Alprazolam

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Structural formula
Structural formula of alprazolam
General
Non-proprietary name Alprazolam
other names

8-Chloro-1-methyl-6-phenyl-4 H - [1,2,4] -triazolo [4,3- a ] [1,4] benzodiazepine

Molecular formula C 17 H 13 ClN 4
External identifiers / databases
CAS number 28981-97-7
EC number 249-349-2
ECHA InfoCard 100,044,849
PubChem 2118
DrugBank DB00404
Wikidata Q319877
Drug information
ATC code

N05 BA12

Drug class
properties
Molar mass 308.76 g · mol -1
Physical state

Solid

density
  • 1.33 g cm −3
  • 1.31 g cm −3 (dihydrate)
Melting point

228-228.5 ° C

pK s value

2.4

solubility

soluble in ethanol , insoluble in water

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302
P: no P-phrases
Toxicological data

1220 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Alprazolam is a drug from the group of benzodiazepines with a medium duration of action, which is used for the short-term treatment of anxiety and panic disorders .

Clinical information

Application areas (indications)

Alprazolam has a calming and anxiolytic effect. It is used for the short-term symptomatic treatment of anxiety and panic disorders .

Alprazolam is used as part of the therapy for depression or as a treatment for accompanying depression in anxiety states. It shows antidepressant properties in acute or short-term treatments.

It is often used as a sleeping aid , but alprazolam has no indication for it ( off-label use ).

Dosis, kind and Time of the Use

The dosage and the duration of use are adapted to the individual reaction situation, the indication area and the severity of the disease. The principle here is to keep the dose as low and the duration of treatment as short as possible in order to minimize the risk of psychological and physical dependence. It is recommended that the total duration - including the tapering phase - not exceed eight to twelve weeks. The patient should also be evaluated at regular intervals to assess the need for continued treatment. To avoid withdrawal symptoms when stopping alprazolam, the dose is slowly reduced.

Contraindications (contraindications)

The use of alprazolam in the following diseases is problematic:

Drug interactions

Alcohol can change the way alprazolam works in unpredictable ways.

The simultaneous use of alprazolam with the following drugs can lead to a mutual reinforcement of the central depressant effects:

Medicinal products that are broken down via the cytochrome P450 3A4 can increase the concentration and effectiveness of alprazolam.

Concomitant administration of ketoconazole , itraconazole, or other azole-type antifungal agents is contraindicated.

Interactions between HIV protease inhibitors (e.g. ritonavir ) and alprazolam are complex and time-dependent. Low doses of ritonavir significantly reduce alprazolam clearance , extending its half-life and increasing clinical efficacy. However, the CYP3A induction reverses this inhibition with prolonged use of ritonavir. The interaction requires either a dose reduction or discontinuation of alprazolam.

Problems can occur when taking the following drugs at the same time:

Use during pregnancy and breastfeeding

Alprazolam must not be used during pregnancy. Women of childbearing potential are advised to discontinue medication if they are pregnant or intend to become pregnant. If administration of the preparation in the late phase of pregnancy or in high doses during labor is unavoidable for urgent medical reasons, adverse effects on the newborn must be expected. These can include hypotension , respiratory failure , hypothermia , decreased muscle tension, and drinking weakness ( floppy infant syndrome ).

Since alprazolam passes into breast milk and accumulates there, the preparation should not be administered during breastfeeding. Newborns metabolize benzodiazepines much more slowly than adults.

Use in children and adolescents

The efficacy and safety of alprazolam in children and adolescents under 18 years of age have not been studied.

Adverse effects (side effects)

The most common side effects are somnolence and lightheadedness / dizziness . The following side effects can also occur, especially at the beginning of therapy: reduced alertness, fatigue, subdued emotions, confusion, muscle weakness, ataxia , movement and gait insecurity (risk of falling, especially in older patients), tremors , headaches, visual disturbances, disorders of the autonomic nervous system (weight change , gastrointestinal disorders, bladder dysfunction). Usually, these symptoms decrease with repeated use.

Furthermore were anorexia , hyperprolactinemia , menstrual disorders and liver function (z. B. jaundice ) observed. Changes in libido and skin reactions have been reported uncommonly. In rare cases, respiratory depression can occur, especially during the night.

