Table of Contents
INTRODUCTION
Alprazolam is one of the most frequently used substances among the benzodiazepine class, for which the first example was created by Leo Sternbach with the name of chlordiazepoxide which aimed to become less addictive and safer substance compared to the conventional drugs such as alcohol and meprobamate. Today, it is traded under the brand name of Xanax which belongs to Pfizer. The drug is used for panic attacks and as an anxiolytic which is stated by Richard Lawrence Miller, in his book of “The Encyclopedia of Addictive Drugs” as “This calming and sleep-inducing substance is probably the most frequently prescribed drug in the benzodiazepine class. Alprazolam is used mainly to help persons suffering from panic attacks and other anxiety disorders” (1). The reasons for Xanax to be mostly prescribed drug of the benzodiazepine class are stated as “Alprazolam (ALP) is the most commonly used anti-anxiety drug because they are believed to be fairly safe and it rapidly reduces the symptoms of anxiety” (2). The first company to synthesize Alprazolam was Upjohn and later it was bought by Pfizer which is the current owner. Alprazolam was firstly used and approved for being an indication for panic disorder. Before Alprazolam, it was believed by the authorities that the only way to treat panic disorder was to use tricyclic antidepressants and the drugs in the benzodiazepines class were not taken into consideration for treating panic disorders. David Sheehan, who was a psychiatrist at that era, proved as a result of his clinical studies that Alprazolam is effective for the treatment of panic disorders (8). Alprazolam works by binding to the GABAA receptors which are located in the brain and in this way the brain activity is lowered and as a result, the panic and the anxiety of the patients are reduced (9).
CLINICAL USAGE OF XANAX
As mentioned above, in nearly 40 years since Alprazolam was created, it has been receiving an increasing demand. Xanax is one of the very few drugs containing Alprazolam. One of the reasons for Alprazolam to have such an increasing demand towards itself is its efficiency in clinical usage. A research made by Actas Psiquitar in 1999 worked on decreasing the global anxiety (HAMA, CGI and CGI improvement) levels of patients. The research was made on 68 patients and was conducted over 21 weeks. As a result of the research, the scientists came up with the results stated as “Global anxiety (HAMA, GCI and CGI improvement) showed a significant reduction throughout the study. There was a reduction in the number of panic attacks and in the severity of agoraphobia. Global clinical impression (efficacy and tolerability) was good or very good in 75% of the patients, both assessed by the investigator and by the patient” (3). The result of the research shows that Xanax has an effective clinical usage in terms of showing compelling decrease in anxiety levels. Today, Xanax is seen as the more effective drug that is currently being used for curing psychological disorders and the results of the research supports this claim.
XANAX AS A CONTROLLED DRUG
Eventhough the abuse of drugs, both prescription and nonprescription, are in a decreasing trend compared to the 50’s and 60’s United States of America and the countries in Europe, it still continues in our time as well. The abuse of drugs is a hazardous situation for the patients who use these drugs result in very serious problems such as fatal overdose, dependency on the drug or being addicted to the drug. According to the U.S. Food and Drug Administration, the content of the controlled drugs is stated as “Many of the drugs included within this subchapter have a useful and legitimate medical purpose and are necessary to maintain the health and general welfare of the American people” (4). The United States Convention seperates drugs into several catagories according to their possible harmful effects on the patients and according to that differentiation made between the drugs, Alprazolam was grouped in the Schedule IV drugs which is a group for hypnotic, anxiolytic and sedative drugs (10). In an article about the relationship between hemoglobin and Alprazolam, it is claimed that “Taken together it seems likely that ALP being a sedative drug may interfere with the normal Hb function particularly in long- term use and may alter different physiological response related with Hb mediated catabolism. Hence, our present study unam- biguously raises the question of the danger of using, overusing and abusing of ALP” (2). In addition to this, Richard Lawrence Miller claims in his book that “abuse of Alprazolam was more likely than abuse of any other benzodiazepine class drugs” (1). Both depending on this information and the United States Convention, the supply and dispense of Alprazolam and thus Xanax should be taken under control by the aid of letting only the individuals with proper licenses and prescriptions.
PHARMACOKINETIC OF XANAX
The drug yields 4-hydroxy-alprazolam and alpha-hydroxy as the principal initial metabolites and the metabolisation of the drug is mainly by hepatic microsomal oxidation. The plasma concentrations of the alpha-hydroxy derivative are exceeded by that of 4-hydroxy metabolite but on the other hand the urinary recovery of 4-hydroxy alprazolam is a way lower than that of alpha-hydroxy-alprazolam. It is claimed by David Greenblatt that this issue can be analyzed through the “chemical instability of 4-hydroxy-alprazolam in vitro” and the writer further adds that “After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%” (5). In addition to these, the pharmacokinetics of Xanax is not dependent on the dose and also not changed in case of a multiple-dose treatment. Also, the pharmacokinetics of alprazolam do not get affected by the gender of the patient as well and this issue is explained by Greenblatt as “Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients” (5). Lastly, the pharmacokinetics of alprazolam are not influenced by the patients being alcoholics, having panic disorder and also being in their menstrual cycle.
