API
Systematic (IUPAC) name
8-chloro-1-methyl-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Clinical data
Trade names | Xanax
AHFS/Drugs.com | monograph
MedlinePlus | a684001
Pregnancy cat. | D (US)
Legal status | POM (UK) Schedule IV (US)
Routes | Oral
Pharmacokinetic data
Bioavailability | 80?90%
Metabolism | Hepatic, via Cytochrome P450 3A4
Half-life | Immediate release: 11.2 hours,[1] Extended release: 10.7?15.8 hours[2]
Excretion | Renal
Identifiers
CAS number | 28981-97-7 Y
ATC code | N05 BA12
PubChem | CID 2118
DrugBank | DB00404
ChemSpider | 2034 Y
UNII | YU55MQ3IZY Y
KEGG | D00225 Y
ChEBI | CHEBI:2611 Y
ChEMBL | CHEMBL661 Y
Chemical data
Formula | C17H13Cl N4
Mol. mass | 308.765
SMILES ClC1=CC2=C(C=C1)N3C(C)=NN=C3CN=C2C4=CC=CC=C4
InChI InChI=1S/C17H13ClN4/c1-11-20-21-16-10-19-17(12-5-3-2-4-6-12)14-9-13(18)7-8-15(14)22(11)16/h2-9H,10H2,1H3 Y Key:VREFGVBLTWBCJP-UHFFFAOYSA-N Y
Y (what is this?) (verify)

Alprazolam /[unsupported input]ʔ l ˈ p r ʔ z ʔ l ʔ m/ (trade name Xanax, available among other generic names) is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. Alprazolam is commonly used and FDA approved for the medical treatment of panic disorder, and anxiety disorders, such as generalized anxiety disorder (GAD) or social anxiety disorder (SAD).[3][4] Alprazolam is available for oral administration in compressed tablet (CT) and extended-release capsule (XR) formulations. Alprazolam possesses anxiolytic, sedative, hypnotic, skeletal muscle relaxant, anticonvulsant, and amnestic properties.[5]

Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak benefits are achieved within the first hour (although onset may begin at 8-25 minutes of ingestion) of using either preparation for panic disorder, and full peak benefits are achieved in 1.5 and 1.6 hours respectively.[6][7] Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week.[8][9] Tolerance to the anxiolytic/antipanic effects is controversial with some authoritative sources reporting the development of tolerance,[10] and others reporting no development of tolerance;[3][11] tolerance will however, develop to the sedative effects within a couple of days.[11] Withdrawal symptoms or rebound symptoms may occur after ceasing treatment abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction.[8][12]

Alprazolam is the most prescribed[13] and the most misused benzodiazepine on the U.S. retail market.[14] The potential for abuse among those taking it for medical reasons is controversial with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs[3] and others stating that there is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam and that the pharmacological properties of alprazolam, high affinity binding, high potency, having a short elimination half-life as well as a rapid onset of action increase the abuse potential of alprazolam.[10][15] Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.[16] Alprazolam is classified as a schedule IV controlled substance by the U.S. Drug Enforcement Administration (DEA).

## Medical uses[edit]

Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy.[15] The FDA label advises that the physician should periodically reassess the usefulness of the drug.[4]

### Panic disorder[edit]

Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks.[4] It however is not a first line treatment, since the development of selective serotonin reuptake inhibitors, and alprazolam is no longer recommended for the treatment of panic disorder (in Australia) due to concerns regarding tolerance, dependence and abuse.[10] Evidence supporting the effectiveness of alprazolam in treating panic disorder has been limited to 4 to 10 weeks. However, people with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit.[4][17]

In the US alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia.[4] Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence, as of 2002.[18]

### Anxiety disorders[edit]

In the US alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the APA Diagnostic and Statistical Manual DSM-III-R diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety associated with depression is responsive to alprazolam. Demonstrations of the effectiveness by systematic clinical study are limited to 4 months duration for anxiety disorder.[4] However, the research into antidepressant properties of alprazolam is of poor quality and only assessed the short-term effects of alprazolam against depression.[19] In one study, some long term, high-dosage users of alprazolam developed reversible depression.[20] In the UK, alprazolam is recommended for the short-term treatment (2?4 weeks) of severe acute anxiety.[17][21][22]

### Nausea due to chemotherapy[edit]

Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.[15]

## Pregnancy and lactation[edit]

Benzodiazepines cross the placenta, enter into the fetus and are also excreted with breast milk. The use of benzodiazepines during pregnancy or lactation has potential risks. The use of alprazolam in pregnancy is believed to be associated with congenital abnormalities. Diazepam and chlordiazepoxide have a better safety profile in pregnancy than alprazolam.

