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Alprazolam

A Review of its Pharmacodynamic Properties and Efficacy in the Treatment of Anxiety and Depression

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Summary

Synopsis: Alprazolam1 is a triazolobenzodiazepine which is related to diazepam and other 1,4-benzodiazepines, and has a similar pharmacological profile. Relative to the newer benzodiazepines, alprazolam has an intermediate half-life of 10 to 12 hours in healthy young subjects. In placebo-controlled and double-blind comparative trials in patients with anxiety, alprazolam was of comparable efficacy to diazepam and generally caused a lower incidence of drowsiness. Alprazolam has antidepressant activity and has been shown to be similar in efficacy to imipramine in the treatment of unipolar depression. Thus, alprazolam may be particularly useful in patients with mixed anxiety/depression. However, its general acceptance as an antidepressant awaits further studies.

Pharmacodynamic Studies: The pharmacological profile of alprazolam is similar to that of other benzodiazepines in that it has antianxiety, anticonvulsant and muscle relaxant activity. However, there is some evidence in animals and in sleep studies that alprazolam also possesses moderate antidepressant activity and this has been confirmed in therapeutic trials in humans (see below). On a weight basis, alprazolam is a more potent anticonvulsant (strychnine and electroshock tests) and antiaggression agent than diazepam or clonazepam and a more potent muscle relaxant (inclined screen test) than diazepam.

Pharmacokinetic Studies: Following single-dose oral administration of alprazolam 0.5 to 3mg, plasma concentrations of 7 to 40 ng/ml are attained in 1 to 2 hours. Volume of distribution and elimination half-life, which in healthy subjects are about 73L and 10 to 12 hours, respectively, are greater in obese patients, but to a lesser extent than with diazepam. Alprazolam is extensively metabolised, with an active metabolite (α-hydroxyalprazolam) accounting for about 17% of the ingested dose. However, plasma concentrations of this metabolite are too low to be of clinical significance. 20% of a dose is excreted unchanged and 80% recovered in the urine within 72 hours of administration.

Therapeutic Trials: Open and controlled trials in patients with anxiety disorders reveal that alprazolam is an effective anxiolytic at doses of 0.25 to 3.0mg daily. In comparative, non-placebo controlled trials, alprazolam was at least as effective as diazepam, chlordiazepoxide or lorazepam, and in some of the placebo-controlled trials, more effective than diazepam. Although the overall incidence of side effects with alprazolam has been similar to that with the other benzodiazepines, some studies reported a lower frequency of drowsiness with alprazolam.

Alprazolam has also been compared with imipramine in the management of depressed patients. Promising results from preliminary studies have been confirmed in a large multicentre trial which compared alprazolam, imipramine and placebo in patients with unipolar depression. Alprazolam was similar in efficacy to imipramine in relieving symptoms of depression and more effective than imipramine in relieving somatic symptoms. Alprazolam showed an earlier onset of effect in some assessment criteria. In these studies alprazolam dosage was 2 to 4mg daily, but optimum dosages in depressive illness have yet to be clearly defined. Placebo-controlled trials indicate that alprazolam causes few anticholinergic side effects. Alprazolam may be of use in the treatment of agoraphobia and panic attacks, but definition of its place in managing these disorders and in the treatment of depressive illness awaits further study in well designed trials.

Side Effects: Clinical studies have shown that alprazolam has a side effect profile similar to that of other benzodiazepines, although drowsiness and lightheadedness occur less frequently than with diazepam. Experience with overdosage is limited but serious adverse events have not been reported to date. Side effects may be accentuated in the elderly or debilitated patient. As other benzodiazepines are known to reach the placenta and be excreted in breast milk, alprazolam should also be avoided in pregnancy, and in nursing mothers until full human distribution data are available.

Dosage: Dosage should be individualised, starting at 0.25mg to 0.5mg thrice daily. In the elderly the starting dose is 0.25mg twice daily. The dose is titrated upwards according to the needs of the patient to the recommended maximum of 4 mg/day in divided doses. Initial doses may be given at bedtime to minimise daytime lethargy. Abrupt withdrawal after longer term administration should be avoided.

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Various sections of the manuscript reviewed by: D.R. Abernethy, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA; G.C. Aden, San Diego Neuropsychiatric Medical Clinic and Human Relations Center, Inc., California, USA; F.J. Ayd, Westlake Avenue, Baltimore, Maryland, USA; G. Bianchi, Ferny Avenue, Surfers Paradise, Queensland, Australia; J.B. Cohn, Department of Psychiatry, University of California, Los Angeles, USA; D.J. Greenblatt, Division of Clinical Pharmacology, New England Medical Center, Boston, Massachusetts, USA; I. Hindmarch, Human Psychopharmacology Research Unit, The University of Leeds, Leeds, England; L.E. Hollister, Veterans Administration Medical Center, Palo Alto, California, USA; I.S. Kolin, Lucerne Terrace, Orlando, Florida, USA; M.H. Lader, Institute of Psychiatry, De Crespigny Park, London, England; B.M. Maletzky, Psychiatrist, Portland, Oregon, USA; K. Rickets, Psychopharmacology Research and Treatment Unit, University of Pennsylvania, Philadelphia, USA; G. Tognoni, Instituto Di Ricerche Farmacologiche Mario Negri, Milano, Italy.

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Dawson, G.W., Jue, S.G. & Brogden, R.N. Alprazolam. Drugs 27, 132–147 (1984). https://doi.org/10.2165/00003495-198427020-00002

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  • DOI: https://doi.org/10.2165/00003495-198427020-00002

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