Lorazepam distribution

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. 

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. 

Since volume of blood in the body is inadequate for holding the complete lorazepam dose at the observed Cp, what volume of blood would hypothetically be required to contain the full 2-mg dose at a Cp of 20 ng/mL The required volume is 100 L (2,000 /jlg -t- 20 /xg / l.j. This volume—the volume of blood required to contain the drug within a body at an observed concentration—is called the volume of distribution (V dj. Volume of distribution is a purely hypothetical value and is sometimes called apparent volume of distribution to hammer home the idea that Vd is not a physiologically real number. A human does not have 100 L of blood, but a V d of 100 L for a drug is completely acceptable. 

Compared with diazepam, lorazepam and oxazepam are relatively less lipophilic and have a slower onset of effect. These benzodiazepines have smaller volumes of distribution and a resulting longer duration of action." Oxazepam absorption is slow, and peak levels are not obtained until 2 to 4 hours after a single dose however, like lorazepam, oxazepam s anxiolytic effects are long lasting because extensive distribution does not occur. 

Lorazepam (No. 10) and oxazepam (No. 14) represent short-acting BZDs tm =15 and 10 hours, respectively). As 3-hydroxy derivatives they are directly derivatized to inactive glucuronides. Since there are no active metabolites, cumulative effects on continuing dosing are not likely. Like diazepam, IV lorazepam produces anticonvulsant and amnesic effects. However, these effects persist longer because drug distribution throughout the body is less rapid and extensive. These properties may be predictable since a comparison of structures with diazepam shows lorazepam to be more polar the absence of lipid-... 

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