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[23] Use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period[24] as well as neonatal flaccidity and respiratory problems.[25] However, in long-term users of benzodiazepines abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines.[26]

Benzodiazepines, including alprazolam, are known to be excreted in human milk.[27] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[28][29]

## Contraindications[edit]

Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly patients, patients with substance abuse history, particularly alcohol dependence and patients with comorbid psychiatric disorders.[30] Use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory weakness including unstable myasthenia gravis, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class, borderline personality disorder (may induce suicidality and dyscontrol).[31][32][33][34]

Like all central nervous system depressants, including alcohol, alprazolam in larger-than-normal doses can cause significant deterioration in alertness, combined with increased feelings of drowsiness, especially in those unaccustomed to the drug's effects.[35] People driving or conducting activities that require vigilance should exercise caution in using alprazolam or any other depressant.

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.[28]

## Adverse effects[edit]

Xanax (alprazolam) 2 mg tri-score tablets

Allergic reactions are unlikely to occur. The only common side effect is sleepiness when treatment is initiated.

Possible side effects include:

- Disinhibition[36]

- Change in libido[37]

- Jaundice (very rare)[38]

- Hallucinations (rare)[39]

- Dry mouth (infrequent)[40]

- Ataxia, slurred speech[41]

- Suicidal ideation (rare)[42][31]

- Urinary retention (infrequent)[43]

- Skin rash, respiratory depression, constipation[44][45]

- Anterograde amnesia[46] and concentration problems

- Drowsiness, dizziness, lightheadedness, fatigue, unsteadiness and impaired coordination, vertigo[44][45]

### Paradoxical reactions[edit]

Although unusual, the following paradoxical reactions have been shown to occur:

- Aggression[47]

- Rage, hostility[36]

- Twitches and tremor[48]

- Mania, agitation, hyperactivity and restlessness[49][50][51]

### Food and drug interactions[edit]

Alprazolam is primarily metabolised via CYP3A4.[52] Combining CYP3A4 inhibitors such as cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in excessive accumulation of alprazolam.[53] This may result in exacerbation of its adverse effect profile.[54][55]

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.[56] Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[57]

Alcohol is one of the most important and common interactions. 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.[36] Combination of alprazolam with the herb kava can result in the development of a semi-comatose state.[58] Hypericum conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.[59][60][61]

### Overdose[edit]

File:Xanax 0.25, 0.5 1 mg.jpg
Xanax 0.25, 0.5 and 1 mg scored tablets
Main article: Benzodiazepine overdose

Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and any other drugs that have been taken.[62]

Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms:[43]

- Somnolence (sleepy state)
- Hypotension (low blood pressure)
- Hypoventilation (shallow breathing)
- Impaired motor functions
  - Dizziness
  - Impaired balance
  - Muscle weakness
  - Impaired or absent reflexes
- Fainting
- Coma
- Death (very rare)

In a study of deaths in Palm Beach County where the drug alprazolam was detected, approx. 50% of cases were attributed to poly-drug use (the combined toxicity of two or more drugs). The majority of these cases included either cocaine or methadone. Alprazolam alone caused only 1% of the deaths. These results indicate alprazolam has a very low incidence of causing death when taken alone.[63]

### Dependence and withdrawal[edit]

See also: Benzodiazepine dependence
See also: Benzodiazepine withdrawal syndrome

Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.[64]

Withdrawal and rebound symptoms occur commonly and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[8]

Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent.[64]

Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment.[65][66] There is a higher chance of withdrawal reactions 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 adjust to a lower-dosage regimen.[67][68]

In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users, and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.[69]

Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.[70]

Patients taking a dosing regimen larger than 4?mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety.

