Alprazolam

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Alprazolam
150px
150px
Systematic (IUPAC) name
8-chloro-1-methyl-6-phenyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Clinical data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80–90%
Metabolism Hepatic, via Cytochrome P450 3A4
Biological half-life Immediate release: 11.2 hours;[1] Extended release: 10.7–15.8 hours[2]
Excretion Renal
Identifiers
CAS Number 28981-97-7
ATC code N05BA12 (WHO)
PubChem CID 2118
DrugBank APRD00280
ChemSpider 2034
Chemical data
Formula C17H13ClN4
Molar mass 308.765[[Script error: No such module "String".]]
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Alprazolam (trade name Xanax, among others) is a potent short-acting drug of the benzodiazepine class. It is primarily used to treat moderate to severe anxiety disorders (e.g., social anxiety disorder) and panic attacks, and is used as an adjunctive treatment for anxiety associated with moderate depression. It is available in an instant release and an extended-release (Xanax XR) preparation, both of which are available under several generic names. Alprazolam possesses anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.[3]

Alprazolam has a fast onset of symptom relief (within the first week). It is the most commonly misused benzodiazepine; however, the majority of prescribed users do not develop a substance use disorder.[4][5] Tolerance to the therapeutic effects of alprazolam is controversial with one view being that alprazolam is ineffective with long term use[6] and the other view being that tolerance to the therapeutic effects does not occur.[7] A physical dependence commonly occurs as a result of alprazolam treatment, typified by a withdrawal and rebound symptoms necessitating a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[4] Withdrawal symptoms similar in character to those noted with sedative-hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include anxiety, abdominal pain, muscle cramps, vomiting, depression, sweating, tremors and in very rare cases suicidal ideation or suicide itself.[8]

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 October 29, 1969, granted on October 19, 1976 and expired in September 1993. Alprazolam was released in 1981.[9][10] 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. Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective.

However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and responsive to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder would both cover new diagnostic territory and emphasize the unique potency of this drug. Sheehan describes that the first group of patients treated by alprazolam was so impressed by its action that 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.[11]

Alprazolam has an exceptional history insofar as soon after its introduction a number of case reports were published in the medical literature of severe withdrawal symptom-related case reports of psychoses, seizures, and intense rebound anxiety upon discontinuation of alprazolam.[12] Several studies found that initial treatment of panic disorder with alprazolam was significantly superior but after 8 weeks of use alprazolam lost its effectiveness and was no more effective than placebo. It was found that behavioural therapy and the drug imipramine however, proved superior to both placebo and alprazolam. It has been argued that placebo is superior than alprazolam after 8 weeks of use due to lack of rebound withdrawal effects and side effects. Controversy exists in that there are allegations that the drug manufacturer suppressed these negative findings regarding lack of sustained efficacy.[13][14]

Indications

File:Xanax.jpg
Xanax 2 mg tri-score tablets (AU)

The main medical uses for alprazolam include:

Panic disorder

Alprazolam is FDA-approved for the short-term treatment (up to 8 weeks) of panic disorder, with or without agoraphobia. Alprazolam is very effective in the short-term symptomatic relief of moderate to severe anxiety, essential tremor, and panic attacks. Physicians that elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks' use, as tolerance to alprazolam's effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation.[15] The physician should periodically reassess the usefulness of the drug for the individual patient.[16] Alprazolam is recommended for treatment resistant cases of panic disorder where there is no history of tolerance or dependence.[17]

Anxiety disorders

Alprazolam is indicated 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.[16] Alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.[18][19]

Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence that it has antidepressant effects in treating clinical depression in outpatient settings; evidence for inpatients is lacking.[20] The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors.[21] Other benzodiazepines are not known to have antidepressant activity.[22][23] Studies show that any antidepressant action of alprazolam is questionable and generally weak in comparison to those of antidepressant medications.[24][25][26][27] In contrast, while alprazolam in acute or short-term treatment may have some antidepressant properties, there is evidence that up to a third of long-term users of alprazolam may develop depression.[28]

