Jump to content

Alprazolam: Difference between revisions

This is a good article. Click here for more information.
From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
Mark Arsten (talk | contribs)
131,188 edits
m Reverted edits by JoshG1977 (talk) to last revision by Attaboy (HG)
No edit summary
Tag: Mobile edit
Line 57: Line 57:
'''Alprazolam''' {{IPAc-en|æ|l|'|p|r|æ|z|ə|l|æ|m}} (trade name '''Xanax'''), [[#Availability|available]] under other [[generic drug|generic]] names, is a short-acting [[anxiolytic]] of the [[benzodiazepine]] [[chemical classification|class]] of [[psychoactive drugs]]. Alprazolam, like other benzodiazepines, binds to specific sites on the [[GABAA|GABA<sub>A</sub>]] gamma-amino-butyric acid receptor. Alprazolam is commonly used and [[Food and Drug Administration (United States)|FDA approved]] for the medical treatment of [[panic disorder]], and [[anxiety disorder]]s, such as [[generalized anxiety disorder]] (GAD) or [[social anxiety disorder]] (SAD).<ref name=APAguide>{{cite book | doi = 10.1176/appi.books.9780890423905.154688 | title = APA Practice Guideline for the Treatment of Patients With Panic Disorder | edition = 2nd | author = Work Group on Panic Disorder | date = January 2009}}</ref><ref name=fdalabel082011/> Alprazolam is available for [[oral administration]] in [[Tablet (pharmacy)|compressed tablet]] (CT) and [[extended-release]] [[capsule (pharmacy)|capsule]] (XR) formulations. Alprazolam possesses [[anxiolytic]], [[sedative]], [[hypnotic]], [[skeletal muscle relaxant]], [[anticonvulsant]], and [[amnestic]] properties.<ref name=mandrioli>{{cite pmid|18855614}}</ref>
'''Alprazolam''' {{IPAc-en|æ|l|'|p|r|æ|z|ə|l|æ|m}} (trade name '''Xanax'''), [[#Availability|available]] under other [[generic drug|generic]] names, is a short-acting [[anxiolytic]] of the [[benzodiazepine]] [[chemical classification|class]] of [[psychoactive drugs]]. Alprazolam, like other benzodiazepines, binds to specific sites on the [[GABAA|GABA<sub>A</sub>]] gamma-amino-butyric acid receptor. Alprazolam is commonly used and [[Food and Drug Administration (United States)|FDA approved]] for the medical treatment of [[panic disorder]], and [[anxiety disorder]]s, such as [[generalized anxiety disorder]] (GAD) or [[social anxiety disorder]] (SAD).<ref name=APAguide>{{cite book | doi = 10.1176/appi.books.9780890423905.154688 | title = APA Practice Guideline for the Treatment of Patients With Panic Disorder | edition = 2nd | author = Work Group on Panic Disorder | date = January 2009}}</ref><ref name=fdalabel082011/> Alprazolam is available for [[oral administration]] in [[Tablet (pharmacy)|compressed tablet]] (CT) and [[extended-release]] [[capsule (pharmacy)|capsule]] (XR) formulations. Alprazolam possesses [[anxiolytic]], [[sedative]], [[hypnotic]], [[skeletal muscle relaxant]], [[anticonvulsant]], and [[amnestic]] properties.<ref name=mandrioli>{{cite pmid|18855614}}</ref>


Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour of using either in preparation for [[panic disorder]], and full peak effects are achieved in 1.5 and 1.6 hours respectively.<ref>{{cite pmid|17514187}}</ref><ref>{{cite pmid|6152055}}</ref> Peak benefits achieved for [[generalized anxiety disorder]] (GAD) may take up to a week.<ref name=Verster2004>{{Cite journal | last1 = Verster | first1 = J. C. | last2 = Volkerts | first2 = E. R. | title = Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature | journal = CNS Drug Reviews | year = 2004 | volume = 10 | issue = 1 | pages = 45–76 | doi = 10.1111/j.1527-3458.2004.tb00003.x | pmid = 14978513 | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00003.x/pdf | format = PDF}}</ref><ref>{{cite book |editor1-last=Tampi |editor1-first=R. R. |editor2-last=Muralee |editor2-first=S. |editor3-last=Weder |editor3-first=N. D. |editor4-last=Penland |editor4-first=H. | displayeditors = 4 | title = Comprehensive Review of Psychiatry | year = 2008 | publisher = Wolters Kluwer / Lippincott Williams & Wilkins Health | location = Philadelphia, PA | isbn = 978-0-7817-7176-4 | page = 226 | url = http://books.google.com/books?id=AANMupaUs6UC&pg=PA226 | accessdate = 2014-01-22}}</ref>
Alprazolam "Joshies" has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour of using either in preparation for [[panic disorder]], and full peak effects are achieved in 1.5 and 1.6 hours respectively.<ref>{{cite pmid|17514187}}</ref><ref>{{cite pmid|6152055}}</ref> Peak benefits achieved for [[generalized anxiety disorder]] (GAD) may take up to a week.<ref name=Verster2004>{{Cite journal | last1 = Verster | first1 = J. C. | last2 = Volkerts | first2 = E. R. | title = Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature | journal = CNS Drug Reviews | year = 2004 | volume = 10 | issue = 1 | pages = 45–76 | doi = 10.1111/j.1527-3458.2004.tb00003.x | pmid = 14978513 | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00003.x/pdf | format = PDF}}</ref><ref>{{cite book |editor1-last=Tampi |editor1-first=R. R. |editor2-last=Muralee |editor2-first=S. |editor3-last=Weder |editor3-first=N. D. |editor4-last=Penland |editor4-first=H. | displayeditors = 4 | title = Comprehensive Review of Psychiatry | year = 2008 | publisher = Wolters Kluwer / Lippincott Williams & Wilkins Health | location = Philadelphia, PA | isbn = 978-0-7817-7176-4 | page = 226 | url = http://books.google.com/books?id=AANMupaUs6UC&pg=PA226 | accessdate = 2014-01-22}}</ref>
[[Drug tolerance|Tolerance]] to the [[anxiolytic]]/antipanic effects is controversial with some authoritative sources reporting the development of tolerance,<ref name="pmid22391278"/> and others reporting no development of tolerance;<ref name=APAguide/><ref name=Pav10>{{cite book | last1 = Pavuluri | first1 = M. N. | last2 = Janicak | first2 = P. G. | last3 = Marder | first3 = S. R. | title = Principles and Practice of Psychopharmacotherapy | year = 2010 | publisher = Wolters Kluwer Health / Lippincott Williams & Wilkins | location = Philadelphia, PA | isbn = 978-1-60547-565-3 | page = 535 | url = http://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535 | edition = 5th | accessdate = 2014-01-22}}</ref> tolerance will however, develop to the [[sedative]]-[[hypnotic]] effects within a couple of days.<ref name=Pav10/> [[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.<ref name=Verster2004/><ref name=APPT/>
[[Drug tolerance|Tolerance]] to the [[anxiolytic]]/antipanic effects is controversial with some authoritative sources reporting the development of tolerance,<ref name="pmid22391278"/> and others reporting no development of tolerance;<ref name=APAguide/><ref name=Pav10>{{cite book | last1 = Pavuluri | first1 = M. N. | last2 = Janicak | first2 = P. G. | last3 = Marder | first3 = S. R. | title = Principles and Practice of Psychopharmacotherapy | year = 2010 | publisher = Wolters Kluwer Health / Lippincott Williams & Wilkins | location = Philadelphia, PA | isbn = 978-1-60547-565-3 | page = 535 | url = http://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535 | edition = 5th | accessdate = 2014-01-22}}</ref> tolerance will however, develop to the [[sedative]]-[[hypnotic]] effects within a couple of days.<ref name=Pav10/> [[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.<ref name=Verster2004/><ref name=APPT/>


Revision as of 21:23, 11 February 2014

Alprazolam
Clinical data
Trade namesXanax
AHFS/Drugs.comMonograph
MedlinePlusa684001
Dependence
liability		High
Routes of
administration		Oral, Sublingual
ATC code
Legal status
Legal status
  • AU: S8 (Controlled drug)
  • UK: POM (Prescription only)
  • US: WARNING[1]Schedule IV
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
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.044.849 Edit this at Wikidata
Chemical and physical data
FormulaC17H13ClN4
Molar mass308.765 g·mol−1
3D model (JSmol)
  • ClC1=CC2=C(C=C1)N3C(C)=NN=C3CN=C2C4=CC=CC=C4
  • 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 checkY
  • Key:VREFGVBLTWBCJP-UHFFFAOYSA-N checkY
  (verify)

Alprazolam /ælˈpræzəlæm/ (trade name Xanax), available under 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).[4][5] 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.[6]

Alprazolam "Joshies" has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour of using either in preparation for panic disorder, and full peak effects are achieved in 1.5 and 1.6 hours respectively.[7][8] Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week.[9][10] Tolerance to the anxiolytic/antipanic effects is controversial with some authoritative sources reporting the development of tolerance,[11] and others reporting no development of tolerance;[4][12] tolerance will however, develop to the sedative-hypnotic effects within a couple of days.[12] 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.[9][13]

Alprazolam is the most prescribed[14] and the most misused benzodiazepine on the U.S. retail market.[15] The potential for misuse 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[4] 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 misuse potential of alprazolam.[11][16] Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.[17] Alprazolam is classified as a schedule IV controlled substance by the U.S. Drug Enforcement Administration (DEA).

