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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 | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| 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;http://www.rxlist.com/cgi/generic/alpraz_cp.htm Extended release: 10.7-15.8 hourshttp://www.rxlist.com/cgi/generic/xanax-xr_cp.htm |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
D(US) |
| Legal status | |
| Routes | Oral |
Alprazolam, also known under the trade names Xanax 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 clinical depression. It is also available in an extended release form, Xanax XR. Both forms are now available generically.
"[The public often] underestimate the extent to which certain disorders affect the general populace. When you treat them, it can make a tremendous amount of difference in their lives." (David Sheehan, first discovered alprazolam\'s efficacy in treating panic disorder.[1] )
Alprazolam was first synthesized by Upjohn (now a part of Pfizer). Its patent (#3,987,052)Patent 3,987,052 was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. It was released in 1981.http://thephoenix.com/article_ektid51411.aspx1981 American Journal of Psychiatry contains advertisements for Xanax as an available drug. The first indication for which alprazolam was approved was panic disorder. Upjohn took this direction at the behest of a young psychiatrist David Sheehan. Sheehan\'s suggestion was to use the confusion DSM-III created in the classification of anxiety disorders (a distinction had just been made in DSM-III between generalized anxiety disorder (GAD) and panic disorder). Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective. However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and well responding to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder will both cover new diagnostic territory and stress 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 them pooled their money and bought the Upjohn’s stock. Several months later, when alprazolam was approved by the FDA, they sold out and made a profit.Healy, David (2000). The Psychopharmacologists, Vol. III: Interviews. London: Arnold, 479-504. ISBN 0-340-761105.
Alprazolam is a triazolobenzodiazepine,J Med. Chem. Vol. 14, p. 1078-1081 (1971) DOI: 10.1021/jm00293a015 that is, a benzodiazepine with a triazolo-ring attached to its structure. Benzodiazepines produce a variety of effects by modulating the GABAA subtype of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to benzodiazepines.
In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated Chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedatory and anxiolytic effects. As mentioned, different benzodiazepines can have different affinities for GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the α1 are associated with sedation whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have greater anxiolytic activity.
The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABA receptor.
There is some evidence for antidepressant treatment of clinical depression in out patient settings, evidence for inpatients is lacking;[2] other benzodiazepines are not known to have antidepressant activity.
Alprazolam is readily absorbed from the gastrointestinal tract. 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. This and other metabolites are later excreted in urine as glucuronides. Some of the drug is also excreted in unchanged form.
The main medical uses for alprazolam include:
Xanax is the main and most commonly known brand name for Alprazolam. There is a large variety of generic brand names for Alprazolam in use throughout the world. In English-speaking countries, Alprazolam is sold under the following brand names: Alprax, Alprox, Alzam, Anxirid, Apo-Alpraz, Azor, Calmax, Frontal, Frontin, Gerax, Helex, Kalma, Kinax, Neurol, Novo-Alprazol, Nu-Alpraz, Restyl, Xanax, Xanor, Zopax, Trika It is also commonly known as "Ladders" or "Bars" or "yellow buses" when laced, when sold or used illegally.
Imprints vary depending on drug manufacturer. The imprints above refer to the name-brand design in the United States and other first world countries,[3] however, every variety of alprazolam is generically available and thus individual pill design is left up to the manufacturer.
Side effects of alprazolam may occur in patients and are more likely the higher the dosage taken. If signs of an allergic reaction occur such as hives, difficulty breathing, swelling of face, lips, tongue or throat occur medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear such as yellowing of the skin or eyes. Other side effects which may occur are as follows:Complete Alprazolam information from Drugs.com. drugs.com. Retrieved on 2nd Aug, 2007.ALPRAZOLAM - ORAL (Xanax) side effects, medical uses, and drug interactions.. medicinenet.com. Retrieved on 2nd Aug, 2007.Alprazolam – Complete medical information regarding this treatment of anxiety disorders on MedicineNet.com. medicinenet.com. Retrieved on 2nd Aug, 2007.alprazolam Side Effects, Interactions and Information - Drugs.com. drugs.com. Retrieved on 2nd Aug, 2007.
There is a consensus among psychiatrists today that alprazolam and other benzodiazepines cause withdrawal symptoms after long-term treatment and discontinuation should be done gradually over a period of months (or even up to a year) to avoid serious withdrawal symptoms such as agitation, panic attacks, rebound anxiety, muscle cramps and seizures.[citation needed] Some patients may benefit from a substitution with diazepam(Valium) or clonazepam(Rivotril) as these drugs remain in the bloodstream longer and therefore have less potential for abuse and dependence.