Side effects

Although the side-effect profile of alprazolam is, in general, benign, side-effects may occur in some patients and are more likely the higher the dosage taken. Some side-effects may disappear with continued treatment. If signs of an allergic reaction occur - such as hives; difficulty breathing; swelling of face, lips, tongue, or throat - medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear: yellowing of the skin or eyes. Other side-effects that may occur are as follows:

Paradoxical reactions

Although unusual, if the following paradoxical reactions occur, the prescribing physician or other healthcare professional should be alerted and the medication gradually discontinued:

Physical dependence and withdrawal

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, GABAnergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.[49]

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.[49]

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.[50][51] 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.[52][53][54]

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.[55]

If a patient feels the need to end treatment with alprazolam, he/she should consult his/her physician before discontinuing the medication. Some common symptoms of alprazolam discontinuation include tachycardia, dysphoria, dry mouth, loss of appetite, insomnia, anxiety, dizziness, tremors, nausea, cramps, vomiting, diarrhea, panic attacks, mood swings, heart palpitations, memory loss. Less common and more severe reactions can occur, including hallucinations, seizures or fever[56]

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. Other withdrawal effects reported from discontinuing alprazolam therapy include homicidal ideation (very rare), rage reactions, hyperalertness, vivid dreams, and intrusive thoughts.[57] Grand mal seizures have occurred after abrupt withdrawal after only short-term use. Therefore, even short-term users of alprazolam should taper off of their medication slowly to avoid serious withdrawal reactions including seizures.[58][59]

Alprazolam should never be abruptly stopped if taken regularly for any length of time because severe withdrawal symptoms may occur. Severe psychosis and seizures have been reported in the medical literature from abrupt alprazolam discontinuation,[60][61] and one death occurred from withdrawal-related seizures after gradual dose reduction.[61]

In a 1983 study of patients that had taken long-acting benzodiazepines, e.g., clorazepate, for extended periods, the medications were stopped abruptly under double-blind conditions (that is, patients were receiving either placebo or the same drug they had been taking). Only 5% of patients that had been taking the drug for less than 8 months demonstrated withdrawal symptoms, but 43% of those that had been taking them for more than 8 months did, whereas, 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.[62]

The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce fewer withdrawal reactions than alprazolam (Xanax) 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/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), use of other short-acting, high-potency benzodiazepines[12][63] and method of discontinuation.[64]

Contraindications

Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals.[65] 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).[66][67][68][69]

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[70] It should be considered that the child born of a mother receiving benzodiazepines may be at risk of developing withdrawal reactions during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers that have been receiving benzodiazepines.[71]

Benzodiazepines, including alprazolam, are known to be excreted in human milk.[72] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[73][74] As a general rule, nursing should not be undertaken by mothers who use alprazolam.

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.[74]

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.[75] People driving or conducting activities that require vigilance should exercise caution in using alprazolam or any other depressant.

Pregnancy and lactation

Benzodiazepines cross the placenta and enter into the fetus and also penetrate into breast milk. The use of benzodiazepines during pregnancy or lactation should be weighed against the potential risks. Alprazolam should not be used during pregnancy and lactation as it is believed to be associated with congenital abnormalities. In general benzodiazepines should not be used during pregnancy. If a benzodiazepine is needed during pregnancy diazepam or chlordiazepoxide are recommended as these benzodiazepines have a better safety profile than alprazolam. Possible adverse effects to the fetus include abortion, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Use in the last trimester may cause fetal drug dependence and withdrawal symptoms.[76] However, in long-term users of benzodiazepines or antidepressants abrupt discontinuation due to concerns of teratogenic effects of the medications is more likely to do harm than good. Abrupt withdrawal has a high risk of causing extreme withdrawal symptoms including suicidal ideation and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines. In general physicians are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.[77]

Pharmacology

Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine,[78][79] that is, a benzodiazepine with a triazole ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine 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 from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, what is significant, different activities with regard to benzodiazepines.[38][80] 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[81] and amnesics.[82]

