Lorazepam absorption

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. 

Oxazepam is available in oral form only, so it is useful only for uncomplicated withdrawal. Other benzodiazepines are available in injectable form and will be further described below. Diazepam and lorazepam are more lipophilic than chlordiazepoxide and oxazepam, resulting in quicker gastrointestinal absorption and passage across the blood-brain barrier, which makes them valuable in an inpatient setting, especially to treat or prevent seizures. However, their faster onset of action maybe associated with feeling high, which can be a disadvantage of their use. 

IM diazepam and chlordiazepoxide should be avoided because of variability in rate and extent of absorption. IM lorazepam provides rapid and complete absorption. 

Benzodiazepines are usually given orally and are well absorbed by this route. Since the benzodiazepines are weak bases, they are less ionized in the relatively alkaline environment of the small intestine, and therefore, most of their absorption takes place at this site. For emergency treatment of seizures or when used in anesthesia, the benzodiazepines also can be given parenter-ally. Diazepam and lorazepam are available for intravenous administration. 

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). 

BZDs with rapid absorption produce a more rapid onset of clinical activity than those with slower absorption. BZDs given orally differ in their speed of absorption from the gastrointestinal tract. For example, absorption time is 0.5 hours for clorazepate, 1 hours for diazepam, 1.3 hours for triazolam, 2 hours for alprazolam and lorazepam, 2 to 3 hours for oxazepam, and 3.6 hours for flurazepam. Absorption, however, may be influenced by the presence or absence of food in the gastrointestinal tract. Thus, patients who take a BZD hypnotic with a bedtime snack may experience a slower onset of hypnotic activity than if the same drug were taken several hours after a meal. 

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. 

Lorazepam is less lipophilic than diazepam and there is evidence that it has a longer duration of anticonvulsant action than diazepam after intravenous administration. This could be due to the fact that diazepam is more rapidly removed from the brain compartment than lorazepam, which limits its duration of antiepileptic activity. In practice, when diazepam is used to control status epilepticus it is often necessary to continue treatment with diphenylhydantoin, which has a longer duration of action in the brain. The principal hazards of benzodiazepines when given intravenously include respiratory depression and hypotension. Diazepam may be administered rectally, its ease of absorption leading to peak plasma levels within about 10 minutes. 

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. 

Parenteral administration via the intramuscular route should be avoided with diazepam and chlordiazepoxide secondary to variability in the rate and extent of drug absorption. Intramuscular lorazepam provides rapid, reliable, and complete absorption however, the preparation requires refrigeration. 

Puglia, C., Bonina, E, Trapani, G., Franco, M., and Ricci, M. (2001). Evaluation of in vitro percutaneous absorption of lorazepam and clonazepam from hydro-alcoholic gel formulations, Int. J. Pharm., 228 79-87. 

B. Convulsions. All three drugs can be used for the treatment of acute seizure activity or status epilepticus resulting from idiopathic epilepsy or convulsant drug overdose. Midazolam and lorazepam have the advantage of rapid absorption after intramuscular injection. Lorazepam also has a longer duration of anticonvulsant action than the other two agents. 

Ranitidine, famotidine and nizatidine appear not to inhibit liver microsomal enzymes. There is some evidence that ranitidine increases the absorption of triazolam, and possibly other benzodiazepines, due to changes in gastric pH, ° although it has been suggested that this effect is negligi-ble. ° Cimetidine has been said to similarly affect the absorption of diazepam and lorazepam. ... 

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