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Home > EMS Products > Ambulance Disposable Supplies
October 06, 2011
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Drug Whys
by Mike McEvoy

Alprazolam (Xanax): Drug Whys

By Mike McEvoy

Generic Name: Alprazolam (multiple manufacturers)
Common U.S. Brand Names: Xanax (Pfizer, USA)
Popularity: 9th most commonly prescribed drug between 2002 – 2009 (U.S.)
Class: Benzodiazepine

Treatment Uses – For treatment of anxiety and panic disorders. Controls 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. Often used for preoperative sedation. Has been useful to control anxiety associated with COPD as well as symptoms of essential tremor.

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.

It should be noted that alprazolam (along with the other benzodiazepines) is not intended for everyday life anxieties and minor distresses. Continued benzodiazepine need should be carefully evaluated if use continues beyond four months.

Long term use of benzodiazepines is associated with physical dependence; patients tend to have a very difficult time discontinuing therapy. Withdrawal effects can be severe.

Dosing and Administration – For anxiety in adults, the recommended initial oral dose of immediate-release or oral disintegrating alprazolam tablets is 0.25 to 0.5 milligrams three times daily.

Adjustments of up to 1 milligram per day can be made every three to four days to a maximum dose of 4 milligrams daily. Effective anxiety dosing ranges from 0.5 to 4 milligrams daily, in divided doses.

Daily totals for treatment of depression range from 2.5 to 3 milligrams; for alcohol withdrawal, 2.2 milligrams, and for panic disorders, 1 to 10 milligrams with a mean dose of 5 to 6 milligrams daily.

Preoperative sedation dosing for adults is normally 0.5 milligrams at bedtime the night before surgery and another 0.5 milligrams one hour before the procedure. Extended release alprazolam should be started at 0.5 to 1 milligram daily, taken in the morning and adjusted upwards in the same fashion as immediate-release tablets.

Conversion from immediate-release to extended release is calculated using the total daily immediate release tablet dose given as extended release once daily. Immediate release tablets can be dosed as needed or between two and four times daily.

Pediatric dosing recommendations vary. Most use in children remains 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 under 18 years old would fall in a range from 0.375 to 3 milligrams daily. Alprazolam oral liquid syrup can be prepared by a compounding pharmacy and is normally concentrated at 1 milligram per milliliter of liquid.

Immediate release alprazolam is not affected by food. Interestingly, many drug references report clinically significant alterations in distribution and effects of alprazolam when taken with food or in patients who consume grapefruit juice.

None of these have been well substantiated by published studies. For patients with nausea or difficulty swallowing, immediate release alprazolam tablets are absorbed 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 then eat immediately after.

Extended release tablets should not be broken, chewed, or crushed. Oral disintegrating tablets should be removed from the bottle with dry hands and placed on the top of the tongue to disintegrate, then swallowed with saliva.

If only half the tablet is used, the unused portion should be discarded as it may not remain stable. Cigarette smoking may decrease any alprazolam concentrations in the blood by up to 50 percent.

Dose reductions are recommended by the manufacturer for geriatric patients. Immediate-release or oral disintegrating tablets should be started at 0.25 milligrams administered two to three times daily and titrated upward as tolerated. Extended release tablets should be started at 0.5 milligrams once daily in the morning with dose increases as needed.

Actual 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 patient with liver disease and patients with other debilitating diseases (using the same dosing regimen as recommended for geriatric patients).

When considering the benzodiazepine class as a whole for patients with liver disease, lorazepam, oxazepam, and temazepam are probably the agents of choice because their metabolism is only slightly affected by liver dysfunction.

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 rather than actual body weight. There are no guidelines for dose reduction in renal patients; however, caution is warranted since much of the drug is eliminated by the kidneys.

Overdoses of alprazolam generally manifest 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, in patients with long term benzodiazepine use, can induce seizures.

