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Alprazolam

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Alprazolam
Clinical data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80-90%
MetabolismHepatic, via Cytochrome P450 3A4
Elimination half-lifeImmediate release: 11.2 hours;[2] Extended release: 10.7-15.8 hours[3]
ExcretionRenal
Identifiers
  • 8-chloro-1-methyl-6-phenyl-4H-
    [1,2,4]triazolo[4,3-a][1,4]benzodiazepine
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.044.849 Edit this at Wikidata
Chemical and physical data
FormulaC17H13ClN4
Molar mass308.765 g·mol−1

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 possesses anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant properties.[4]

Alprazolam is a potentially 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.[5]

History

Alprazolam was first synthesized by Upjohn (now a part of Pfizer). It is covered under U.S. patent 3,987,052, which was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. Alprazolam was released in 1981.[6][7] The first approved indication 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 responsive to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder would both cover new diagnostic territory and emphasize 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.[8]

Pharmacology

Alprazolam is classed as a high potency benzodiazepine and is a triazolobenzodiazepine,[9][10] 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 GABAA and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to benzodiazepines.[11][12]

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.[13]

Therapeutic uses

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.[14]
  • 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.[15][16]
  • 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.[17] The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors.[18] Other benzodiazepines are not known to have antidepressant activity.[19][20] Studies show that any antidepressant action of alprazolam is questionable and generally weak in comparison to antidepressant medications.[21][22][23][24] 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.[25]

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:

Contraindications

Use of alprazolam should be avoided, or carefully monitored by medical professionals, in individuals with the following conditions:[47][48]

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[51] It should be considered that the child born of a mother who is receiving benzodiazepines may be at risk of developing withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.[52]

Benzodiazepines, including alprazolam are known to be excreted in human milk.[53] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[54][55] As a general rule, nursing should not be undertaken by mothers who use alprazolam.

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side effects, especially loss of coordination and drowsiness.[55]

Like all central nervous system depressants, including alcohol, alprazolam in doses of 0.5 mg and above can cause significant deterioration in alertness, combined with increased feelings of sleepiness.[56] People driving or conducting activities which require vigilance should exercise caution in using alprazolam or any other depressant.

Food and drug interactions

The effect of drinking grapefruit juice or consuming grapefruit while using alprazolam is not certain. Some web sites suggest that it increases blood concentrations by inhibiting the intestinal metabolism.[57] However, there is a published paper,[58] which suggests that the effect are in fact negligible because the effect on the inhibition of the CYP3A4 enzyme did not correlate, in a statistically significant manner, to the increase of blood plasma concentrations of alprazolam due to alprazolam's high bioavailability.

Cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene and ritonavir all interact with alprazolam leading to a delayed clearance of alprazolam which may result in excessive accumulation of alprazolam.[13][59]

Imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day.[60]

Oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[61]

Alcohol is an important interaction. Alcohol and benzodiazepines such as alprazolam taken in combination have a synergistic effect on one another which can cause severe sedation, behavioral changes and intoxication. The more alcohol and alprazolam taken the worse the interaction.[62]

Physical dependence and withdrawal

See also: Benzodiazepine withdrawal syndrome

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.[63][64] 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 recommended, or if a patient stops taking the medication altogether without slowly allowing the body to wean itself off the drug.[65][66][67]

If a consumer of the drug feels the need to end treatment with alprazolam, they should consult their doctor/physician before discontinuing medication. Some immediate symptoms of alprazolam withdrawal include:[68]

Common Withdrawal Symptoms

Possible/Less Common Withdrawal Symptoms

Patients treated with alprazolam or other benzodiazepines for generalized anxiety disorder were found (when abruptly discontinuing their medication) to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms.[69]

Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety. Other withdrawal effects reported from discontinuing alprazolam therapy include homicidal ideation, rage reactions, hyperalertness, increased nightmares and intrusive thoughts.[70] Grand mal seizures have occurred after abrupt withdrawal after only short term use. Therefore even short term users of alprazolam should taper off of their medication slowly and carefully to avoid serious withdrawal effects including seizures.[71][72]

After 8–9 weeks of alprazolam taken at a fixed prescribed dose, the following symptoms have been found to occur during abrupt discontinuation: dysphoric mood, fatigue, low energy, confusion, and elevated systolic blood pressure, severe anxiety.[73]

Alprazolam should never be abruptly discontinued if taken regularly for any length of time because severe withdrawal symptoms may occur. Severe psychosis and seizures have been reported in the medical literature from abrupt alprazolam withdrawal,[74][75] and one death occurred from withdrawal-related seizures after gradual dose reduction.[75]

