Continuing Education Activity

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 misused for recreational purposes because of its disinhibition, euphoria, and anxiolytic effects. FDA-labeled indications include anxiety disorders and panic disorders with or without agoraphobia. This activity outlines the indications, mechanism of action, administration, dosing, contraindications, warnings, precautions, adverse drug reactions, and toxicity of alprazolam in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients with mental health disorders.

Objectives:

• Identify the mechanism of action of benzodiazepines, including alprazolam.
• Review the adverse effects of alprazolam to identify the signs of benzodiazepine toxicity.
• Explain the proper indications for alprazolam therapy.
• Outline the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care when dosing alprazolam to improve patient outcomes for patients.

Indications

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[2]

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

 Non-FDA-labeled Indications[2]

• Insomnia
• Premenstrual syndrome
• Depression

Mechanism of Action

Alprazolam belongs to a class of psychoactive medications called benzodiazepines. Benzodiazepines bind to the GABA-A receptor. This receptor is comprised of five subunits, e.g., alpha, beta, gamma, delta, epsilon, rho, etc. A common GABA-A receptor in the CNS is comprised 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 subunits. 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 binding sites appear to exhibit coupling with GABA-A receptors, enhancing the effects of gamma-aminobutyric acid (GABA) by increasing GABA affinity at the GABA-A receptor. When bound to the GABA-A receptor, the major inhibitory neurotransmitter GABA mediates the calming or inhibitory effects of alprazolam on the human nervous system.[3][4]

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.

Administration

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 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 be put in a pillbox. The extended-release tablets are not to be chewed, crushed, or split but instead swallowed whole. Alprazolam is a controlled substance with the C-IV designation.[5][6]

Treatment of Anxiety Disorders

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

Adult Dosage

• 0.25 mg to 0.5 mg three 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 two or three 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 (immediate-release tablets, orally disintegrating tablets, solution):

Adult Dosage

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

Geriatric Dosage

• 0.25 mg two or three times a day

Pediatric Considerations

The safety and effectiveness of alprazolam are not being established in pediatric patients.

Hepatic Impairment Dose Adjustments

Oral dosage forms (immediate-release tablets/orally disintegrating tablets): 0.25 mg orally two or three times daily

Oral dosage forms (extended-release tablets): 0.5 mg orally once a day

Debilitating Disease Dose Adjustments

Oral dosage forms (immediate-release tablets/orally disintegrating tablets): 0.25 mg orally two or three 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. The dosage should be gradually reduced in all patients when discontinuing therapy or decreasing the daily dosage. The suggested method is that the daily dosage reduction is 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.[7] 

Pregnancy Considerations

Alprazolam is categorized as pregnancy category D medicine. A pregnancy exposure registry is established to monitor pregnancy outcomes in women exposed to alprazolam when pregnant. Clinicians are encouraged to register their patients by calling the National Pregnancy Registry for Psychiatric Medications.

Maternal exposure to alprazolam in the later trimester of pregnancy may result in sedation (lethargy, respiratory depression, hypotonia) and withdrawal symptoms (irritability, hyperreflexia, restlessness, tremors, feeding difficulties, and inconsolable crying, and) in the neonate. As benzodiazepines can cross the placenta, clinicians should observe newborns for signs/symptoms of sedation, respiratory depression, feeding problems, and neonatal withdrawal syndrome and manage them appropriately. Available data of published observational studies of pregnant women exposed to alprazolam have not related alprazolam-associated risk of miscarriage, major congenital disabilities, or adverse maternal or fetal outcomes.

Breastfeeding Considerations 

Limited reports from published literature show the presence of alprazolam in human breast milk. Sedation and withdrawal symptoms are reported in breastfed neonates/infants exposed to alprazolam via breastmilk. The effects of alprazolam on milk production and lactation are unknown. Since there is a potential for serious adverse reactions for breastfed neonates and infants, lactating women are advised against breastfeeding if treated with alprazolam.[8]

Adverse Effects

Common adverse effects for patients taking alprazolam are[9]:

• 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
• Worsening depression
• Hypomania
• Decreased mental alertness
• Neonatal sedation and withdrawal syndrome

Contraindications

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.[10]

Drug Interactions

Alprazolam is affected by drugs that inhibit or induce CYP3A4. Drugs that are potent inhibitors of CYP3A may increase plasma concentrations of alprazolam, resulting 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.

Dosage Modifications for Drug Interactions

Alprazolam dose should be reduced to 50% of the recommended dose when a patient is started on ritonavir and alprazolam concomitantly or when ritonavir is administered to a patient using alprazolam. Clinicians can increase the alprazolam dose to the target dose after 10 to 14 days of administering ritonavir and alprazolam concomitantly. There is no need to reduce the alprazolam dose in patients taking ritonavir for 10 to 14 days.

Monitoring

The patient's respiratory and cardiovascular status should undergo monitoring when treated with alprazolam. Patients should also have monitoring for orthostasis, excessive sedation, and a periodic basic metabolic panel. Liver function tests and complete blood counts also require observation during chronic therapy. In addition, patients at risk for substance misuse disorder should require surveillance as alprazolam use can become addictive in patients. Benzodiazepines can cross the placenta, so clinicians should observe newborns for signs/symptoms of sedation, respiratory depression, feeding problems, and neonatal withdrawal syndrome for infants having in-utero exposure to alprazolam.

Toxicity

The continued use of alprazolam, like all benzodiazepines, may lead to clinically significant physical dependence. The risks of withdrawal and dependence increase with chronic treatment using alprazolam for a longer duration and in high daily doses. After long-term treatment, rapid dosage reduction and abrupt discontinuation of alprazolam may precipitate acute withdrawal. Therefore, it is recommended to taper to discontinue alprazolam gradually To reduce the risk of alprazolam withdrawals and reactions, which can be fatal.

In alprazolam overdose cases, respiration, blood pressure, and pulse rate require monitoring. Intravenous fluids are necessary, and an adequate airway should be maintained. Flumazenil, a benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines.[11][12]

Enhancing Healthcare Team Outcomes

Alprazolam misuse potential comes from its pharmacokinetic properties of a short half-life, rapid absorption, and low lipophilicity. Compared to other benzodiazepines, alprazolam effects may be felt within 30 minutes and last for about 6 hours. Alprazolam, taken in large doses, produces strong depressive effects, which may cause memory loss. Due to alprazolam's many adverse effects, the nurse practitioner, a pharmacist, and the primary care provider must educate the patient on how to use the drug[13]:

• Discuss the specific use of alprazolam with the patient as it relates to treatment
• Discuss possible adverse effects and immediately report signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), severe fatigue, shortness of breath, severe dizziness, passing out, change in balance, confusion, memory impairment, difficulty speaking, menstrual changes, or difficult urination
• Discuss to the patient how taking alprazolam may cause drowsiness and sedation, so they should not drive, operate dangerous machinery, or perform any other activity or task that requires optimal attention.
• Discuss how alcohol and/or illegal drugs with alprazolam increase the chances of life-threatening side effects.

Nurses can be invaluable in observing and verifying that the patient is adherent, not misusing the medication, and offering counsel. The pharmacist can verify dosing and check for drug interactions and inform the prescriber of signs of possible misuse (e.g., doctor shopping, early refills, etc.)  When healthcare professionals function as an interprofessional team, alprazolam therapy stands to have increased odds of being effective while avoiding adverse events and misuse, leading to better patient outcomes. [Level V]