Alprazolam


Article Author:
Tobin George


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Jayson Tripp


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Updated:
3/3/2019 6:23:47 PM

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 used 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

Mechanism of Action

Alprazolam belongs to a class of psychoactive medications called benzodiazepines. Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ-1 and BNZ-2. The 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 GABA by increasing GABA affinity at the GABA receptor. The neurotransmitter GABA, when bound to the GABA receptor, mediates the calming or inhibitory effects of alprazolam on the 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.

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, 1mg, 2mg, and 3 mg. Alprazolam is also available as an oral solution in strengths of 0.5 mg/5 mL and as 1 mg/10mL. Alprazolam may be taken without regard to food. Take with food if you experience 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.[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 1mg per day.
  • Maximum dose: 4mg/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: 10mg/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, abrupt discontinuation of treatment is to be avoided. In all patients, 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 side effects. 

Adverse 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 in your hands or feet
  • Muscle weakness
  • Dry mouth
  • Stuffy nose
  • Loss of interest in sex

Contraindications

Contraindications to alprazolam include patients with known alprazolam or benzodiazepine hypersensitivity or known allergies to any of its components. 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 with that inhibit or induce CYP3A4. Drugs that are potent inhibitors of CYP3A may lead to increase plasma concentrations which may result in increased adverse events. Drugs known to impact alprazolam include azole antifungals, cimetidine, certain anti-depressants (fluoxetine, fluvoxamine, and nefazodone), macrolide antibiotics, rifamycins, St. John’s wort, seizure medications (carbamazepine, phenytoin), antihistamines and muscle relaxants.

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 should be monitored during chronic therapy. Patients at risk for substance misuse disorder should require surveillance as alprazolam can become addictive in patients.

Toxicity

In alprazolam overdose cases; respiration, blood pressure and pulse rate require monitoring. Intravenous fluids are necessary and an adequate airway maintained. Flumazenil, a benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines.[8][9]

Enhancing Healthcare Team Outcomes

Alprazolam abuse potential comes from its pharmacokinetic properties of short half-life, rapid absorption, and low lipophilicity. Compared to other benzodiazepines, alprazolam effects may be felt within 30 minutes and can 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[10]:

  • 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 the use of alcohol and/or illegal drugs with alprazolam increases the chances of life-threatening side effects

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Alprazolam - Questions

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What schedule drug is alprazolam?



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Which drug is an anxiolytic?



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Xanax is the brand name for which of the following generic drugs?



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Which of the following is a primary indication for the use of alprazolam?



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A 16-year-old attempted suicide by ingesting an unknown substance that he found in his mother's closet. He is currently dizzy and is shouting at the nurses to leave him alone. He is not oriented to time, place and person and complains of blurred vision. On physical examination, his respiratory rate is 9/min. and he has nystagmus. Over time, he starts talking to people who are not present. Upon inquiry, it is known that the mother has alcohol use disorder, takes inhalant drugs, and is currently undergoing therapy. The patient's other medical history is unremarkable. Which of the following is the most likely substance ingested?



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A banker was driving home after work and was pulled over by the police for erratic driving. He tested negative for alcohol on the breathalyzer. On examination, the individual had a dry mouth, was drowsy, and had difficulty in thinking clearly. He had active prescriptions for all the medications he uses yet he was still given a ticket. He is currently being treated for diabetes, hypertension, depression, and panic disorder. Which of the following drugs is most likely responsible for his condition?



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Alprazolam - References

References

Hedegaard H,Bastian BA,Trinidad JP,Spencer M,Warner M, Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016. National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System. 2018 Dec;     [PubMed]
Masiulis S,Desai R,Uchański T,Serna Martin I,Laverty D,Karia D,Malinauskas T,Zivanov J,Pardon E,Kotecha A,Steyaert J,Miller KW,Aricescu AR, GABA{sub}A{/sub} receptor signalling mechanisms revealed by structural pharmacology. Nature. 2019 Jan;     [PubMed]
Ibáñez J,González de la Aleja J,Gallego JA,Romero JP,Saíz-Díaz RA,Benito-León J,Rocon E, Effects of alprazolam on cortical activity and tremors in patients with essential tremor. PloS one. 2014;     [PubMed]
Preuss CV,Kalava A,King KC, Prescription of Controlled Substances: Benefits and Risks 2018 Jan;     [PubMed]
Quagliato LA,Freire RC,Nardi AE, Risks and benefits of medications for panic disorder: a comparison of SSRIs and benzodiazepines. Expert opinion on drug safety. 2018 Mar;     [PubMed]
Guina J,Merrill B, Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives. Journal of clinical medicine. 2018 Jan 30;     [PubMed]
Arvat E,Maccagno B,Ramunni J,Di Vito L,Giordano R,Gianotti L,Broglio F,Camanni F,Ghigo E, The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans. The Journal of clinical endocrinology and metabolism. 1999 Aug;     [PubMed]
Yamamoto T,Dargan PI,Dines A,Yates C,Heyerdahl F,Hovda KE,Giraudon I,Sedefov R,Wood DM, Concurrent Use of Benzodiazepine by Heroin Users-What Are the Prevalence and the Risks Associated with This Pattern of Use? Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2019 Jan;     [PubMed]
Huang Z,Xu Z,Wang H,Zhao ZQ,Rao Y, Influence of ethanol on the metabolism of alprazolam. Expert opinion on drug metabolism     [PubMed]
Navy HJ,Weffald L,Delate T,Patel RJ,Dugan JP, Clinical Pharmacist Intervention to Engage Older Adults in Reducing Use of Alprazolam. The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists. 2018 Dec 1;     [PubMed]

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