Alprazolam, known by various trade names, is the most commonly prescribed psychotropic medication in the United States. Alprazolam is frequently prescribed to manage panic and anxiety disorders. Alprazolam has also been subject to misuse for recreational purposes because of its disinhibition, euphoria, and anxiolytic effects. Most of the near-fatal cases with alprazolam are due to polydrug use.[1]

 FDA- labeled indications

• Anxiety disorders- generalized anxiety disorder
• Panic disorders- with or without agoraphobia

 Non-FDA-labeled indications

• Insomnia
• Premenstrual syndrome
• Depression

Alprazolam belongs to a class of psychoactive medications called benzodiazepines. Benzodiazepines bind to the GABA-A receptor. This receptor is made up of five subunits, e.g., alpha, beta, gamma, delta, epsilon, rho, etc. A common GABA-A receptor found in the CNS is made up of two alpha-1 subunits, two beta-2 subunits and one gamma-2 subunit. The benzodiazepine binding site is between the alpha-1 and gamma-2 subunit. Studies in mice suggest that the alpha-1 subunit mediates sedation, amnesia, and ataxic effects of benzodiazepines, and alpha-2 and alpha-3 subunits mediate anxiolytic and muscle-relaxing effects of benzodiazepines. Also, research suggests that BNZ-1 receptors affect sedation and anti-anxiety, while the BNZ-2 affects muscle relaxation, anticonvulsant activity, memory, and motor coordination. Benzodiazepine receptors appear to exhibit coupling with GABA-A receptors, and this enhances the effects of gamma-aminobutyric acid (GABA) by increasing GABA affinity at the GABA receptor. The major inhibitory neurotransmitter GABA, when bound to the GABA-A receptor, mediates the calming or inhibitory effects of alprazolam on the human nervous system.[2][3]

Pharmacokinetics

Absorption: Alprazolam is rapidly absorbed after oral administration with a peak plasma concentration at 1 to 2 hours. The bioavailability of oral alprazolam averages 80 to 100%. 

Distribution:

Alprazolam is 80% bound to serum protein, mainly albumin.

Metabolism:

Alprazolam is metabolized in the liver by cytochrome P450 3A4 (CYP3A4) to 4-hydroxyalprazolam and alpha-hydroxyalprazolam metabolites

Excretion

Alprazolam and its metabolites are filtered out by the kidneys and excreted in the urine. The mean plasma half-life of alprazolam is about 11.2 hours in healthy adults.

Alprazolam is available as a regular release and orally disintegrating tablets in strengths of 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets, while extended-release tablets are available in strengths of 0.5 mg, 1 mg, 2 mg, and 3 mg. Alprazolam is also available as an oral solution in strengths of 0.5 mg/5 mL and as 1 mg/10 mL. Administration of alprazolam may be without regard to food. Take with food if the patient experiences an upset stomach. The orally disintegrating tablets must remain in their original packaging and must not put tablets in a pillbox. The extended-release tablets are not to chewed, crushed or split, but instead swallowed whole. Alprazolam is a controlled substance with the C-IV designation.[4][5]

Treatment of Anxiety Disorders

 Oral dosage forms (tablets, orally disintegrating tablets, and solution):

Adult Dosage

• 0.25 to 0.5 mg 3 times a day
• Dosage increases should occur at intervals of 3 to 4 days with increments of no more than 1 mg per day.
• Maximum dose: 4 mg/day

 Geriatric Dosage

• 0.25 mg 2 or 3 times a day.

Treatment of Panic Disorders

Oral Dosage form (extended-release tablets):

Adult Dosage

• 0.5 to 1 mg once a day
• Maintenance dose: 3 to 6 mg orally per day
• Maximum dose: 10 mg/day

Geriatric Dosage

• 0.5 mg orally once a day

Oral Dosage forms (tablets, orally disintegrating tablets, solution):

Adult Dosage

• 0.5 mg 3 times a day
• Maximum dose: 10 mg/day

Geriatric Dosage

• 0.25 mg 2 or 3 times a day

Hepatic Impairment Dose Adjustments

Oral dosage forms (tablets/orally disintegrating tablets):

• 0.25 mg orally 2 or 3 times daily

Oral dosage forms (extended-release tablets):

• 0.5 mg orally once a day

Debilitating Disease Dose Adjustments

Oral Dosage forms (tablets/orally disintegrating tablets):

• 0.25 mg orally 2 or 3 times daily

Oral Dosage forms (extended-release tablets):

• 0.5 mg orally once a day

Dose Reduction

As a result of the danger of withdrawal, avoid abrupt discontinuation of treatment. In all patients, the dosage should undergo gradual reduction when discontinuing therapy or when decreasing the daily dosage. The suggested method is that the daily dosage reduction is not by not more than 0.5 mg every three days, and some patients may require an even slower dosage reduction. In patients with long term chronic alprazolam use, one should switch to a longer-acting benzodiazepine such as clonazepam or diazepam and titrate down gradually; this results in fewer withdrawal side effects. 

Common adverse effects for patients taking alprazolam are[6]:

• Drowsiness
• Tiredness
• Dizziness
• Sleep problems (insomnia)
• Memory problems
• Poor balance or coordination
• Slurred speech
• Trouble concentrating
• Irritability
• Diarrhea
• Constipation
• Increased sweating
• Headache
• Nausea
• Vomiting
• Upset stomach
• Blurred vision
• Appetite or weight changes
• Swelling of hands or feet
• Muscle weakness
• Dry mouth
• Stuffy nose
• Loss of interest in sex

Contraindications to alprazolam include patients with known alprazolam or benzodiazepine hypersensitivity or known allergies to any of its components in the drug dosage form. Alprazolam should be avoided if possible by anyone with pulmonary disease. Using alprazolam with CNS depressants, especially opioids, increases the risk of respiratory depression, low blood pressure, and death.[7]

Drug Interactions:

Alprazolam is affected by drugs that inhibit or induce CYP3A4. Drugs that are potent inhibitors of CYP3A may lead to an increase in plasma concentrations, which may result in increased adverse events. Medications known to impact alprazolam include azole antifungals (ketoconazole), cimetidine, certain anti-depressants (fluoxetine, fluvoxamine, and nefazodone), macrolide antibiotics (clarithromycin), rifamycins (rifampin), St. John’s wort, seizure medications (carbamazepine, phenytoin), antihistamines and muscle relaxants.