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ATIVAN (lorazepam) Pharmacology

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Pharmacology

Ativan (lorazepam) is chemically 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1, 4-benzodiazepin-2-one and has the following structural formula:

Figure 1: Lorazapam Structural Formula

Lorazepam is a benzodiazepine with CNS depressant properties. In laboratory animals, it produces disinhibitory, sedative, anti-convulsant, muscle relaxant, ataxic and hypnotic effects.

Studies with lorazepam in rats demonstrated a decrease in treadmill avoidance without modifying the escape response, an increase in responding during the shock schedule in the conflict test, an increase in incorrect responses in a discrimination test, and a reduction of conditioned suppression if lorazepam was given prior to the fear conditioning trial, while increasing conditioned suppression, if given prior to re-testing. These effects were observed at doses from 0.05 to 20 mg/kg i.p. In some of the tests, diazepam was also used with similar results obtained at approximately 2-5 times the lorazepam dose.

Lorazepam was the most potent of several benzodiazepines tested in affecting state-dependent learning in trained, hungry rats rewarded with sweetened milk and conditioned to simple fear responses by mild electric shock. While 70-75% inhibition of conditioned fear was achieved with intraperitoneal doses of 0.9 mg/kg of lorazepam on the training day, 2.7 mg/kg of diazepam and 5 mg/kg of either chlordiazepoxide or oxazepam were required to obtain similar results. Consistent with state-dependent learning interpretations, a second injection of lorazepam administered to rats just prior to being tested for fear retention fully reinstated the conditioned suppression response.

Daily intraperitoneal injections of lorazepam, diazepam, oxazepam, chlordiazepoxide, scopolamine, or amobarbital, after initially interfering with feeding behaviour, later facilitated it. Following fear conditioning of the animals, all of the drugs, with the exception of scopolamine, increased conditioned suppression in the retention test. These repeated dose experiments, which permit tolerance of depressant side effects to develop, make it unlikely that benzodiazepines or amobarbital increase conditioned suppression retention through some depressant side effect.

In rats, fear-conditioned by electric shocks of different intensities, lorazepam increased retention-test drinking latencies of strongly shocked rats more than it did those of rats given shocks of intermediate or weak intensities.

In mice, lorazepam prevented pentylenetetrazol-induced convulsions at low doses (ED50-0.07 mg/kg p.o.), while much higher doses (0.5-5.0 mg/kg p.o.) were required to raise the threshold to electroshock-induced convulsions. It was demonstrated that lorazepam was more potent than diazepam in antagonizing pentylenetetrazol-induced convulsions by all three routes tested: oral, intraperitoneal, and intravenous. Lorazepam also inhibited the stimulation caused by morphine. Both lorazepam and clonazepam had ED50s for the antagonism of convulsions of less than 1 mg/kg when they were given intravenously or orally only 1 minute before the pentylenetetrazol challenge.

Observations of monkeys provided strong evidence of the sedative action of lorazepam. Here, relatively high doses of lorazepam caused brief initial depression followed by long periods of obvious sedation. The behaviour of cats and mice, after receiving lorazepam supported these findings. In mice, it was shown that lorazepam is a more potent sedative than diazepam or flurazepam.

Its ability to inhibit foot shock induced fighting between mice, together with reactions of rats and squirrel monkeys in a series of conflict tests considered specific predictors of anti-anxiety activity, confirmed the anxiolytic potential of lorazepam.

The general depressant effects of repeated dosings of lorazepam in rats diminished rapidly while its anticonflict action remained, findings suggesting that while the anti-anxiety effects of lorazepam endure, any behaviour disruption is transitory.

Doses of 5 to 50 mg/kg I.V. caused ataxia and obvious CNS depression in rhesus monkeys, lasting for over 5 hours at the highest dose. Suppression of the linguomandibular reflex was demonstrated in anaesthetized cats suggesting a central muscle-relaxant effect of lorazepam in this species. Higher doses, however, were required than with diazepam to produce significant reflex inhibition.

Using suppression of linguomandibular reflexes in cats as a measure of centrally mediated muscle relaxation, it was demonstrated that intravenous doses of 0.25 to 2 mg/kg of lorazepam were active in a dose-related manner, that the patellar reflex was not suppressed indicated a preferential effect on polysynaptic pathways.