Medical uses

Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy.[16] The FDA label advises that the physician should periodically reassess the usefulness of the drug.[5]

Panic disorder

Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks.[5] 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.[11] 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.[5][18]

In the US alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia.[5] 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.[19]

Anxiety disorders

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.[5] However, the research into antidepressant properties of alprazolam is of poor quality and only assessed the short-term effects of alprazolam against depression.[20] In one study, some long term, high-dosage users of alprazolam developed reversible depression.[21] 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-IV-TR diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.[18][22][23]

Nausea due to chemotherapy

Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.[16]

Pregnancy and lactation

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.[24] Use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period[25] as well as neonatal flaccidity and respiratory problems.[26] 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.[27]

Benzodiazepines, including alprazolam, are known to be excreted in human milk.[28] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[29][30]

Contraindications

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.[31] 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).[23][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 until they know how it affects them.

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.[29]

Adverse effects

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:

Paradoxical reactions

Side effects from Alprazolam

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

Food and drug interactions

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

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]

In a study of deaths in Palm Beach County where the drug alprazolam was detected, approximately 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

See also: Benzodiazepine dependence and 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 commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[9]

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.[67]

Detection in body fluids

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 μg/L in persons receiving the drug therapeutically, 100–300 μg/L in those arrested for impaired driving and 300–2000 μg/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.[77][78][79]

Pharmacology

Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine,[80][81] 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][82] 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[83] and amnesic.[6]

Administration of alprazolam has been demonstrated to elicit an increase in striatal dopamine concentrations.[84]

Pharmacokinetics

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 α- hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Half-lives are similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration 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 α-hydroxyalprazolam. Such low concentrations and lesser potencies of 4-hydroxyalprazolam and α-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.

Forms of Alprazolam

Alprazolam regular release and orally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, 2 mg strength tablets.[85]

Alprazolam extended release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg strength tablets.

Alprazolam oral solutions are available as 0.5 mg/5 mL and as 1 mg/1 mL oral solutions.

  • Active ingredient: alprazolam
  • Inactive ingredients: microcrystalline cellulose, corn starch, docusate sodium, povidone, sodium starch glycollate, lactose monohydrate, magnesium stearate, colloidal silicon dioxide and sodium benzoate. In addition, the 0.25 mg tablet contains D&C Yellow No. 10 and the 0.5 mg tablet contains FD&C Yellow No. 6 and D&C Yellow No. 10

Chemistry

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.[86][87][88] 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.[89][90][91] 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

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.[92] The first approved indication was panic disorder. Alprazolam was originally perceived to have been a poor investment, as Upjohn management did not believe there to be a market for panic disorder-oriented anxiolytics. However, alprazolam soon proved itself in clinical phase, FDA-mandated trials. It became a blockbuster drug with two years of its original marketing in the US market. Today it is the most commonly prescribed benzodiazepine in the United States, and has been available as generic instant-release and extended-release tablets for years.

Alprazolam may also be indicated for the treatment of Generalized Anxiety Disorder, as well as for the treatment of anxiety conditions with co-morbid depression.[93] Alprazolam is also often prescribed with instances of hypersomnia and co-morbid sleep deficits.

Society and culture

Recreational use

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 addictive 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.[11] Despite this, most prescribed alprazolam users do not misuse their medication, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation.[94] 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.[95] 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."[96]

Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States.[13][15] 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 are equally likely to use benzodiazepines recreationally. 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.[15]

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.[15]

At a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence[97][98] and people with borderline personality disorder.[99]

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 the drug-induced agitation and insomnia in the "comedown" stages of stimulant use, such as amphetamine, 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.[100][101]

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.[102]

Anecdotally injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization) and decay of muscle tissue (rhabdomyolysis).[103] Alprazolam is practically not soluble in water, when crushed in water it will not fully dissolve (40 µg/ml of H2O at pH 7).[104] There have also been anecdotal reports of alprazolam being snorted.[105] 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.[106]

In Music

In the year 2000 the English rock band Duran Duran released an album named Pop Trash with a song named "Lady Xanax". The song's lyrics talk about a lady who can't socialize and is afraid, and at the end of the song this lady seems to fall asleep.

Availability

Alprazolam is available in English-speaking countries under the following brand names:[107]

  • Alprax, Alprocontin, Alzam,Alzolam, Anzilum, Apo-Alpraz, Kalma, Mylan-Alprazolam, Niravam, Novo-Alprazol, Nu-Alpraz, Pacyl, Restyl, Tranax, Trika, Xycalm, Xanax, Xanor, Zolam, Zopax, Helex.