Pharmacokinetics

Alprazolam is readily absorbed from the gastrointestinal tract with a bioavailability of 80–100%. The peak plasma concentration is achieved in 1–2 hours. Most of the drug is bound to plasma protein, mainly serum albumin. Alprazolam is hydroxylated in the liver to α-hydroxyalprazolam, which is also pharmacologically active but much less so than the parent compound. This and other metabolites are later excreted in urine as glucuronides. Some of the drug is also excreted in unchanged form. The elderly clear alprazolam more slowly than younger adults.[83]

Food and drug interactions

Alprazolam is primarily metabolised via CYP3A4.[84] Combining CYP3A4 inhibitors with alprazolam can lead to profound sedating effects.[85] Cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir all interact with alprazolam leading to a delayed clearance of alprazolam, which may result in excessive accumulation of alprazolam. This may result in excessive sedation and other adverse effects associated with excessive intake of alprazolam.[83][86]

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.[87] Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[88]

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.[31] Combination of alprazolam with the herb kava can result in the development of a semi-comatose state.[89] Hypericum conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.[90][91][92]

Recreational use

See also: Benzodiazepine drug misuse
File:Xanax2mg.jpg
Sandoz generic 2 mg alprazolam tablets

Alprazolam has a relatively high potential for recreational use[93] and is the most commonly misused benzodiazepine.[5] Injection of alprazolam, though extremely rare, is considered especially dangerous by medical professionals[94] because, when crushed in water it will not fully dissolve (40 µg/ml of H2O at pH 7, and 12 mg/mL at pH 1.2[95]), potentially causing severe damage to arteries if not filtered properly. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, has the potential to cause a serious, and potentially fatal, overdose. Alprazolam may also be insufflated.[96] Snorting alprazolam is highly inefficient, as it is insoluble in water and does not readily cross the nasal membranes, resulting in reduced bioavailability. However, long-term use of benzodiazepines does not usually result in notable dose escalation, and most prescribed alprazolam users do not use their medication recreationally.[97]

Alprazolam is sometimes used with other recreational drugs to relieve the panic or distress of dysphoric reactions to psychedelics such as LSD, and also to promote sleep in the "come-down" period following use of recreational drugs with stimulant or insomniac properties (such as LSD, cocaine, amphetamine and other related amphetamines, DXM, and MDMA). It is also often used in conjunction with marijuana or heroin to potentiate the relaxing effect.[98][99][100][101][102] 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.[103]

A large-scale nationwide USA government study conducted by SAMHSA found that, in the USA, benzodiazepines are recreationally the most frequently-used pharmaceutical due to their widespread availability, with 35% of drug-related visits to the Emergency Department involving them. Benzodiazepines are more commonly used recreationally than opioid pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly used recreationally than benzodiazepines; however, benzodiazepines remain in Schedule IV of the Controlled Substances Act, whereas opioids are much more strictly controlled due to their higher abuse potential. Men use benzodiazepines recreationally as commonly as women. The report found that alprazolam is the most common benzodiazepine for recreational use followed by clonazepam, lorazepam, and diazepam.[8]

Patients at a high risk for misuse and addiction

At a particularly high risk for misuse and dependence are patients with a history of alcoholism (including a family history of alcoholism) or drug abuse and/or dependence[104][105][106][107][108] and patients with borderline personality disorder.[109]

Overdose

Main article: Benzodiazepine overdose

Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Alprazolam is significantly more toxic in overdose having higher rates of fatalities compared to other benzodiazepines. A study in New Zealand found that alprazolam is almost 8 times more likely to result in death in overdose than other sedative hypnotics as a group, with higher rates of intensive-care unit admissions and mechanical ventilation. Combined overdose with tricyclic antidepressants, alcohol, or opiates, or overdoses of alprazolam in the elderly, significantly increases the likelihood for severe toxicity and possible fatality.[110] Alprazolam (Xanax) overdose reflect the central nervous system depression of the brain and may include one or more of the following symptoms:[34]

About 50% of the cases of death involving alprazolam were attributed to combined drug toxicity of alprazolam and another drug, most often cocaine and methadone. Only 1% of such deaths were attributed to alprazolam alone.[111][112]

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.[113][114][115]

Availability

Alprazolam instant release (IR) is available in 0.25 mg, 0.5 mg, 1 mg and 2 mg strength regular and orally disintegrating tablets.[116] Alprazolam Extended Release (XR) is available in 0.5 mg, 1 mg, 2 mg, and 3 mg strength oral.