INTERACTIONS OF XANAX
Kava plant is used for producing kava which is a drink with intoxicating properties and it is being questioned that this drink interacts with alprazolam and as a result of this interaction, the patient may end up with a coma. On the other hand, in order to avoid alprazolam, people use itraconazole and ketoconazole which extend the alprazolam effect and increase power. In addition to that, use of alprazolam with diazepam cause patients to forget the events happened while the patient is under the influence of the drug (1). Additively, the interactions of Xanax is also studied in terms of light and humidity conditions where the alprazolam tablets, which include a degradation product, analyzed under some elucidation techniques, an isolation method and the synthesis of the product. The result of the study and the interactions of Xanax are stated as “Accelerated degradation studies have proven that this impurity, identified as triazolaminoquinoleine, is generated from the interaction between alprazolam and excip- ients under high temperature and humidity conditions, but is independent of the presence of light” (6).

AN INTERACTION BETWEEN ETHANOL AND HIGH-DOSE ALPRAZOLAM
A research was conducted by a group of researchers with the aim of investigating the metabolic interactions where the alprazolam metabolites are involved and human liver microsomes using ethanol over the therapeutic in vitro. In the result part of the study, statements about Alprazolam are made as “Alprazolam is a substrate of human CYP3A isoforms, mainly CYP3A4/5, present in both liver and gastrointesti-nal tract mucosa and two main metabolites are pro- duced.10,11 The metabolites, a-OH alprazolam and 4-OH alprazolam, exhibit approximately 66% and 19% of the potency of the parent drug, respectively.12 Its metabolism is inhibited by fluvoxamine, citalopram and fluoxetine, in vivo and/or in vitro” (7). As a result of the research conducted to find the interaction between ethanol and high-dose alprazolam, the researchers conclude by claiming that “these results using a human liver micro- somal preparation show that the production of 4-OH alprazolam was weakly inhibited by higher doses of etha- nol but not a-OH alprazolam. Toxic levels may be reached by simultaneous administration of ethanol and high-dose alprazolam”(7).
CONCLUSION
Alprazolam is one of the most frequently used substances among the benzodiazepine class. Alprazolam is today traded under the brand name of Xanax. Alprazolam is believed to be fairly safe and it rapidly reduces the symptoms of anxiety and thus it has the highest prescription rates. Today Xanax has an effective clinical usage in terms of showing compelling decrease in anxiety levels. Xanax is a sedative drug, because of this and some other harmful sides of the drug, the supply and dispense of Alprazolam and thus Xanax should be taken under control by the aid of letting only the individuals with proper licenses and prescriptions. The pharmacokinetic of Alprazolam is not affected by age, gender and the patient’s alcohol usage. In addition to all these, Alprazolam has some interactions too. Itraconazole and ketoconazole extends the alprazolam effect and increase power. There are some metabolic interactions between Alprazolam and ethanol and it is claimed that there is a possibility to reach toxic levels by administrating ethanol and high-dose alprazolam simultaneously.
- REFERENCES
- Miller, R. L. (2002). The Encyclopedia of Addictive Drugs. Greenwood.
- Satwata Maitra a, 1. B. (2007). Alprazolam induced conformational change in hemoglobin. International Journal of Biological Macromolecules, 23-29.
- De La Gándara Martín JJ1, S. G. (1999). Clinical use of sustained release of alprazolam: A naturalistic study. Actas Esp Psiquiatr, 191-197.
- (2009, 11 06). U.S Food and Drug Administration: Retrieved from http://www.fda.gov/regulatoryinformation/legislation/ucm148726.htm
- Greenblatt DJ1, W. C. (1993). Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet, 453-471.
- A.L. Huidobro, F. R. (2007). Isolation, identification and determination of the major degradation product in alprazolam tablets during their stability assay. Journal of Pharmaceutical and Biomedical Analysis, 404-413.
- Einosuke Tanaka, T. N. (2007). Metabolic interaction between ethanol, high-dose alprazolam and its two main metabolites using human liver microsomes in vitro. Journal of Forensic and Legal Medicine, 348-351.
- Friedman, C. (no date). FDA Approves Pharmacia and UpJohn’s Xanax. Retrieved from worldhistoryproject.org: https://worldhistoryproject.org/1981/10/16/fda-approves-pharmacia-and-upjohns-xanax
- Giordano R, G. S. (2003). Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin-induced hypoglycaemia in humans. Clin Endocrinol (Oxf), 314-320.
- DRUG SCHEDULING (no date). Taken from www.dea.gov: http://www.dea.gov/druginfo/ds.shtml
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