As of December 2013—in anticipation of the rescheduling of alprazolam to Schedule 8 in Australia—Pfizer Australia announced they would be discontinuing the Xanax brand in Australia as it is no longer commercially viable.[108]

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.[109] Under the UK drug misuse classification system benzodiazepines are class C drugs (Schedule 4).[110] In the UK, alprazolam is not available on the NHS and can only be obtained on a private prescription.[111] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[112] In Ireland, alprazolam is a Schedule 4 medicine.[113] In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).[114] In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription. In Australia, alprazolam was originally a Schedule 4 (Prescription Only) medication; however, as of January 2014, it will become a Schedule 8 medication, subjecting it to more rigorous prescribing requirements.[115]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ "Xanax (Alprazolam) Clinical Pharmacology – Prescription Drugs and Medications". RxList. First DataBank. July 2008.
  3. ^ "Xanax XR (Alprazolam) Clinical Pharmacology – Prescription Drugs and Medications". RxList. First DataBank. July 2008.
  4. ^ a b c Work Group on Panic Disorder (January 2009). APA Practice Guideline for the Treatment of Patients With Panic Disorder (2nd ed.). doi:10.1176/appi.books.9780890423905.154688.
  5. ^ a b c d e f "FDA approved labeling for Xanax revision 08/23/2011" (PDF). Federal Drug Administration. 23 August 2011. p. 4. Retrieved 14 September 2011. 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.
  6. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18855614, please use {{cite journal}} with |pmid=18855614 instead.
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17514187, please use {{cite journal}} with |pmid=17514187 instead.
  8. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 6152055, please use {{cite journal}} with |pmid=6152055 instead.
  9. ^ a b c Verster, J. C.; Volkerts, E. R. (2004). "Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature" (PDF). CNS Drug Reviews. 10 (1): 45–76. doi:10.1111/j.1527-3458.2004.tb00003.x. PMID 14978513.
  10. ^ Tampi, R. R.; Muralee, S.; Weder, N. D.; Penland, H., eds. (2008). Comprehensive Review of Psychiatry. Philadelphia, PA: Wolters Kluwer / Lippincott Williams & Wilkins Health. p. 226. ISBN 978-0-7817-7176-4. Retrieved 22 January 2014. {{cite book}}: Unknown parameter |displayeditors= ignored (|display-editors= suggested) (help)
  11. ^ a b c d Moylan, S.; Giorlando, F.; Nordfjærn, T.; Berk, M. (2012). "The Role of Alprazolam for the Treatment of Panic Disorder in Australia" (PDF). The Australian and New Zealand Journal of Psychiatry. 46 (3): 212–224. doi:10.1177/0004867411432074. PMID 22391278.
  12. ^ a b Pavuluri, M. N.; Janicak, P. G.; Marder, S. R. (2010). Principles and Practice of Psychopharmacotherapy (5th ed.). Philadelphia, PA: Wolters Kluwer Health / Lippincott Williams & Wilkins. p. 535. ISBN 978-1-60547-565-3. Retrieved 22 January 2014.
  13. ^ 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. Retrieved 22 January 2014.
  14. ^ Langreth, Robert; Herper, Matthew (11 May 2010). "In Pictures: The Most Popular Prescription Drugs". Forbes.
  15. ^ a b c d "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits" (PDF). U.S. Department of Health and Human Services. Substance Abuse and Mental Health Services Administration. 2006. Retrieved 13 February 2012.
  16. ^ a b c "Alprazolam". The American Society of Health-System Pharmacists. Archived from the original on 15 May 2011. Retrieved 3 April 2011. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  17. ^ "DEA Brief Benzodiazepines". Archived from the original on 12 March 2009. 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.
  18. ^ a b "Xanax (Alprazolam) Clinical Pharmacology – Prescription Drugs and Medications at RxList". RxList. First DataBank. July 2008.
  19. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12516310, please use {{cite journal}} with |pmid=12516310 instead.
  20. ^ van Marwijk, H.; Allick, G.; Wegman, F.; Bax, A.; Riphagen, I. I. (2012). van Marwijk, Harm (ed.). "Alprazolam for depression". Cochrane Database Syst Rev. 7: CD007139. doi:10.1002/14651858.CD007139.pub2. PMID 22786504.
  21. ^ Lydiard, R. B.; Laraia, M. T.; Ballenger, J. C.; Howell, E. F. (May 1987). "Emergence of Depressive Symptoms in Patients Receiving Alprazolam for Panic Disorder". The American Journal of Psychiatry. 144 (5): 664–665. PMID 3578580.