Delirium and seizures have been anecdotally reported in the medical literature from abrupt alprazolam discontinuation.[71][72][73]

In a 1983 study of patients who had taken long-acting benzodiazepines, e.g., clorazepate, for extended periods, the medications were stopped abruptly. Only 5% of patients who had been taking the drug for less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam ? a short-acting benzodiazepine ? taken for 8 weeks, 35% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.[74]

The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce fewer withdrawal reactions than alprazolam (Xanax), temazepam (Restoril/Normison), or lorazepam (Temesta/Ativan). Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms experienced during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines,[75][76] and method of discontinuation.[77]

## Detection in body fluids[edit]

Alprazolam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10?100 ?g/L in persons receiving the drug therapeutically, 100?300 ?g/L in those arrested for impaired driving and 300?2000 ?g/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with alprazolam, but confirmation and quantitation is usually performed using chromatographic techniques.[78][79][80]

## Pharmacology[edit]

Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine,[81][82] namely a benzodiazepine with a triazole ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine receptor site on the GABAA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. The GABAA receptor is made up of 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 with regard to benzodiazepines.[46][83] Benzodiazepines and in particular alprazolam causes a marked suppression of the hypothalamicpituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic[84] and amnesic.[5]

## Pharmacokinetics[edit]

Absorption

Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.

Distribution

In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism/Elimination

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (Cyp3A4), to two major metabolites in plasma: 4-hydroxyalprazolam and ?- hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Theirs half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and ?-hydroxyalprazolam relative to unchanged alprazolam coincentration were always less than 4%. The reported relative potencies in benzodiazepines receptor binding experiments and in animals models of induced seizure inhibition are 0.2 and 0.66, respectively, for 4-hydroxyalprazolam and ?-hydroxyalprazolam. Such low concentrations and lesser potencies of 4-hydroxyalprazolam and ?-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Alprazolam and its metabolites are excreted primarily in the urine.

## Chemistry[edit]

Alprazolam is a chemical analog of triazolam that differs by the absence of a chlorine atom in the o-position of the 6-phenyl ring. The same scheme that was used to make triazolam can be used to make alprazolam, with the exception that it begins with 2-amino-5-chlorobenzophenone.[85][86][87] However, a non-standard way of making alprazolam has been suggested, which comes from 2,6-dichloro-4-phenylquinoline, the reaction of which with hydrazine gives 6-chloro-2-hydrazino-4-phenylquinoline. Boiling this with triethyl orthoacetate in xylene leads to the heterocyclization into a triazole derivative. The resulting product undergoes oxidative cleavage using sodium periodate and ruthenium dioxide in an acetone?water system to give 2-[4-(3?-methyl-1,2,4-triazolo)]-5-chlorobenzophenone.[88][89][90] Oxymethylation of the last using formaldehyde and subsequent substitution of the resulting hydroxyl group by phosphorus tribromide,gives 2-[4-(3?-methyl-5?-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone. Substitution of the bromine atom with an amino group using ammonia and the spontaneous, intramolecular heterocyclization following that reaction gives alprazolam.

## History[edit]

Alprazolam was first released by Upjohn (now a part of Pfizer). It is covered under U.S. Patent 3,987,052, which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993. Alprazolam was released in 1981.[91] 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 new distinction the DSM-III created in the classification of anxiety disorders between generalized anxiety disorder (GAD) and panic disorder in order to market alprazolam specifically for the latter.[clarification needed] 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 the first group of patients treated by alprazolam as so impressed by its action that the company knew outright that the 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 United States Food and Drug Administration, they sold out and made a profit.[92][clarification needed]

Soon after its introduction a number of case reports were published in the medical literature of severe withdrawal symptoms, including psychoses, seizures and intense rebound anxiety, upon discontinuation of alprazolam.[75]

## Society and culture[edit]

### Recreational use[edit]

See also: Benzodiazepine misuse

There is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam; the pharmacological properties of alprazolam such as high affinity binding, high potency, being short-acting and having a rapid onset of action increase the abuse potential of alprazolam. The physical dependence and withdrawal syndrome of alprazolam also adds to the additive nature of alprazolam. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders.[10] Despite this, most prescribed alprazolam users do not misuse their medication, and the long-term use of benzodiazepines doesn't generally collaborate with the need for dose escalation.[93] However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise.[94] The New York Times also reported in 2011 that "The Centers for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008."[95]

Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States.[14][12] A large-scale nationwide U.S. government study conducted by SAMHSA found that, in the U.S., benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women use benzodiazepines recreationally as commonly. The report found that alprazolam is the most common benzodiazepine for recreational use followed by clonazepam, lorazepam, and diazepam. The number of emergency room visits due to benzodiazepines increased by 36% between 2004 and 2006.[14]

> Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals

> dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or in ED use

> between 2004 and 2006.[14]

At a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence[96][97] and people with borderline personality disorder.[98]

Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric ("bad trip") reactions to psychedelic drugs, such as LSD, and is often used in the "comedown" stages of stimulant use, such as amphetamine, in order to help relieve drug-induced agitation and insomnia, allowing sleep. Alprazolam may also be used in conjunction with other depressant drugs, such as alcohol, marijuana, heroin or other opiates, in an attempt to enhance the psychological effect of these drugs.