Studies on the cardiovascular system in anaesthetized animals demonstrated that lorazepam, at a dose of 0.1 mg/kg, given by intraperitoneal injection had little effect on either blood pressure or heart rate. Second injections of 0.9 mg/kg one hour later caused some depression of cardiovascular parameters of anaesthetized cats and dogs. Doses greater than 0.9 mg/kg resulted in an average decrease of approximately 40% in both blood pressure and heart rate. Electrocardiograms taken near the conclusion of a 33-34 day study in which beagle dogs received daily intramuscular injections of lorazepam showed only slight increases in the heart rates of both vehicle control and drug-treated animals.

In anticipation of lorazepam being used concomitantly with other therapeutic agents in a variety of clinical situations, drug interaction studies were undertaken. Lorazepam was without effect on the LD50 of morphine in rats. Although the oral LD50 of lorazepam in mice was not modified by phenelzine, the depressor effect of intravenous lorazepam or diazepam in the presence of phenelzine, was increased in rats. In common with other anxiolytic-sedatives, oral lorazepam in mice reduced the amount of I.V. thiopental required for hypnosis and respiratory arrest.

Oral doses of lorazepam administered daily for 59 days to beagle dogs did not alter the anticoagulant activity of bishydroxycoumarin. In decerebrate cats, the intensity and duration of the skeletal neuromuscular blocking action of gallamine and suxamethonium were unaffected by intravenous doses of either diazepam or lorazepam.

The drug dependency potential of lorazepam (10 mg/kg), diazepam (5 mg/kg) and chlordiazepoxide (20 mg/kg) by several routes of administration was evaluated in normal, barbital-dependent and withdrawn rhesus monkeys. Like chlordiazepoxide and diazepam, lorazepam suppressed signs of barbital withdrawal. In long-term toxicity studies, convulsions were noted, at the high-dose levels, particularly following withdrawal of lorazepam.

The irritant potential of injectable lorazepam was compared with that of diazepam in mice and rabbits. While the degrees of irritation produced by either compound varied with the routes of administration, it appeared that the experimental vehicles were the principle cause of irritation. The degree of hemolytic potential of lorazepam in an experimental vehicle varied from mild to moderate in rabbit blood, and slight to mild in human or dog blood.

Metabolic studies in mice, rats, cats, dogs and miniature swine were conducted on the absorption, excretion, tissue distribution and biotransformation of lorazepam. Both 14C-labelled and unlabelled drug was used. The most important finding was the conjugation of lorazepam with glucuronic acid in all investigated species. Lorazepam glucuronide, essentially inactive as an anti-anxiety agent, accounted for most of the drug-related urinary excretion products in all species except the rat in which, in addition to glucuronide formation, more extensive biotransformation took place.

Maximum concentrations of unchanged lorazepam in whole blood and plasma of rats occurred one-half to one hour after oral drug administration, and these concentrations declined to low levels within 24 hours. In dogs and miniature swine, concentrations of orally administered lorazepam peaked and declined rapidly, but they consisted principally of lorazepam glucuronide. These findings correlated with the rapid elimination observed in dogs administered lorazepam intravenously when no free drug was detected in plasma six hours later, and the half-life was estimated to be 1.6 hours. The major route of lorazepam excretion for the dog and the miniature swine is by the kidneys. Biliary excretion has been demonstrated in the rat.

Except for the organs of absorption and excretion, tissue distribution of 14C-lorazepam in rats was nearly uniform.

Species differences in urinary excretion patterns were investigated qualitatively in the mouse, rat, cat, dog, and miniature swine. The major urinary excretion product was the glucuronide conjugate of lorazepam. In dogs, the pattern of biotransformation of lorazepam seemed independent of dose; in rats, it appeared dose-dependent and produced significant amounts of several metabolites rather than the predominance of glucuronide found in other species, including the human. No sex differences were noted in the urinary excretion patterns of the several species tested. Peak urinary excretion was noted at 2-6 hours and total recovery in urine and feces over 48 hours was as high as 100% in some species.

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