  22. ^ "Xanax". Netdoctor.co.uk. NetDoctor. 1 October 2006. Archived from the original on 9 August 2007. Retrieved 2 August 2007. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  23. ^ a b "Alprazolam". British National Formulary. 2007. Retrieved 3 August 2007.
  24. ^ "Xanax (Alprazolam) Drug Information: Uses, Side Effects, Drug Interactions and Warnings". RxList.com. United States: RxList. July 2008. p. 4.
  25. ^ Iqbal, M. M.; Sobhan, T.; Ryals, T. (2002). "Effects of Commonly Used Benzodiazepines on the Fetus, the Neonate, and the Nursing Infant". Psychiatric Services. 53 (1): 39–49. doi:10.1176/appi.ps.53.1.39. PMID 11773648.
  26. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17453885, please use {{cite journal}} with |pmid=17453885 instead.
  27. ^ Einarson, A.; Selby, P.; Koren, G. (2001). "Abrupt Discontinuation of Psychotropic Drugs During Pregnancy: Fear of Teratogenic Risk and Impact of Counselling" (PDF). Journal of Psychiatry and Neuroscience. 26 (1): 44–48. PMC 1408034. PMID 11212593.
  28. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8527284, please use {{cite journal}} with |pmid=8527284 instead.
  29. ^ a b "Alprazolam – Oral (Xanax) Side Effects, Medical Uses, and Drug Interactions". Medicinenet.com. MedicineNet. July 2005. Archived from the original on 18 December 2008. Retrieved 7 December 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  30. ^ "Xanax (Alprazolam) Drug Information: Uses, Side Effects, Drug Interactions and Warnings". RxList.com. RxList. July 2008. p. 8. Archived from the original on 5 December 2008. Retrieved 7 December 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  31. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, A. A.; Vennat, B.; Llorca, P. M.; Eschalier, A. (2009). "Benzodiazepine Dependence: Focus on Withdrawal Syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  32. ^ a b Hori, A. (1998). "Pharmacotherapy for Personality Disorders". Psychiatry and Clinical Neurosciences. 52 (1): 13–19. doi:10.1111/j.1440-1819.1998.tb00967.x. PMID 9682928.
  33. ^ Gardner, D. L.; Cowdry, R. W. (1985). "Alprazolam-Induced Dyscontrol in Borderline Personality Disorder". American Journal of Psychiatry. 142 (1): 98–100. PMID 2857071.
  34. ^ "Alprazolam". mentalhealth.com. 2007. Retrieved 3 August 2007.
  35. ^ Kozená, L.; Frantik, E.; Horváth, M. (1995). "Vigilance Impairment after a Single Dose of Benzodiazepines". Psychopharmacology. 119 (1): 39–45. doi:10.1007/BF02246052. PMID 7675948.
  36. ^ a b c Michel, L.; Lang, J. P. (2003). "Benzodiazépines et passage à l'acte criminel". Encephale (in French). 29 (6): 479–485. PMID 15029082. Retrieved 9 April 2013. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help); Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  37. ^ "ALPRAZOLAM – ORAL (Xanax) side effects, medical uses, and drug interactions". Medicinenet.com. Archived from the original on 25 August 2007. Retrieved 2 August 2007. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  38. ^ Noyes, R.; DuPont, R. L.; Pecknold, J. C.; Rifkin, A.; Rubin, R. T.; Swinson, R. P.; Ballenger, J. C.; Burrows, G. D. (1988). "Alprazolam in Panic Disorder and Agoraphobia: Results from a Multicenter Trial. II. Patient Acceptance, Side Effects, and Safety". Archives of General Psychiatry. 45 (5): 423–428. doi:10.1001/archpsyc.1988.01800290037005. PMID 3358644. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  39. ^ "Complete Alprazolam Information". Drugs.com. Archived from the original on 5 August 2007. Retrieved 2 August 2007. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  40. ^ Elie, R.; Lamontagne, Y. (1984). "Alprazolam and Diazepam in the Treatment of Generalized Anxiety". Journal of Clinical Psychopharmacology. 4 (3): 125–129. doi:10.1097/00004714-198406000-00002. PMID 6145726.
  41. ^ Cassano, G. B.; Toni, C.; Petracca, A.; Deltito, J.; Benkert, O.; Curtis, G.; Hippius, H.; Maier, W.; Shera, D.; Klerman, G. (1994). "Adverse Effects Associated with the Short-term Treatment of Panic Disorder with Imipramine, Alprazolam or Placebo". European Neuropsychopharmacology. 4 (1): 47–53. doi:10.1016/0924-977X(94)90314-X. PMID 8204996. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  42. ^ Kravitz, H. M.; Fawcett, J.; Newman, A. J. (1993). "Alprazolam and Depression: A Review of Risks and Benefits". Journal of Clinical Psychiatry. 54 (Supplement): 78–84, discussion 85. PMID 8262892.