The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose which may result in fatal respiratory depression.[99][100]

A 1990 study claimed that diazepam has a higher misuse potential relative to other benzodiazepines, and that some data suggests that alprazolam and lorazepam resemble diazepam in this respect.[101]

Anecdotally injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization) and decay of muscle tissue (rhabdomyolysis).[102] Alprazolam is practically not soluble in water, when crushed in water it will not fully dissolve (40??g/ml of H2O at pH 7).[103] There have also been anecdotal reports of alprazolam being snorted.[104] Due to the low weight of a dose, alprazolam in one case was found to be distributed on blotter paper in a manner similar to LSD.[105]

### Availability[edit]

Alprazolam is available in English-speaking countries under the following brand names:[106]

- Alprax, Alprocontin, Alzam, Anzilum, Apo-Alpraz, Kalma, Niravam, Novo-Alprazol, Nu-Alpraz, Pacyl, Restyl, Tranax, Xycalm, Xanax, Zolam, Zopax

### Legal status[edit]

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.[107] Under the UK drug misuse classification system benzodiazepines are class C drugs (Schedule 4).[108] In the UK, alprazolam is not available on the NHS and can only be obtained on a private prescription.[109] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[110] In Ireland, alprazolam is a Schedule 4 medicine.[111] In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).[112] In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.

## References[edit]

1. ^ First DataBank (July 2008). "Xanax (Alprazolam) Clinical Pharmacology ? Prescription Drugs and Medications at RxList". RxList.
2. ^ First DataBank (July 2008). "Xanax XR (Alprazolam) Clinical Pharmacology ? Prescription Drugs and Medications at RxList". RxList.
3. ^ a b c Work Group on Panic Disorder (January 2009). "APA Practice Guideline for the Treatment of Patients With Panic Disorder, Second Edition". Retrieved 2009-12-07.
4. ^ a b c d e f FDA (2011-08-23). "FDA approved labeling for Xanax revision 08/23/2011" (pdf). Federal Drug Administration. p. 4. Retrieved 2011-09-14. "Anxiety Disorders ? XANAX Tablets (alprazolam) are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSMIII-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic... Panic Disorder ? XANAX is also indicated for the treatment of panic disorder, with or without agoraphobia... Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis without any apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient."
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12. ^ a b Galanter, M. (2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). American Psychiatric Publishing. p. 222. ISBN 978-1-58562-276-4.
13. ^ Langreth, Robert; Herper, Matthew. "The most prescribed drugs in the US". Forbes. Retrieved 9 February 2009.
14. ^ a b c d United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2006). "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits" (pdf). Substance Abuse and Mental Health Services Administration. Retrieved 13 February 2012.
15. ^ a b c "Alprazolam". The American Society of Health-System Pharmacists. Archived from the original on 15 May 2011. Retrieved 3 April 2011.
16. ^ "DEA Brief Benzodiazepines". Retrieved 1 October 2011. "Given the millions of prescriptions written for benzodiazepines (about 100 million in 1999), relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior."
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## External links[edit]

