healthy volunteers. Br J Clin Pharmacol 1999 48(4) 510-2. 

Wermeling DP, Miller JL, Archer SM, Manaligod JM, Rudy AC. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol 2001 41(11) 1225-31. 

Prior use of benzodiazepines or opiates limits the psychotomimetic effects of ketamine. There has been a double-blind, placebo-controlled study of the role of lorazepam in reducing these effects after subanesthetic doses of ketamine in 23 volunteers who received lorazepam 2 mg or placebo, 2 hours before either a bolus dose of ketamine 0.26 mg/kg followed by an infusion of 0.65 mg/kg/hour or a placebo infusion (438). The ability of lorazepam to block the undesirable effects of ketamine was limited to just some effects. It reduced the ketamine-associated emotional distress and perceptual alterations, but exacerbated the sedative, attention-impairing, and amnesic effects of ketamine. However, it failed to reduce many of the cognitive and behavioral effects of ketamine. There were no pharmacokinetic interactions between subanesthetic doses of ketamine and lorazepam. 

Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 1981 6 89-105. 

Table 1-2 includes a list of major CYPs that are responsible for the phase I metabolism of commonly used psychotropics as well as selected substances that are psychoactive and are commonly used by psychiatric patients. With very few exceptions (e.g., lithium does not require biotransformation lorazepam and oxazepam are directly conjugated without first going through oxidation), the pharmacokinetics of practically all psychotropics are dependent on one or more of the CYPs, whose activity significantly influences the tissue concentrations, dose requirement, and side-effect profiles of their substrates. 

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