Alprazolam

MECHANISM OF ACTION

Alprazolam produces its effects by enhancing the action of gamma-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter. It binds to the benzodiazepine site on GABA-A receptors, increasing the frequency of chloride channel opening. This hyperpolarizes neurons, reducing neuronal excitability, which produces anxiolytic, sedative, muscle relaxant, and anticonvulsant effects. Its rapid onset and short half-life make it effective for acute anxiety and panic episodes.

PHARMACOKINETICS

Absorption

Alprazolam is rapidly and well absorbed after oral administration, with bioavailability of approximately 80–90%. Maximum plasma levels are typically achieved within 1 to 2 hours after administration. Its absorption is not significantly affected by food, although high-fat meals may slightly delay the time to peak levels without reducing overall bioavailability.

Distribution

The volume of distribution for alprazolam is approximately 0.84 to 1.42 L/kg for the immediate-release formulation in healthy adults. 

Metabolism

Alprazolam is primarily metabolized in the liver by the enzyme cytochrome P450 3A4 (CYP3A4). It undergoes oxidation to form active and inactive metabolites, including α-hydroxyalprazolam and 4-hydroxyalprazolam, which have minor pharmacological activity. Most metabolites are eventually conjugated and excreted in the urine, with less than 10% of the parent drug eliminated unchanged. Hepatic function and CYP3A4 inhibitors can significantly affect alprazolam metabolism.

Excretion

Alprazolam is mainly excreted in the urine as metabolites, with less than 10% eliminated unchanged.

PHARMACODYNAMICS

Alprazolam enhances GABAergic neurotransmission by binding to benzodiazepine sites on GABA-A receptors, increasing chloride ion influx and hyperpolarizing neurons. This produces anxiolytic, sedative, muscle relaxant, and anticonvulsant effects, with rapid onset making it effective for acute anxiety and panic symptoms. Its effects are dose-dependent and primarily central nervous system-mediated.

DOSAGE AND ADMINISTRATION

Oral dosage:

Anxiety: Typically 0.25–0.5 mg orally 3 times daily; may be increased gradually based on response.

Panic disorder: Start at 0.5 mg orally 3 times daily, with gradual titration as needed.

Maximum dose: Usually 4 mg/day in divided doses for panic disorder; higher doses require careful monitoring.

Administration tips:

• Take by mouth, with or without food.

• Avoid sudden discontinuation; reduce the dose slowly to prevent withdrawal effects.

• Use the minimum effective dose for the shortest necessary period to lower the risk of dependence.

DRUG INTERACTIONS

Alprazolam interacts mainly with CYP3A4 inhibitors or inducers, which can increase or decrease its levels, and with other CNS depressants like alcohol or opioids, which can enhance sedation and respiratory depression. Dose adjustments and caution are advised when used with these agents.

FOOD INTERACTIONS

Alprazolam has important food interactions: grapefruit and grapefruit juice can significantly increase drug levels and side effects, while alcohol can dangerously enhance drowsiness and respiratory depression. It is generally safe to take with food, though high-fat meals may slightly alter absorption. Caffeine may reduce its effectiveness, and juices like cranberry or pomegranate can inhibit metabolism, increasing drug effects. Patients should discuss their diet with a healthcare provider.

CONTRAINDICATIONS

Alprazolam is contraindicated in individuals with a known hypersensitivity to alprazolam or other benzodiazepines, in patients with acute narrow-angle glaucoma, and in those taking strong CYP3A inhibitors like itraconazole or ketoconazole.

SIDE EFFECTS

• Drowsiness/Sedation and fatigue.

• Dizziness and light-headedness.

• Impaired coordination and balance problems.

• Memory impairment or trouble concentrating.

• Irritability and talkativeness.

• Gastrointestinal issues like nausea, constipation, or a dry mouth.

• Headache.

• Changes in appetite and potential weight changes.

• Changes in sex drive.

Serious Side Effects:

• Depression or suicidal thoughts/actions.

• Seizures.

• Breathing problems, which can be severe, especially when combined with opioids or alcohol.

• Hallucinations or feeling detached from reality (depersonalization).

• Serious allergic reactions may occur, such as swelling of the face, lips, tongue, or throat, accompanied by difficulty breathing.

OVERDOSE

Common/Mild Symptoms:

• Drowsiness and extreme sleepiness.

• Confusion or mental status changes.

• Problems with coordination and balance (ataxia).

• Slurred or difficulty speaking.

• Muscle weakness.

• Severe/Life-Threatening Symptoms:

• Slowed, shallow, or stopped breathing (respiratory depression).

• Profound confusion or unresponsiveness.

• Loss of consciousness or coma.

• Seizures.

• Yellowing of the skin or eyes (jaundice).

• Slowed heart rate.

TOXICITY

Alprazolam overdose causes central nervous system depression, with effects ranging from drowsiness and confusion to coma. Although overdose is rarely fatal on its own, the risk becomes significantly higher when combined with other CNS depressants such as alcohol or opioids, due to the increased likelihood of severe respiratory depression.