Alprazolam

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Alprazolam
Systematic (IUPAC) name
8-chloro-1-methyl-6-phenyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Identifiers
CAS number 28981-97-7
ATC code N05BA12
PubChem 2118
DrugBank APRD00280
ChemSpider 2034
Chemical data
Formula C17H13ClN4 
Mol. mass 308.765
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
Therapeutic considerations
Pregnancy cat.

D(US)
Legal status

Schedule IV(US)
Routes Oral

Alprazolam, also known under the trade names Xanax, Xanor and Niravam, is a short-acting drug of the benzodiazepine class used to treat moderate to severe anxiety disorders, panic attacks, and as an adjunctive treatment for anxiety associated with moderate depression. It is also available in an extended release form, Xanax XR. Both forms are now available generically. Alprazolam possesses anxiolytic, sedative, hypnotic, anticonvulsant and muscle relaxant properties.[3]

Alprazolam may be habit-forming and long term use and/or abuse may cause a physical dependence to develop along with withdrawal reactions during abrupt or rapid discontinuation. In the USA, alprazolam is a schedule IV controlled substance under the Controlled Substances Act.[4]

Contents

[edit] History

Alprazolam was first synthesized by Upjohn (now a part of Pfizer). It is covered under U.S. Patent 3,987,052 , which was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. Alprazolam was released in 1981.[5][6] 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 they knew outright—this drug was going to be a hit. A few of those patients actually pooled their money and purchased stock in Upjohn. Several months later, when alprazolam was approved by the FDA, they sold out and made a profit.[7]

Alprazolam has an exceptional history insofar as soon after its introduction a large 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.[8]

[edit] Pharmacology

Alprazolam is classed as a high potency benzodiazepine and is a triazolobenzodiazepine,[9][10] 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 produces 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 importantly, different activities in regards to benzodiazepines.[11][12]

[edit] 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.[13]

[edit] Indications

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 treating moderate to severe anxiety, essential tremor and panic attacks. Physicians who elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks use as tolerance to alprazolam's effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation.[14] However, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.[15]

Anxiety disorder

Alprazolam is indicated for the management of anxiety disorder (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.[15] Alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety. Alprazolam should only very rarely be used for longer periods of time – the body becomes rapidly tolerant to the drug's effects, which may translate to decreased efficacy.[16][17]

Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence for antidepressant treatment of clinical depression in outpatient settings, evidence for inpatients is lacking.[18] The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors.[19] Other benzodiazepines are not known to have antidepressant activity.[20][21] Studies show that any antidepressant action of alprazolam is questionable and generally weak in comparison to antidepressant medications.[22][23][24][25] Conversely, whilst alprazolam in acute or short term treatment may have some antidepressant properties there is evidence that up to a third of long term users of alprazolam may develop depression.[26]

[edit] Side effects

Although the side effect profile of alprazolam is generally 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 occur, medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear such as yellowing of the skin or eyes. Other side effects which may occur are as follows:

Paradoxical Reactions

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

[edit] Contraindications

Use of alprazolam should be avoided,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).[48][49][50][51]

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[52] It should be considered that the child born of a mother who is 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 who have been receiving benzodiazepines.[53]

Benzodiazepines, including alprazolam are known to be excreted in human milk.[54] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[55][56] 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.[56]

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

[edit] Food and drug interactions

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.[13][58]

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.[59] Oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[60]

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.[61]

[edit] 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.[62]

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 actually being drug-dependent.[62]

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.[63][64] 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.[65][66][67]

In 1992 Romach and colleagues reported that dose escalation was not a characteristic of long-term alprazolam users, and the majority of patients indicated that alprazolam continued to be effective, suggesting that tolerance to the anti-anxiety effect is limited.[68]

If a patient feels the need to end treatment with alprazolam, they should consult their 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[69]

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.[70] Grand mal seizures have occurred after abrupt withdrawal after only short term use. Therefore even short term users of alprazolam should taper off of their medication slowly to avoid serious withdrawal reactions including seizures.[71][72]

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,[73][74] and one death occurred from withdrawal-related seizures after gradual dose reduction.[74]

In a 1983 study of patients who had taken long acting benzodiazepines ie 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 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, 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.[75]

The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce less withdrawal reactions than alprazolam (Xanax) or lorazepam (Temesta/Ativan). Factors which 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[8][76] and method of discontinuation.[77]

[edit] Recreational use

Sandoz generic 2mg alprazolam tablets.