  43. ^ a b "Alprazolam Side Effects, Interactions and Information". Drugs.com. Archived from the original on 19 August 2007. Retrieved 2 August 2007. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  44. ^ a b Rawson, N. S.; Rawson, M. J. (1999). "Acute Adverse Event Signalling Scheme Using the Saskatchewan Administrative Health Care Utilization Datafiles: Results for Two Benzodiazepines". Canadian Journal of Clinical Pharmacology. 6 (3): 159–166. PMID 10495368.
  45. ^ a b "Alprazolam – Complete Medical Information Regarding This Treatment of Anxiety Disorders". Medicinenet.com. MedicineNet. Retrieved 2 August 2007.
  46. ^ a b Barbee, J. G. (1993). "Memory, Benzodiazepines, and Anxiety: Integration of Theoretical and Clinical Perspectives". The Journal of Clinical Psychiatry. 54 (Suppl): 86–97, discussion 98–101. PMID 8262893.
  47. ^ Rapaport, M.; Braff, D. L. (1985). "Alprazolam and Hostility". American Journal of Psychiatry. 142 (1): 146. PMID 2857070.
  48. ^ Béchir, M.; Schwegler, K.; Chenevard, R.; Binggeli, C.; Caduff, C.; Büchi, S.; Buddeberg, C.; Lüscher, T. F.; Noll, G. (2007). "Anxiolytic Therapy with Alprazolam Increases Muscle Sympathetic Activity in Patients with Panic Disorders". Autonomic Neuroscience. 134 (1–2): 69–73. doi:10.1016/j.autneu.2007.01.007. PMID 17363337. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  49. ^ Arana, G. W.; Pearlman, C.; Shader, R. I. (1985). "Alprazolam-Induced Mania: Two Clinical Cases". American Journal of Psychiatry. 142 (3): 368–369. PMID 2857534.
  50. ^ Strahan, A.; Rosenthal, J.; Kaswan, M.; Winston, A. (1985). "Three Case Reports of Acute Paroxysmal Excitement Associated with Alprazolam Treatment". American Journal of Psychiatry. 142 (7): 859–861. PMID 2861755.
  51. ^ Reddy, J.; Khanna, S.; Anand, U.; Banerjee, A. (1996). "Alprazolam-Induced Hypomania". Australia and New Zealand Journal of Psychiatry. 30 (4): 550–552. doi:10.3109/00048679609065031. PMID 8887708.
  52. ^ Otani, K. (2003). "Cytochrome P450 3A4 and Benzodiazepines". Seishin Shinkeigaku Zasshi (in Japanese). 105 (5): 631–642. PMID 12875231.
  53. ^ Dresser, G. K.; Spence, J. D.; Bailey, D. G. (2000). "Pharmacokinetic-Pharmacodynamic Consequences and Clinical Relevance of Cytochrome P450 3A4 Inhibition". Clinical Pharmacokinetics. 38 (1): 41–57. doi:10.2165/00003088-200038010-00003. PMID 10668858.
  54. ^ Greenblatt, D. J.; Wright, C. E. (1993). "Clinical Pharmacokinetics of Alprazolam. Therapeutic Implications". Clinical Pharmacokinetics. 24 (6): 453–471. doi:10.2165/00003088-199324060-00003. PMID 8513649.
  55. ^ Wang, J. S.; Chase, C. L. (2003). "Pharmacokinetics and Drug Interactions of the Sedative Hypnotics" (PDF). Psychopharmacological Bulletin. 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946. Archived from the original (PDF) on 9 July 2007.
  56. ^ "AD535DF9-6361-460D-9648-450A0A6F61CD.xml". {{cite journal}}: |contribution= ignored (help); Cite journal requires |journal= (help)
  57. ^ Back, D. J.; Orme, M. L. (1990). "Pharmacokinetic Drug Interactions with Oral Contraceptives". Clinical Pharmacokinetics. 18 (6): 472–484. doi:10.2165/00003088-199018060-00004. PMID 2191822.
  58. ^ Izzo, A. A.; Ernst, E. (2001). "Interactions between Herbal Medicines and Prescribed Drugs: A Systematic Review". Drugs. 61 (15): 2163–2175. doi:10.2165/00003495-200161150-00002. PMID 11772128.
  59. ^ Izzo, A. A. (2004). "Drug Interactions with St. John's Wort (Hypericum perforatum): A Review of the Clinical Evidence". International Journal of Clinical Pharmacology and Therapeutics. 42 (3): 139–148. doi:10.5414/CPP42139. PMID 15049433.
  60. ^ Madabushi, R.; Frank, B.; Drewelow, B.; Derendorf, H.; Butterweck, V. (2006). "Hyperforin in St. John's Wort Drug Interactions". European Journal of Clinical Pharmacology. 62 (3): 225–233. doi:10.1007/s00228-006-0096-0. PMID 16477470.
  61. ^ Izzo, A. A.; Ernst, E. (2009). "Interactions between Herbal Medicines and Prescribed Drugs: An Updated Systematic Review". Drugs. 69 (13): 1777–1798. doi:10.2165/11317010-000000000-00000. PMID 19719333.
  62. ^ Isbister, G. K.; O'Regan, L.; Sibbritt, D.; Whyte, I. M. (2004). "Alprazolam is Relatively more Toxic than other Benzodiazepines in Overdose". British Journal of Clinical Pharmacology. 58 (1): 88–95. doi:10.1111/j.1365-2125.2004.02089.x. PMC 1884537. PMID 15206998.
  63. ^ Wolf, B. C.; Lavezzi, W. A.; Sullivan, L. M.; Middleberg, R. A.; Flannagan, L. M. (2005). "Alprazolam-Related Deaths in Palm Beach County". American Journal of Forensic Medicine and Pathology. 26 (1): 24–27. doi:10.1097/01.paf.0000153994.95642.c1. PMID 15725773.
