Clinical pharmacokinetics of alprazolam. Therapeutic implications.

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Greenblatt DJ, Wright CE

Clinical pharmacokinetics of alprazolam. Therapeutic implications.

Clin Pharmacokinet. 1993 Jun;24(6):453-71. doi: 10.2165/00003088-199324060-00003.

PubMed ID
8513649 [ View in PubMed
]
Abstract

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 alpha-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 alpha-hydroxy derivative, but urinary recovery of alpha-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro. After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/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 micrograms/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 micrograms/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.(ABSTRACT TRUNCATED AT 400 WORDS)

DrugBank Data that Cites this Article

Drugs
Drug Carriers
DrugCarrierKindOrganismPharmacological ActionActions
Alprazolamalpha1-acid glycoprotein (Protein Group)Protein groupHumans
Unknown
Binder
Details
Drug Reactions
Reaction
Details
Drug Interactions
DrugsInteraction
1,2-Benzodiazepine
Fluoxetine
The serum concentration of 1,2-Benzodiazepine can be increased when it is combined with Fluoxetine.
Bromazepam
Fluoxetine
The serum concentration of Bromazepam can be increased when it is combined with Fluoxetine.
Chlordiazepoxide
Fluoxetine
The serum concentration of Chlordiazepoxide can be increased when it is combined with Fluoxetine.
Clobazam
Fluoxetine
The serum concentration of Clobazam can be increased when it is combined with Fluoxetine.
Clonazepam
Fluoxetine
The serum concentration of Clonazepam can be increased when it is combined with Fluoxetine.