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Clinical Pharmacokinetics

, Volume 24, Issue 6, pp 453–471 | Cite as

Clinical Pharmacokinetics of Alprazolam

Therapeutic Implications
  • David J. Greenblatt
  • C. Eugene Wright
Review Article Drug Disposition

Summary

Alprazolam is a triazolobenzodiazepine that is extensively prescribed in the Western world for the treatment of anxiety and panic disorders. Its benzodiazepine receptor binding characteristics are qualitatively similar to those of other benzodiazepines. The drug is metabolised primarily by hepatic microsomal oxidation, yielding α-hydroxy- and 4-hydroxy-alprazolam as principal initial metabolites. Both have lower intrinsic benzodiazepine receptor affinity than alprazolam and appear in human plasma at less than 10% of the concentrations of the parent drug. Plasma concentrations of the 4-hydroxy metabolite exceed those of the α-hydroxy derivative, but urinary recovery of α-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro.

After single 1mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 μg/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%. Pharmacokinetics are dose-independent and are unchanged during multiple-dose treatment. On average, mean steady-state plasma alprazolam concentrations change by 10 to 12 μg/L for each daily dosage change of 1 mg/day.

Most studies show that alprazolam pharmacokinetics are not significantly influenced by gender. Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients. Pharmacokinetics of alprazolam are not significantly altered in abstinent alcoholics or patients with panic disorder, and are not influenced by the phase of the menstrual cycle in women.

Coadministration of Cimetidine, fluoxetine, fluvoxamine or propoxyphene significantly impairs alprazolam clearance. However, alprazolam clearance is not altered by coadministration of propranolol, metronidazole, disulfiram, oral contraceptives or ethanol. Imipramine clearance may be impaired if alprazolam is coadministered. Alprazolam does not alter the pharmacokinetics of digoxin.

Although a therapeutic concentration range is not clearly established, some studies indicate that optimal reduction of anxiety associated with panic disorder occurs at steady-state plasma alprazolam concentrations of 20 to 40 μg/L. Concentrations higher than this may be needed for suppression of the actual panic attacks. Side effects associated with alprazolam (drowsiness, sedation, etc.) are consistent with its primary benzodiazepine agonist action and increase in frequency with higher steady-state plasma concentrations. As with other benzodiazepines, tolerance develops to the central depressant effects of alprazolam. Side effects diminish over time with continuous administration.

Because of its relatively short half-life, abrupt termination of alprazolam treatment can be followed by one or more discontinuation syndromes (recurrence, rebound or withdrawal). For this reason, alprazolam should be tapered rather than abruptly discontinued when treatment is stopped. Clinical consequences of alprazolam discontinuation are no different than those occurring after discontinuation of any benzodiazepine with a short half-life.

Keywords

Clinical Pharmacology Panic Disorder Alprazolam Triazolam Digit Symbol Substitution Test 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1993

Authors and Affiliations

  • David J. Greenblatt
    • 1
    • 2
  • C. Eugene Wright
    • 3
  1. 1.Department of Pharmacology and Experimental TherapeuticsTufts University School of MedicineBostonUSA
  2. 2.Division of Clinical PharmacologyNew England Medical Center HospitalBostonUSA
  3. 3.Clinical Pharmacokinetics UnitThe Upjohn CompanyKalamazooUSA

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