Aggressive and manic behaviors have also been reported with alprazolam overdoses. In one case report, a 7.5 milligram dose was fatal in a medically unstable patient.

Pharmacology/Pharmacokinetics/Stability – Oral alprazolam is rapidly absorbed. Immediate release tablets and liquid reach peak blood levels within 45 minutes to 2 hours and remain in the body for up to 11 hours in healthy adults. Initial relief of anxiety is usually seen in 1 to 1.5 hours.

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 7 percent in feces.

The half life (time to eliminate half the drug from the body) of alprazolam is prolonged in Asians (compared to Caucasians), as well as elderly, obese, and alcoholic liver disease patients.

It is unknown if alprazolam crosses the placenta during pregnancy although other benzodiazepines most certainly do. Studies of pregnant women who took alprazolam or other benzodiazepines during pregnancy did not demonstrate increased incidence of fetal malformations except when the mothers had attempted suicide with benzodiazepines during their pregnancy.

Alprazolam is excreted in breast milk. The American Academy of Pediatrics rates alprazolam as a drug "of concern" for breastfeeding mothers, although the World Health Organization rates it safe for occasional use in small doses while breastfeeding.

Alprazolam is a central nervous system (CNS) drug with an unknown mechanism of action in the body. It is theorized to exert its effects by binding to specific CNS receptor sites.

Immediate-release and oral disintegrating alprazolam tablets come in 0.25, 0.5, 1 and 2 milligram strengths. Extended release doses come in 0.5, 1, 2, and 3 milligram tablets. Color, shape, and size of tablets vary by manufacturer. Tablets should be stored 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. It should be used cautiously in patients with liver disease or obesity for reasons previously described. In patients with severe pulmonary disease, alprazolam's propensity to depress respirations warrants particularly cautious use.

Patients should be cautioned to avoid activities requiring mental alertness or coordination when starting alprazolam until the effects of the drug are fully appreciated. Like other benzodiazepines, alprazolam has potential for dependence and abuse.

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 appears greater in patients with long term use (greater than 4 milligrams daily for more than 12 weeks), but can appear in any benzodiazepine treated patient. Onset usually occurs 18 hours to three days following abrupt discontinuation or large dose decreases.

Cautions and Warnings – Alprazolam can exacerbate narrow angle glaucoma and should not be given to these patients. It should be used cautiously in patients with liver disease or obesity for reasons previously described. In patients with severe pulmonary disease, alprazolam's propensity to depress respirations warrants particularly cautious use.

Patients should be cautioned to avoid activities requiring mental alertness or coordination when starting alprazolam until the effects of the drug are fully appreciated. Like other benzodiazepines, alprazolam has potential for dependence and abuse.

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 appears greater in patients with long term use (greater than 4 milligrams daily for more than 12 weeks), but can appear in any benzodiazepine treated patient. Onset usually occurs 18 hours to three days following abrupt discontinuation or large dose decreases.

Average Costs – U.S.
• 0.25 mg and 0.5 mg tablet (generic)
Patient cost: $0.40 and $0.43 each*
Large Hospital cost: $0.04 and $0.04 each
*(Wal Mart and Target don’t include this med in their $4/month programs)

References:
1. MICROMEDEX Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed August, 2011).
2. Albany Medical Center Pharmacy, Albany, New York.



About the author

Mike McEvoy, PhD, REMT-P, RN, CCRN is the EMS Coordinator for Saratoga County, New York, a paramedic for Clifton Park-Halfmoon Ambulance, and Chief Medical Officer for West Crescent Fire Department. He is a clinical specialist in cardiac surgery and teaches critical care medicine at Albany Medical College. Mike is the EMS editor for Fire Engineering magazine, a popular speaker at EMS, fire, and medical conferences, and lead editor of the Jones & Bartlett textbook, "Critical Care Transport". In his free time, he is an avid hiker and winter mountain climber. Contact Mike at mike.mcevoy@ems1.com.
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