Alprazolam is available in English-speaking countries under the following brand names:[117]

  • Alganax
  • Alzolam
  • Alprax
  • Alprox
  • Alzam
  • Anxirid
  • Apo-Alpraz
  • Calmax
  • Gerax
  • Helex
  • Kalma
  • Nervin
  • Niravam
  • Novo-Alprazol
  • Nu-Alpraz
  • Tafil
  • Texidep
  • Trika
  • Xanax
  • Xanor
  • Zamhexal
  • Zopax

Legal status

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.[118] Under the UK drug misuse classification system benzodiazepines are class C drugs;[119] alprazolam itself is not available on the NHS and can only be obtained on private prescription.[120] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[121] In Ireland, alprazolam is a Schedule 4 medicine.[122] In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).[123] In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.

See also

References

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Use <references />, or <references group="..." />
Benzodiazepine derivatives (N05BA, N05CD)
1,4-Benzodiazepines

Bromazepam · Camazepam · Carburazepam · Chlordiazepoxide · Cinolazepam · Clonazepam · Clorazepate · Cyprazepam · Delorazepam · Demoxepam · Devazepide* · Diazepam · Doxefazepam · Elfazepam · Ethyl carfluzepate · Ethyl dirazepate · Ethyl loflazepate · Fletazepam · Fludiazepam · Flunitrazepam · Flurazepam · Flutemazepam · Flutoprazepam · Fosazepam · Gidazepam · Halazepam · Iclazepam · Ketazolam · Lorazepam · Lormetazepam · Meclonazepam · Medazepam · Menitrazepam · Metaclazepam · Motrazepam · Nimetazepam · Nitrazepam · Nitrazepate · Nordazepam · Nortetrazepam · Oxazepam · Phenazepam · Pinazepam · Pivoxazepam · Prazepam · Proflazepam · Quazepam · QH-II-66 · Reclazepam · Ro5-2904 · Sulazepam · Temazepam · Tetrazepam · Tifluadom* · Tolufazepam · Tuclazepam · Uldazepam

1,5-Benzodiazepines
2,3-Benzodiazepines *
Triazolobenzodiazepines

Adinazolam · Alprazolam · Estazolam · Flubromazolam · Triazolam

Imidazobenzodiazepines
Oxazolobenzodiazepines
Thienodiazepines
Pyridodiazepines
Pyrazolodiazepines
Pyrrolodiazepines
Tetrahydroisoquinobenzodiazepines
Benzodiazepine prodrugs
 * atypical activity profile (not GABAA receptor ligands)
GABAA PAMs
Others
α2δ VDCC Blockers
5-HT1A Agonists
Azapirones: Buspirone • Gepirone • Tandospirone; Others: Flesinoxan • Oxaflozane
H1 Antagonists
Diphenylmethanes: Captodiame • Hydroxyzine; Others: Brompheniramine • Chlorpheniramine • Pheniramine
CRH1 Antagonists
NK2 Antagonists
MCH1 antagonists
mGluR2/3 Agonists
mGluR5 NAMs
TSPO agonists
σ1 agonists
Others

M: PSO/PSI

dsrd (o, p, m, p, a, d, s), sysi/epon, spvo

proc, drug(N5A/5B/5C/6A/6B/6D)

External links

bg:Алпразолам cs:Alprazolam de:Alprazolam es:Alprazolam fa:آلپرازولام fr:Alprazolam gl:Alprazolam ko:알프라졸람 it:Alprazolam he:אלפראזולאם hu:Alprazolám nl:Alprazolam ja:アルプラゾラム no:Alprazolam pl:Alprazolam pt:Alprazolam ru:Алпразолам sl:Alprazolam fi:Alpratsolaami sv:Alprazolam ta:அல்ப்பிரசோலம் tr:Alprazolam

zh:阿普唑仑
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