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Alprazolam , also known under the trade names Xanax , Xanor and Niravam , is a short-acting drug of the benzodiazepine class used to treat moderate to severe anxiety disorders, panic attacks, and as an adjunctive treatment for anxiety associated with moderate depression. It is also available in an extended release form, Xanax XR . Both forms are now available generically. Alprazolam is potentially an addictive drug and long term use of alprazolam may cause a physical dependence to develop and benzodiazepine withdrawal syndrome to appear during discontinuation. In the USA alprazolam is the most commonly misused benzodiazepine and is a schedule IV controlled drug.

History

Alprazolam was first synthesized by Upjohn (now a part of Pfizer). Its patent (#3,987,052) was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. It was released in 1981. The first indication for which alprazolam was approved was panic disorder. Upjohn took this direction at the behest of a young psychiatrist David Sheehan. Sheehan's suggestion was to use the confusion DSM-III created in the classification of anxiety disorders (a distinction had just been made in DSM-III between generalized anxiety disorder (GAD) and panic disorder). Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective. However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and well responding to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder will both cover new diagnostic territory and stress the unique potency of this drug. Sheehan describes that the first group of patients treated by alprazolam was so impressed by its action that they knew outright—this drug was going to be a hit. A few of those patients actually pooled their money and purchased stock in Upjohn. Several months later, when alprazolam was approved by the FDA, they sold out and made a profit.

Pharmacology

Alprazolam is a triazolobenzodiazepine , that is, a benzodiazepine with a triazolo-ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine site on the GABA _A and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA _A receptor is made up from 5 subunits out of a possible 19, and GABA _A receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to benzodiazepines.

Pharmacokinetics

Alprazolam is readily absorbed from the gastrointestinal tract with a bioavailability of 80–100%. The peak plasma concentration is achieved in 1-2 hours. Most of the drug is bound to plasma protein, mainly serum albumin. Alprazolam is hydroxylated in the liver to α-hydroxyalprazolam, which is also pharmacologically active but much less so than the parent compound. This and other metabolites are later excreted in urine as glucuronides. Some of the drug is also excreted in unchanged form. The elderly clear alprazolam more slowly than younger patients.

Indications

The main medical uses for alprazolam include:

• Alprazolam is FDA-approved for the short term treatment (up to 8 weeks) of panic disorder, with or without agoraphobia. Alprazolam is very effective in treating moderate to severe anxiety, essential tremor and panic attacks. Physicians who elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks use as tolerance to alprazolam's effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation. However, long-term maintenance therapy on alprazolam is not unheard-of in the medical community, and, if a genuine therapeutic need exists, benefits must be weighed against risks.

• Alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety. Alprazolam should only very rarely be used for longer periods of time – the body becomes rapidly tolerant to the drug's effects, which may translate to decreased efficacy.

• Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence for antidepressant treatment of clinical depression in outpatient settings, evidence for inpatients is lacking. The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors. Other benzodiazepines are not known to have antidepressant activity. Studies show that any antipressant action of alprazolam is questionable and generally weak in comparison to antidepressant medications. Conversely, whilst alprazolam in acute or short term treatment may have some antidepressant properties there is evidence that up to a third of long term users of alprazolam may develop depression. However, many physicians and practictioners prescribe a benzodiazepine (i.e. alprazolam, diazepam, etc.) in conjunction with an antidepressant not to augment such a medication, as may be done with methylphenidate, but to lessen the severity of common side effects associated with an antidepressant regiment (i.e. anxiety, insomnia, restlessness, etc.).

Availability

Alprazolam is available in English-speaking countries under the following brand names: Alprax , Alprox , Alzam , Anxirid , Apo-Alpraz , Azor , Calmax , Gerax , Kalma , Niravam , Novo-Alprazol , Nu-Alpraz , Xanax , Xanor , Zopax .

Side effects

Side effects of alprazolam may occur in patients and are more likely the higher the dosage taken. If signs of an allergic reaction occur such as hives, difficulty breathing, swelling of face, lips, tongue or throat occur medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear such as yellowing of the skin or eyes. Other side effects which may occur are as follows:

• euphoria
• drowsiness
• decreased inhibitions, no fear of danger (increased risk taking behavior)
• depressed mood with thoughts of suicide or self harm or elevated mood and confidence
• hallucinations
• agitation
• feeling dizziness, light headed or fainting
• urinating less than usual or not at all
• headache, fatigue, joint pain and unusual weakness (flu like symptoms)
• speech problems,
• Short term memory loss and impairment of memory functions
• anterograde amnesia and concentration problems
• changes in appetite (including changes in weight)
• blurred vision, unsteadiness and clumsiness (impaired coordination and balance)
• constipation, diarrhea, nausea and vomiting
• decreased or increased sex drive
• dry mouth or, more likely, increased salivation
• sweating
• increase in appetite aka "the munchies"
• skin inflammation
• Aggression
• Mania

Paradoxical side effects

Paradoxical side effects occasionally occur. Severe paradoxical effects such as seizures only rarely occur.

• hyperactivity
• nervousness
• restlessness
• sleeplessness
• muscle twitching
• tremor
• seizure (convulsions)

Physical dependence and withdrawal

Alprazolam and other benzodiazepines cause the development of a physical dependence, tolerance and benzodiazepine withdrawal symptoms during dose reduction or cessation of therapy after long-term treatment. When a patient discontinues use, they may experience the symptoms they had before taking medication but in an exaggerated form. This is known as rebound withdrawal. Symptoms may also be accompanied by other reactions including changes in mood, anxiety, or sleep. Severe rebound anxiety is usually a result of abrupt or over rapid discontinuation of this medication; patients who taper off slowly are less likely to experience these symptoms. Physical dependence is the major limiting factor against long-term use of alprazolam and other benzodiazepines. Discontinuation should be done gradually over a period of months (or even up to a year) to avoid serious withdrawal symptoms such as agitation, panic attacks, rebound anxiety, muscle cramps and seizures. Faster withdrawals are not recommended. If faster withdrawals are required eg for problematic substance misusers then it should be done in a hospital environment as an inpatient. Some patients on alprazolam (Xanax) may benefit from a substitution with a benzodiazepine equivalent dose of another benzodiazepine drug such as diazepam (Valium) or chlordiazepoxide (Librium) as these drugs remain in the bloodstream longer and therefore have less potential for misuse and the long half life and lower potency dose tablets available for diazepam and chlordiazepoxide allow for a smoother more gradual reducing withdrawal program with less intense withdrawal symptoms. There is a higher chance of withdrawal symptoms if the drug is administered in a higher dosage than re