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Drug Whys
Mike McEvoy
By Mike McEvoy, Ph.D., REMT-P, RN, CCRN
[alprazolam]
Generic Name: alprazolam (multiple manufacturers)
Common U.S. Brand Names: Xanax (Pfizer, USA)
Popularity: 8th most commonly prescribed drug in 2005 (U.S.)
Class: benzodiazepine
Treatment Uses
For treatment of anxiety and panic disorders. For control of symptoms associated with alcohol withdrawal. Used as adjunctive therapy to narcotic analgesics for control of cancer pain and in treatment and prevention of chemotherapy-induced nausea and vomiting. For control of disruptive behavioral episodes associated with delirium, dementia, amnesic, and other cognitive disorders. Alprazolam has been used with mixed results for treatment of post-traumatic stress disorder, depression, premenstrual syndrome, schizophrenia, obsessive-compulsive disorder, migraine headaches, essential tremor, and tinnitus.
Dosing and Administration
For anxiety in adults, the recommended initial dose of alprazolam is 0.25 to 0.5 milligrams three times daily. Upward adjustments can be made every three to four days to a maximum dose of four milligrams daily. Effective doses for anxiety usually range from 0.5 to four milligrams daily, in divided doses. Daily totals for effective treatment of depression range from 2.5 to three milligrams; for alcohol withdrawal, 2.2 milligrams; for panic disorders, one to 10 milligrams with a mean dose of five to six milligrams daily. Extended-release alprazolam is dosed once daily using the total daily immediate-release tablet dose. Immediate release tablets can be dosed as needed or between two and four times daily.
Pediatric dosing recommendations vary, and most uses in children remain investigational. For anxiety, initial dosing by weight is typically 0.005 milligrams per kilogram of body weight per dose given three times daily. This is increased in increments of 0.125 to 0.25 milligrams every three to four days up to a maximum of 0.02 milligrams per kilogram per dose or 0.06 milligrams per kilogram daily. Typical total doses for children younger than 18 years old would fall in a range from 0.375 to three milligrams daily. Alprazolam oral liquid syrup can be prepared by a compounding pharmacy and is normally concentrated at one milligram per milliliter of liquid.
Food does not affect immediate-release alprazolam. Patients with nausea or difficulty swallowing absorb immediate-release alprazolam tablets sublingually (under the tongue), provided adequate saliva is present to dissolve the tablet. Absorption of extended-release alprazolam is reduced by about one-third in patients who eat immediately before taking a dose and increased by the same amount in patients who take an extended-release dose on an empty stomach and eat immediately after. Extended-release tablets should not be broken, chewed, or crushed. Cigarette smoking may decrease any alprazolam concentrations in the blood by up to 50 percent.
The manufacturer recommends dose reductions for geriatric patients, starting at 0.25 milligrams administered two to three times daily and titrated upward as tolerated. Studies demonstrate prolonged elimination in elderly men, but not women. Most practitioners prescribe lower doses only in older men. Alprazolam’s short duration of action makes it one of the preferred benzodiazepines for use in the elderly. Lower doses are also recommended for patients with liver disease and other debilitating diseases. Prescribers are warned that steady-state concentrations of alprazolam take longer to achieve in obese patients but ultimately will be similar to normal weight patients when dosed by ideal instead of actual body weight. There are no guidelines for dose reduction in renal patients, but caution is warranted, given that much of the drug is eliminated by the kidneys.
Overdoses of alprazolam generally manifest themselves in the form of sleepiness, confusion, diminished levels of consciousness, and respiratory depression. Treatment is supportive. Flumazenil selectively blocks benzodiazepine binding at CNS receptors, reversing alprazolam-induced sedation. Use of flumazenil, however, may not reverse respiratory depression and may induce seizures in patients with long-term benzodiazepine use. Aggressive and manic behaviors have also been reported with alprazolam overdoses.