Patients treated with alprazolam or other benzodiazepines for generalized anxiety disorder were found when abruptly discontinuing their medication to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms.Chouinard G; Labonte A, Fontaine R, Annable L (1983). "New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines". Prog Neuropsychopharmacol Biol Psychiatry 7 (4-6): 669-73. PMID 6141609.
Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety. Other withdrawal effects reported from discontinuing alprazolam therapy include homicidal ideation, rage reactions, hyperalertness, increased nightmares, and intrusive thoughts.Risse SC; Whitters A, Burke J, Chen S, Scurfield RM, Raskind MA. (1990). "Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder.". The Journal of clinical psychiatry. 51 (5): 206-9. PMID 2335496.
When a patient discontinues use, they may experience the symptoms they had before taking medication. Symptoms may also be accompanied by other reactions including changes in mood, anxiety, or sleep. Rebound anxiety is usually a result of abrupt discontinuation of this medication; patients who taper off are less likely to experience these symptoms.
Physical dependence is the major limiting factor against long-term use of alprazolam and other benzodiazepines.
Factors which determine the severity of the benzodiazepine withdrawal syndrome experienced during dose reduction of alprazolam include:Wolf B; Griffiths RR. (1991). "Physical dependence on benzodiazepines: differences within the class.". Drug and alcohol dependence. 29 (2): 153-6. PMID 1686752.
Alprazolam has an exceptional history insofar soon after its introduction a large number of case reports were published in the medical literature of severe withdrawal symptoms related case reports of withdrawal psychoses, seizures and intense rebound anxiety upon discontinuation of alprazolam. In the United States a survey of physicians showed that 84% of physicians reported alprazolam as being extremely problematic in terms of the severity and prolonged nature of the benzodiazepine withdrawal syndrome after discontinuation.
However, in 1993 the New England Journal of Medicine reported there is no reliable evidence to support the existence of a persistent benzodiazepine withdrawal syndrome, and this syndrome has been described only in anecdotal reports, with patients typically reporting "withdrawal" symptoms not present during or before benzodiazepine treatment that persist for many months or years after treatment is stopped. Experimental neuropharmacologic studies document that all the side effects of benzodiazepines, whether behavioral or neurochemical, disappear within several days or weeks after the drug is eliminated. The weight of evidence indicates that any new symptoms that persist for more than two months after the last dose of a benzodiazepine either are part of the premorbid condition or have appeared by coincidence or as a consequence of the natural history of the underlying illness. Shader RI, Greenblatt DJ (1993). "Use of benzodiazepines in anxiety disorders". N. Engl. J. Med. 328 (19): 1398–405. PMID 8292115.
The benzodiazepines diazepam(Valium) and oxazepam(Seresta) were found to produce less severe withdrawal symptoms than alprazolam(Xanax) or lorazepam(Temesta/Ativan).Wolf B; Griffiths RR. (1991). "Physical dependence on benzodiazepines: differences within the class.". Drug and alcohol dependence. 29 (2): 153-6. PMID 1686752.
Alprazolam should never be abruptly discontinued if taken regularly for any length of time because severe withdrawal symptoms may occur. Severe psychosis and seizures have been reported in the medical literature from abrupt alprazolam withdrawal,Levy AB (1984). "Delirium and seizures due to abrupt alprazolam withdrawal: case report". J Clin Psychiatry 45 (1): 38–9. PMID 6141159. Haque W, Watson DJ, Bryant SG (1990). "Death following suspected alprazolam withdrawal seizures: a case report". Tex Med 86 (1): 44–7. PMID 2300914. and one death occurred from withdrawal-related seizures after gradual dose reduction.
Use of alprazolam should be avoided, or carefully monitored by medical professionals, in individuals with the following conditions:Alprazolam. British National Formulary (2007). Retrieved on 3rd Aug, 2007.mentalhealth.com (2007). Alprazolam. Retrieved on 3rd Aug, 2007.
Overdoses can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Xanax overdose reflect the central nervous system depresson of the brain and may include one or more of the following symptoms:
Although death is considered to be less commonly thought than barbiturates, benzodiazepines (xanax) have caused death in some situations.[citation needed] Choking on a person\'s own mucus and vomit and or if a person falls asleep behind the wheel have been been reported. Also if a person is taking a bath he or she may fall unconscious and drown. If mixed with another depressant (ex: alcohol) overdose and death increase intensely.[citation needed]
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.Wolf BC, Lavezzi WA, Sullivan LM, Middleberg RA, Flannagan LM (2005). "Alprazolam-related deaths in Palm Beach County". Am J Forensic Med Pathol 26 (1): 24–7. PMID 15725773.
Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[4] If one is currently planning to become pregnant, one should discuss this and all medicines with their obstetrician or other doctor.
Marked Pregnancy Category D by the U.S. FDA.
It should be considered that the child born of a mother who is receiving benzodiazepines may be at risk of developing withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.García-Algar O; López-Vílchez MA, Martín I, Mur A, Pellegrini M, Pacifici R, Rossi S, Pichini S. (2007). "Confirmation of gestational exposure to alprazolam by analysis of biological matrices in a newborn with neonatal sepsis.". Clinical toxicology (Philadelphia, Pa.). 45 (3): 295-8. PMID 17453885.
Alprazolam has no established use in labor or delivery.
Benzodiazepines, including alprazolam are known to be excreted in human milk.Oo CY; Kuhn RJ, Desai N, Wright CE, McNamara PJ. (Sep 1995). "Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk.". British journal of clinical pharmacology. 40 (3): 231-6. PMID 8527284. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[5][6] 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.http://www.medicinenet.com/alprazolam-oral/article.htm]
Eating grapefruits or drinking grapefruit juice while using alprazolam increases blood concentrations by inhibiting the intestinal metabolism.http://www.fhma.com/grapefruit.htm
In fact, any drug that inhibits CYP3A4, for which alprazolam is a substrate, will increase serum concentrations of alprazolam significantly if administered prior or concurrently. Tagamet (cimetidine) is a widely used H2 blocker antacid that inhibits numerous cytochrome P450 enzymes.
Oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.Back DJ; Orme ML. (Jun 1990). "Pharmacokinetic drug interactions with oral contraceptives.". Clin Pharmacokinet. 18 (6): 472-84. PMID 2191822.
Like all central nervous system depressants, including alcohol, alprazolam in doses of 0.5 mg and above can cause significant deterioration in alertness, combined with increased feelings of sleepiness.Kozená L; Frantik E, Horváth M. (May 1995). "Vigilance impairment after a single dose of benzodiazepines.". Psychopharmacology (Berl). 119 (1): 39-45. PMID 7675948. People driving or conducting activities which require vigilance should exercise caution in using alprazolam or any other depressant.
alprazolam 2mg tablets
Alprazolam, like all benzodiazepines, has the potential for abuse. Although it is not manufactured illegally, and its misuse and abuse is dwarfed by benzodiazepines like flunitrazepam and temazepam, it is still often diverted to the black market, particularily in the United States where alprazolam is the most widely prescribed benzodiazepine. The state of relaxation, anxiolysis, and disinhibition induced by benzodiazepines is the main reason for their illicit use.
Most alprazolam abusers "are generally but not entirely limited to patients involved in a polydrug use pattern"Landry, J. Understanding Drugs of Abuse: The Processes of Addiction, 1994. In fact, according to an April 2004 report by the U.S. SAMHSA, "over three-quarters (78%) of benzodiazepine-related (emergency room) visits involved 2 or more drugs."http://www.oas.samhsa.gov/DAWN/benzodiazepines.pdf.
Injection of alprazolam is considered especially dangerous by medical professionalsEric C; Wang, Felix S, Chew. (2006). "MR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis" (pdf). Radiology Case Reports 1 (3). because, when crushed in water it will not fully dissolve (40µg/ml of H2O at pH 7, and 12 mg/mL at pH 1.2 per 1mg of alprazolam[7]), 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; clinical testing indicates potent activity through insufflation yet some sources indicate sublingual activity is greater.http://www.panthrax.host.sk/snort_benzos.html
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. As with all drugs, taking it on an empty stomach ensures the most powerful effect. Some anti-drug sources provide disinformation by stating that alprazolam is more potent when taken with cola--the acidic nature of colas actually decreases its absorption--acidity decreases the absorption of almost every orally taken pharmaceutical.
At a particularly high risk for misuse, abuse, and dependence are polydrug abusers (someone who already uses at least one substance in a recreational context). However, the following can also indicate potential problems in the future:
Patients from the aforementioned group should be monitored very closely during therapy for signs of abuse and development of dependence because it may cause addiction. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended, unless the net benefit to the patient outweighs the net risk.
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. Under the UK drug misuse classification system benzodiazepines are class C drugs.[8] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.List of psychotropic substances under international control
There is a group of psychiatrists, for example Peter Breggen, who argue that rarely makes sense to prescribe a drug which, when taken more than for a week or so, produces, when the drug is discontinued, the very condition in aggravated form, in this case panic attacks, that it was prescribed to reduce in the first place. He suggests that a substantial percentage of people who are taking Xanax are using it, often unbeknown to themselves, to treat Xanax withdrawal. [http://www.breggin.com/minortranqs.html
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