  64. ^ a b Stahl, S. (1996). Essential Pharmacology: Neuroscientific Basis and Practical Applications. Cambridge: Cambridge University Press. ISBN 0-521-42620-0.[page needed]
  65. ^ Juergens, S. M.; Morse, R. M. (1988). "Alprazolam Dependence in seven Patients". The American Journal of Psychiatry. 145 (5): 625–627. PMID 3258735.
  66. ^ Klein, E. (2002). "The Role of Extended-Release Benzodiazepines in the Treatment of Anxiety: A Risk-Benefit Evaluation with a Focus on Extended-Release Alprazolam". The Journal of Clinical Psychiatry. 63 (Suppl 14): 27–33. PMID 12562116.
  67. ^ a b Ashton, Heather (August 2002). "The Ashton Manual – Benzodiazepines: How They Work and How to Withdraw". Benzo.org.uk. Retrieved 31 October 2008.
  68. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 7966502, please use {{cite journal}} with |pmid=7966502 instead.
  69. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1479048, please use {{cite journal}} with |pmid=1479048 instead.
  70. ^ Fyer, A. J.; Liebowitz, M. R.; Gorman, J. M.; Campeas, R.; Levin, A.; Davies, S. O.; Goetz, D.; Klein, D. F. (1987). "Discontinuation of Alprazolam Treatment in Panic Patients". American Journal of Psychiatry. 144 (3): 303–308. PMID 3826428. Retrieved 10 December 2008. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  71. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 6150649, please use {{cite journal}} with |pmid=6150649 instead.
  72. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 2867122, please use {{cite journal}} with |pmid=2867122 instead.
  73. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 6141159, please use {{cite journal}} with |pmid=6141159 instead.
  74. ^ Schatzberg, A.; DeBattista, C. (2003). Manual of Clinical Psychopharmacology. Washington, DC: American Psychiatric Pub. p. 391. ISBN 1-58562-209-5. Retrieved 22 January 2014.
  75. ^ Wolf, B.; Griffiths, R. R. (1991). "Physical Dependence on Benzodiazepines: Differences Within the Class". Drug and Alcohol Dependence. 29 (2): 153–156. doi:10.1016/0376-8716(91)90044-Y. PMID 1686752.
  76. ^ Higgitt, A.; Fonagy, P.; Lader, M. (1988). "The Natural History of Tolerance to the Benzodiazepines". Psychological Medicine. Monograph Supplement. 13: 1–55. doi:10.1017/S0264180100000412. PMID 2908516.
  77. ^ Jones, A. W.; Holmgren, A.; Kugelberg, F. C. (2007). "Concentrations of Scheduled Prescription Drugs in Blood of Impaired Drivers: Considerations for Interpreting the Results". Therapeutic Drug Monitoring. 29 (2): 248–260. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081.
  78. ^ Fraser, A. D.; Bryan, W. (1991). "Evaluation of the Abbott ADx and TDx Serum Benzodiazepine Immunoassays for Analysis of Alprazolam". Journal of Analytic Toxicology. 15 (2): 63–65. doi:10.1093/jat/15.2.63. PMID 1675703.
  79. ^ Baselt, R. (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 45–48. ISBN 978-0-9626523-8-7.
  80. ^ Skelton, K. H.; Nemeroff, C. B.; Owens, M. J. (2004). "Spontaneous Withdrawal from the Triazolobenzodiazepine Alprazolam Increases Cortical Corticotropin-Releasing Factor mRNA Expression". Journal of Neuroscience. 24 (42): 9303–9312. doi:10.1523/JNEUROSCI.1737-04.2004. PMID 15496666.
  81. ^ Chouinard, G. (2004). "Issues in the Clinical Use of Benzodiazepines: Potency, Withdrawal, and Rebound". Journal of Clinical Psychiatry. 65 (Suppl 5): 7–12. PMID 15078112.
  82. ^ White, G.; Gurley, D. A. (1995). "α Subunits Influence Zn Block of γ2 Containing GABAA Receptor Currents". NeuroReport. 6 (3): 461–464. doi:10.1097/00001756-199502000-00014. PMID 7766843.
  83. ^ Arvat, E.; Giordano, R.; Grottoli, S.; Ghigo, E. (2002). "Benzodiazepines and Anterior Pituitary Function". Journal of Endocrinological Investigation. 25 (8): 735–747. PMID 12240908.
  84. ^ Bentué-Ferrer, D.; Reymann, J. M.; Tribut, O.; Allain, H.; Vasar, E.; Bourin, M. (2001). "Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 11 (1): 41–50. doi:10.1016/S0924-977X(00)00137-1. PMID 11226811.
  85. ^ "Alprazolam Dosage, Uses, Overdose Info and More". RXwiki.com. 18 November 2013. Retrieved 22 January 2014.[unreliable source?] ( Page will play audio when loaded)
  86. ^ US patent 3987052, Jackson, H.B. 
  87. ^ DE 2012190, Jackson, H.B. 
  88. ^ Hester, J. B. Jr.; Duchamp, D. J.; Chidester, C. G. (1971). "A Synthetic Approach to New 1,4-Benzodiazepine Derivatives". Tetrahedron Letters. 12 (20): 1609–1612. doi:10.1016/S0040-4039(01)87414-1.
