CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.
Following oral administration, alprazolam is readily absorbed. The peak plasma concentration is reached about 1.5 to 2 hours after administration of NIRAVAM™ given with or without water. When taken with water, mean Tmax occurs about 15 minutes earlier than when taken without water with no change in Cmax or AUC. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL are observed. The elimination half-life of alprazolam is approximately 12.5 hours (range 7.9 - 19.2 hours) after administration of NIRAVAM™ in healthy adults.
Food decreased the mean Cmax by about 25% and increased the mean Tmax by 2 hours from
2.2 hours to 4.4 hours after the ingestion of a high-fat meal. Food did not affect the extent of absorption (AUC) or the elimination half-life.
In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of
4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
Alprazolam and its metabolites are excreted primarily in the urine.
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 -
26.9 hours, n=16) compared to 11.0 hours (range: 6.3 - 15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease, the half-life of alprazolam ranged between
5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects, the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.
Race — Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.
Pediatrics — The pharmacokinetics of alprazolam in pediatric patients have not been studied.
Gender — Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.
Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see Contraindications, Warnings, and Drug interactions).
CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90 ± 0.21 mL/min/kg to 2.13 ± 0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1 ± 4.9 to 7.7 ± 1.7 h) following administration of 300 mg/day carbamazepine for
10 days (see Drug interactions). However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 - 1200 mg/day); the effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Alprazolam was compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these
4-week studies as judged by the following psychometric instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions and Self-Rating Symptom Scale.
Pan ic D isorder
Support for the effectiveness of alprazolam in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.
The average dose of alprazolam was 5 - 6 mg/day in two of the studies, and the doses of alprazolam were fixed at 2 and 6 mg/day in the third study. In all three studies, alprazolam was superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37 - 83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3 - 5.2), and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.