Alprazolam has a relatively high potential for abuse.[78] Injection of alprazolam, though extremely rare, is considered especially dangerous by medical professionals[79] because, when crushed in water it will not fully dissolve (40 µg/ml of H2O at pH 7, and 12 mg/mL at pH 1.2 per 1 mg of alprazolam[80]), 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.[81] However, long-term use of benzodiazepines does not usually result in notable dose escalation and most prescribed alprazolam users do not abuse their medication.[82]

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

A large scale nation wide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involving benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines, however, benzodiazepines remain in Schedule IV of the Controlled Substances Act, whereas opiates are much more strictly scheduled. Men abuse benzodiazepines as commonly as women. The report found that alprazolam is the most commonly abused benzodiazepine followed by clonazepam, lorazepam and then diazepam.[4]

[edit] Patients at a high risk for abuse and addiction

At a particularly high risk for misuse, abuse, and dependence are polydrug abusers (someone who already uses at least one substance in a recreational context). Patients with a history of alcoholism (including a family history of alcoholism) or drug abuse and/or dependence[88][89][90][91][92] and patients with borderline personality disorder are at increased risk of misusing alprazolam.[93]

[edit] Overdose

See also: Benzodiazepine overdose

Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Alprazolam is significantly more toxic in overdose than other benzodiazepines with higher rates of fatalities. A study in New Zealand found that alprazolam was almost 8 times more likely to result in death in overdose than other sedative hypnotics as a group, with higher rates of ICU admissions and mechanical ventilation. Combined overdose with tricyclic antidepressants, alcohol or opiates or overdoses of alprazolam in the elderly significantly increases the likelihood for severe toxicity and possible fatality.[94] Alprazolam (Xanax) overdose reflect the central nervous system depression of the brain and may include one or more of the following symptoms:[33]

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

[edit] Availability

Alprazolam is available in 0.25 mg, 0.5 mg, 1 mg and 2 mg strength oral, extended release or orally disintegrating tablets.[97]

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

Brand Names[98]
Alprax, Alprox, Alzam, Anxirid, Apo-Alpraz, Alzolam, Azor, Calmax, Gerax, Kalma, Niravam, Novo-Alprazol, Nu-Alpraz, Texidep, Xanax, Xanor, Zopax

[edit] 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.[99] Under the UK drug misuse classification system benzodiazepines are class C drugs.[100] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[101]

[edit] See also

[edit] References

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v • d • e
Benzodiazepines (N05BA, N05CD)
1,4-Benzodiazepines
1,5-Benzodiazepines
2,3-Benzodiazepines
Triazolobenzodiazepines

Adinazolam • Alprazolam • Estazolam • Triazolam 
Imidazobenzodiazepines
Oxazolobenzodiazepines
Thienodiazepines
Pyridodiazepines
Pyrazolodiazepines
Pyrrolodiazepines
Benzodiazepine Prodrugs
Others
v • d • e
Psycholeptics: anxiolytics (tranquilisers) (N05B)
GABAA receptor
Adipiplon • Alpidem • CGS-9896 • CGS-20625 • DOV-51892 • ELB-139 • Etifoxine • L-838,417 • MK-0343 • NS-2664 • NS-2710 • Ocinaplon • Pagoclone • Panadiplon • Pipequaline • RWJ-51204 • SB-205,384 • TP-003 • TP-13 • TPA-023 • Tracazolate • Y-23684
Serotonin 5-HT1A agonist
Other
Histamine H1 antagonist
CRF antagonists
CRF-1 antagonists
Other/ungrouped
Other
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