The benzodiazepines diazepam (Valium) and oxazepam (Seresta) were found to produce less severe withdrawal symptoms than alprazolam (Xanax) or lorazepam (Temesta/Ativan). Alprazolam has an exceptional history insofar soon after its introduction a large number of case reports were published in the medical literature of severe withdrawal symptoms related case reports of withdrawal psychoses, seizures and intense rebound anxiety upon discontinuation of alprazolam. In the United States a survey of physicians showed that 84% of physicians reported alprazolam as being extremely problematic in terms of the severity and prolonged nature of the benzodiazepine withdrawal syndrome after discontinuation. Factors which determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal syndrome experienced during dose reduction of alprazolam include:[76][77]

  • dosage
  • length of use
  • frequency of dosing
  • method of withdrawal[78]
  • personality characteristics of the individual
  • previous use of cross dependent/cross tolerant drugs (alcohol or other sedative hypnotic drugs)
  • current use of cross dependent/cross tolerant drugs (alcohol or other sedative hypnotic drugs)
  • Use of short-acting high potency benzodiazepines for example alprazolam or lorazepam

Recreational misuse

Sandoz generic 2mg alprazolam tablets.

Alprazolam, together with lorazepam and diazepam, have the highest abuse liability among the benzodiazepine medications.[79] Injection of alprazolam, though extremely rare, is considered especially dangerous by medical professionals[80] because, when crushed in water it will not fully dissolve (40 µg/ml of H2O at pH 7, and 12 mg/mL at pH 1.2 per 1 mg of alprazolam[81]), potentially causing severe damage to arteries if not filtered properly. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, has the potential to cause a serious, and potentially fatal overdose. Alprazolam may also be insufflated.[82]

Alprazolam is sometimes used with other recreational drugs to relieve the panic or distress of dysphoric reactions to psychedelics such as LSD and also to promote sleep in the "come-down" period following use of recreational drugs with stimulant or insomniac properties (such as LSD, cocaine, amphetamines, DXM, and MDMA along with the related amphetamines). It is also often used in conjunction with marijuana or heroin to potentiate the relaxing effect.[83][84][85][86][87]

A large scale nation wide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. The report found that alprazolam is the most commonly abused benzodiazepine followed by clonazepam, lorazepam and then diazepam. Temazepam was responsible for a majority of benzodiazepine related-deaths, according to US Poison Control Centers.[5]

Patients at a high risk for abuse and addiction

At a particularly high risk for misuse, abuse, and dependence are polydrug abusers (someone who already uses at least one substance in a recreational context). However, the following can also indicate potential problems in the future:

"One is very unlikely to overdose on alprazolam, the lethal dose is about 140mg per kilogram of mass in rats, meaning you would have to take a lot to overdose and die. However, overdoses that psychoactively change perspective of life and time are common at doses as low as 4-5 milligrams (Bracaglia 1)."

  • Patients with a history of alcoholism (including a family history of alcoholism) or drug abuse and/or dependence[88][89][90][91][92]
  • Patients with borderline personality disorder[93]

Overdose

See also: Benzodiazepine overdose

Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Alprazolam is significantly more toxic in overdose than other benzodiazepines with higher rates of fatalities. A study in New Zealand found that alprazolam was almost 8 times more likely to result in death in overdose than other sedative hypnotics as a group, with higher rates of ICU admissions and mechanical ventilation. Combined overdose with tricyclic antidepressants, alcohol or opiates or overdoses of alprazolam in the elderly significantly increases the likelyhood for severe toxicity and possible fatality.[94] Alprazolam (Xanax) overdose reflect the central nervous system depression of the brain and may include one or more of the following symptoms:[32]

About 50% of the cases of death involving alprazolam were attributed to combined drug toxicity of alprazolam and another drug, most often cocaine and methadone. Only 1% of such deaths was attributed to alprazolam alone.[95][96]

Availability

Alprazolam is available in English-speaking countries under the following brand names:

Brand Names[97]
Alprax, Alprox, Alzam, Anxirid, Apo-Alpraz, Alzolam, Azor, Calmax, Gerax, Kalma, Niravam, Novo-Alprazol, Nu-Alpraz, Texidep, Xanax, Xanor, Zopax

In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration.[98] Under the UK drug misuse classification system benzodiazepines are class C drugs.[99] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[100]

See also

References

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