  89. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1021/jm00222a035, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1021/jm00222a035 instead.
  90. ^ US patent 3709898, Hester, J. 
  91. ^ US patent 3781289, Hester, J. 
  92. ^ Walker, S. (1996). A Dose of Sanity: Mind, Medicine, and Misdiagnosis. New York: John Wiley & Sons. pp. 64–65. ISBN 978-0-471-19262-6.
  93. ^ "Xanax (Alprazolam) Drug Information: Indications, Dosage and How Supplied – Prescribing Information". Rxlist.com. RxList. Retrieved 20 September 2013.
  94. ^ Soumerai, S. B.; Simoni-Wastila, L.; Singer, C.; Mah, C.; Gao, X.; Salzman, C.; Ross-Degnan, D. (2003). "Lack of Relationship between Long-Term Use of Benzodiazepines and Escalation to High Dosages". Psychiatric Services. 54 (7): 1006–1011. doi:10.1176/appi.ps.54.7.1006. PMID 12851438. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  95. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18295321, please use {{cite journal}} with |pmid= 18295321 instead.
  96. ^ Goodnough, Abby (14 September 2011). "Abuse of Xanax Leads a Clinic to Halt Supply". New York Times.
  97. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 6151647, please use {{cite journal}} with |pmid=6151647 instead.
  98. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 3417618, please use {{cite journal}} with |pmid=3417618 instead.
  99. ^ Vorma, H.; Naukkarinen, H. H.; Sarna, S. J.; Kuoppasalmi, K. I. (2005). "Predictors of Benzodiazepine Discontinuation in Subjects Manifesting Complicated Dependence". Substance Use & Misuse. 40 (4): 499–510. doi:10.1081/JA-200052433. PMID 15830732.
  100. ^ Walker, B. M.; Ettenberg, A. (2003). "The Effects of Alprazolam on Conditioned Place Preferences Produced by Intravenous Heroin". Pharmacology, Biochemistry, and Behavior. 75 (1): 75–80. doi:10.1016/S0091-3057(03)00043-1. PMID 12759115.
  101. ^ "OSAM-O-GRAM Highlights of Statewide Drug Use Trends" (PDF). Ohio, US: Wright State University and the University of Akron. January 2008. Retrieved 10 December 2008.
  102. ^ Griffiths, R. R.; Wolf, B. (1990). "Relative Abuse Liability of Different Benzodiazepines in Drug Abusers". Journal of Clinical Psychopharmacology. 10 (4): 237–243. doi:10.1097/00004714-199008000-00002. PMID 1981067.
  103. ^ Wang, E. C.; Chew, F. S. (2006). "MR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis" (PDF). Radiology Case Reports. 1 (3). doi:10.2484/rcr.v1i3.33.
  104. ^ "DB00404 (Alprazolam)". Canada: DrugBank. 26 June 2008. Archived from the original on 6 July 2011. Retrieved 12 July 2011. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  105. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1684083, please use {{cite journal}} with |pmid=1684083 instead.
  106. ^ "INTELLIGENCE ALERT – XANAX BLOTTER PAPER IN BARTLESVILLE, OKLAHOMA" (Microgram Bulletin). US DEA. May 2008. Archived from the original on 21 May 2008.
  107. ^ "Benzodiazepine Names". Non-benzodiazepines.org.uk. Archived from the original on 8 December 2008. Retrieved 31 October 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  108. ^ "Discontinuation of Xanax" (PDF). Pfizer Australia. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  109. ^ "DEA, Drug Scheduling". DEA. Archived from the original on 4 November 2008. Retrieved 31 October 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  110. ^ "Misuse of Drugs Act 1971 (c. 38)". The UK Statute Law database. 1991.
  111. ^ British Medical Association, Royal Pharmaceutical Society of Great Britain (September 2010). "4.1.2: Anxiolytics". British National Formulary (BNF 60). United Kingdom: BMJ Group and RPS Publishing. p. 212. ISBN 978-0-85369-931-6.
  112. ^ "List of Psychotropic Substances under International Control" (PDF). Incb.org. International Narcotics Control Board. August 2003. Archived from the original (PDF) on 17 December 2008. Retrieved 7 December 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  113. ^ "Misuse Of Drugs (Amendment) Regulations". Irish Statute Book. Office of the Attorney General. 1993.
  114. ^ "Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika" (PDF) (in Swedish). Sweden: Läkemedelsverket. October 2011. {{cite web}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  115. ^ "Alprazolam to be rescheduled from next year". 2013. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
Wikimedia Commons has media related to Alprazolam.

Retrieved from "https://en.wikipedia.org/w/index.php?title=Alprazolam&oldid=595037503"