- U.S. National Library of Medicine: Drug Information Portal ? Alprazolam

Benzodiazepine derivatives
1,4-Benzodiazepines | Bromazepam Camazepam Carburazepam Chlordiazepoxide Cinazepam Cinolazepam Clonazepam Clorazepate Cyprazepam Delorazepam Demoxepam Devazepide * Diazepam Diclazepam Doxefazepam Elfazepam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Flubromazepam Fletazepam Fludiazepam Flunitrazepam Flurazepam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Iclazepam Ketazolam Lorazepam Lormetazepam Lufuradom * Meclonazepam Medazepam Menitrazepam Metaclazepam Motrazepam Nimetazepam Nitrazepam Nitrazepate Nordazepam Nortetrazepam Oxazepam Phenazepam Pinazepam Pivoxazepam Prazepam Proflazepam Quazepam QH-II-66 Reclazepam RO4491533 * Ro5-2904 Ro5-4864 * Sulazepam Temazepam Tetrazepam Tifluadom * Tolufazepam Tuclazepam Uldazepam
1,5-Benzodiazepines | Arfendazam Clobazam CP-1414S Lofendazam Triflubazam
2,3-Benzodiazepines * | Girisopam GYKI-52466 GYKI-52895 Nerisopam Talampanel Tofisopam
Triazolobenzodiazepines | Adinazolam Alprazolam Estazolam Flubromazolam Pyrazolam Triazolam
Imidazobenzodiazepines | Bretazenil Climazolam FG-8205 Flumazenil Imidazenil Iomazenil (123I) L-655,708 Loprazolam Midazolam PWZ-029 Remimazolam Ro15-4513 Ro48-6791 Ro48-8684 Ro4938581 Sarmazenil SH-053-R-CH3-2′F
Oxazolobenzodiazepines | Cloxazolam Flutazolam Haloxazolam Mexazolam Oxazolam
Thienodiazepines | Bentazepam Brotizolam Ciclotizolam Clotiazepam Etizolam JQ1 * Olanzapine *
Pyridodiazepines | Lopirazepam Zapizolam
Pyrazolodiazepines | Razobazam * Ripazepam Zolazepam Zomebazam Zometapine *
Pyrrolodiazepines | Premazepam
Tetrahydroisoquinobenzodiazepines | Clazolam
Benzodiazepine prodrugs | Avizafone Rilmazafone
* atypical activity profile (not GABAA receptor ligands)

Anxiolytics (N05B)
GABAA PAMs |
non-N05B | Alcohols (2M2B, Ethanol (beverage), Ethchlorvynol, Methylpentynol) Chlormezanone Etifoxine Inhalants Kavalactones (Kava) Skullcap Valerenic acid (Valerian)
Benzodiazepine | Adinazolam Alprazolam Bretazenil Bromazepam Camazepam Chlordiazepoxide Clobazam Clonazepam Clorazepate Clotiazepam Cloxazolam Diazepam# Ethyl Loflazepate Etizolam Fludiazepam Halazepam Imidazenil Ketazolam Lorazepam# Medazepam Nordazepam Oxazepam Pinazepam Prazepam
Carbamates | Difebarbamate Emylcamate Febarbamate Mebutamate Meprobamate (Carisoprodol, Tybamate) Phenprobamate Procymate
Nonbenzodiazepines | Abecarnil Adipiplon Alpidem CGS-8216 CGS-9896 CGS-13767 CGS-20625 Divaplon ELB-139 Fasiplon GBLD-345 Gedocarnil L-838,417 NS-2664 NS-2710 Ocinaplon Pagoclone Panadiplon Pipequaline RWJ-51204 SB-205,384 SL-651,498 Taniplon TP-003 TP-13 TPA-023 Y-23684 ZK-93423
Pyrazolopyridines | Cartazolate Etazolate ICI-190,622 Tracazolate
α2δ VDCC Blockers | Atagabalin Gabapentin Imagabalin PD-217,014 Pregabalin 4-methylpregabalin
5-HT1A Agonists | Azapirones: Buspirone Gepirone Tandospirone; Others: Flesinoxan Naluzotan Oxaflozane
H1 Antagonists | Diphenylmethanes: Captodiame Hydroxyzine; Others: Brompheniramine Chlorphenamine Pheniramine
CRH1 Antagonists | Antalarmin CP-154,526 Pexacerfont Pivagabine
NK2 Antagonists | GR-159,897 Saredutant Ibodutant
MCH1 antagonists | ATC-0175 SNAP-94847
mGluR2/3 Agonists | Biphenylindanone A DCG-IV Eglumegad HYDIA LY-379,268 LY-404,039
mGluR5 NAMs | Fenobam GRN-529 MPEP MTEP
TSPO agonists | DAA-1097 DAA-1106 Emapunil FGIN-127 FGIN-143
σ1 agonists | Afobazole BD1031 BD1052 L-687,384 Opipramol Pentoxyverine PRE-084 SA-4503 4-PPBP
Antidepressants | Clomipramine Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Lofepramine Maprotiline Moclobemide Nefazodone Paroxetine Phenelzine Sertraline Venlafaxine
Others | Benzoctamine Cannabidiol Carbetocin Clozapine Cycloserine Demoxytocin Emoxypine Kava Mephenoxalone Mepiprazole Oxanamide Oxytocin Periciazine Promoxolane Quetiapine Risperidone Tofisopam Tramadol Trimetozine Valproate WAY-267,464
#WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III
M: PSO/PSI | mepr | dsrd (o, p, m, p, a, d, s), sysi/epon, spvo | proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)