Pharmacology/Pharmacokinetics/Stability
Oral alprazolam is rapidly absorbed. Immediate-release tablets and liquid reach peak blood levels within 45 minutes to two hours and remain in the body for up to 11 hours in healthy adults. Mean times for elimination of alprazolam are extended to 21.8 hours in obese patients and 19.7 hours in patients with liver disease. Extended-release alprazolam takes slightly longer to reach peak blood levels and remains in the body for up to 16 hours in healthy adults. Alprazolam is metabolized extensively in the liver, 80 percent is excreted by the kidneys, and seven percent in feces. Alprazolam is excreted in breast milk. The American Academy of Pediatrics rates alprazolam as a drug “of concern” for breastfeeding mothers.
Immediate-release alprazolam tablets come in 0.25-, 0.5-, one- and two-milligram strengths. Extended-release doses come in 0.5-, one-, two-, and three-milligram tablets. Color, shape, and size of tablets vary by manufacturer. Store tablets at room temperature between 68-77°F with occasional variations to 59-86°F permitted.
Cautions and Warnings
Alprazolam can exacerbate narrow angle glaucoma and should not be given to these patients. Use it cautiously in patients with liver disease or obesity for reasons previously described. In patients with severe pulmonary disease, alprazolam’s propensity to depress respiration mandates cautious use.
Benzodiazepine withdrawal syndrome is a potentially dangerous condition that can result from abrupt discontinuation of alprazolam. Dose reduction or discontinuation should be accomplished no faster than a total daily dose decrease of 0.5 milligrams every three days. Benzodiazepine withdrawal syndrome often begins with distorted perceptions such as sensations of movement or perceptions of body parts being separated from the body. Sensations of floating, falling, and faulty depth perception have also been reported. Confusion, muscle cramps, and blurred vision are common. Hypertension, tachycardia, delirium, and seizures can result from abrupt withdrawal. Symptoms resolve with reinstitution of alprazolam. Risk and severity of withdrawal symptoms appear greater in patients with long-term use (greater than four milligrams daily for more than 12 weeks) but can appear in any benzodiazepine-treated patient.
Important Side Effects and Interactions
Drowsiness is the most commonly reported alprazolam side effect, occurring in up to half of all patients. Dry mouth has also been reported by up to 15 percent of patients. Other adverse reactions occurring in one to 10 percent of patients include hypotension, palpitations, amnesia, fatigue, constipation, rash, and visual disturbances.
There are 38 drugs and drug classes specifically reported to interact with alprazolam. Most are either poorly documented or extremely uncommon. Seven are worth noting:
- Azole antifungal agents substantially increase the duration alprazolam remains in the body and can lead to toxicity. The two drugs should not be used together.
- Barbiturates and other CNS-depressant drugs have additive effects when combined with alprazolam and require close monitoring for respiratory and CNS depression when used in combination.
- Carbamazepine has been reported to significantly decrease alprazolam levels, requiring higher doses of alprazolam. Use caution when starting or stopping either of these agents.
- Macrolide antibiotics inhibit liver enzymes responsible for benzodiazepine metabolism, leading to increased alprazolam concentrations and longer duration of action. A 50- to 75-percent alprazolam dose reduction may be required when used in concert with macrolide antibiotics.
- Digoxin levels can significantly increase with alprazolam. Monitoring digoxin levels is recommended when starting or stopping alprazolam.
- Numerous oral contraceptives are reported to inhibit metabolism of alprazolam, leading to increased risks of toxicity without dose reduction.
- St. John’s Wort has been reported to significantly reduce benzodiazepine effectiveness, requiring up to 50 precent greater benzodiazepine dosing.
Average Costs - U.S.
• 0.25 mg and 0.5 mg tablet (generic)
Patient cost: $0.25 and $0.50 each
Large Hospital cost: $0.04 and $0.04 each
References:
1. MICROMEDEX® Healthcare Series: MICROMEDEX, Greenwood Village, Colorado (Edition expires 9/2006).
2. Albany Medical Center Pharmacy, Albany, New York.
If you have a “Whys” experience or unique question about an upcoming drug, e-mail Mike McEvoy at mcevoymike@aol.com.
MIKE McEVOY is the fireEMS editor for Fire Engineering, a critical care nurse, an instructor in critical care medicine, and a member of the Pharmacy and Therapeutics Committee at Albany (NY) Medical Center. McEvoy is also the EMS coordinator for Saratoga County, New York, and chief medical officer for the West Crescent Fire Department.