  • Amnesia: Benzodiazepines can cause anterograde amnesias (memory lapses for the period after ingestion).
  • Depression: Pre-existing depression can be unmasked while using benzodiazepines.
  • Psychiatric and paradoxical reactions: Restlessness, irritability, aggressiveness, anger, nightmares, hallucinations, psychoses, inappropriate behavior and other behavioral disorders can occur, especially in older patients or children. In such cases, treatment with this preparation should be stopped.

Effects on ability to drive and use machines

Patients taking alprazolam are not recommended to drive, operate complex machines, or perform other potentially dangerous activities until it is known whether their ability to perform such activities is impaired.

Dependence and development of tolerance

If you take Alprazolam for several weeks, the effect may decrease due to the development of tolerance .

Like all benzodiazepines, alprazolam can lead to psychological and physical dependence after a short period of use. The risk of addiction increases with the dose and length of drug intake. Patients with known pill addiction , drug or alcohol addiction in history have an increased risk of addiction development.

If physical dependence on alprazolam has developed, abrupt discontinuation of the drug triggers withdrawal symptoms such as: B. headache and muscle pain, anxiety, tension, restlessness, confusion and irritability. In severe cases, loss of reality, loss of personality, hyperacusis , numbness and tingling in the extremities, hypersensitivity reactions to light, noise and physical contact, hallucinations or epileptic seizures may occur. The frequent withdrawal symptoms after alprazolam therapy are well documented in the literature.

After stopping the medication, a so-called rebound phenomenon can occur. Here the symptoms that led to treatment with benzodiazepines reappear in an intensified form. Changes in mood, anxiety and restlessness are possible accompanying reactions. Since withdrawal symptoms occur more frequently after abrupt discontinuation of the medication, a gradual reduction in dosage is recommended.

Overdose

Overdosing on alprazolam leads to general central nervous depression, which can range from drowsiness to coma . There is generally no danger to life from taking alprazolam alone, unless in combination with other centrally acting substances such as alcohol; this can lead to respiratory arrest and support the vital functions become necessary.

For detoxification with clear awareness patient vomiting can be induced or after intubation a gastric lavage and treatment with activated carbon are performed. Treatment with flumazenil as an antidote may be considered. Forced diuresis or dialysis treatment , however, has no effect .

Analytics

The reliable qualitative and quantitative determination of alprazolam is possible after appropriate sample preparation in plasma and breast milk by coupling the HPLC with the mass spectrometry . This procedure is also suitable for determination in urine and in wastewater or river water samples.

Pharmacological properties

Mechanism of action (pharmacodynamics)

Alprazolam binds to GABA receptors in the brain and in this way increases the inhibitory effects of the neurotransmitter GABA .

Pharmacokinetics

In addition to unmetabolized alprazolam (approx. 20%), the main metabolites excreted are α-hydroxyalprazolam (approx. 17%) and 4-hydroxyalprazolam. A large number of other metabolites have also been identified. The pharmacological activity of α-hydroxyalprazolam is about 50% compared to alprazolam. 4-Hydroxyalprazolam shows no pharmacological activity. The half-life of the two main metabolites is in the same range as that of alprazolam. Because of their low concentration, the metabolites probably hardly contribute to the therapeutic effect.

Alprazolam is quickly and well absorbed after oral administration. Maximum plasma levels are reached after one to two hours after a single oral dose. The bioavailability is 80%. Plasma protein binding is 70 to 80%. The volume of distribution averages 1.0 to 1.2 l / kg and is significantly greater in obese patients. The elimination half-life after a single dose is between 12 and 15 hours. The elimination half-life may be prolonged in elderly male patients.

The delayed release of the active substance of the prolonged- release tablet does not affect the distribution, metabolism or elimination of alprazolam. Peak serum concentrations are reached five to eleven hours after administration of a prolonged-release tablet.

Physical Properties

Alprazolam occurs in different crystal forms. Using thermoanalytical investigations and X-ray diffraction measurements , two polymorphic forms, a dihydrate and two non-stoichiometric solvates with ethanol and acetonitrile could be characterized. The crystal structures were determined for the commercial polymorph I and the dihydrate. Both crystallize in a triclinic lattice, the polymorph I with a space group P 1 and the dihydrate with the space group P 1. Desolvation of the dihydrate and the ethanol solvate result in polymorph I. Polymorph II results from the acetonitrile solvate, which at 233 ° C has a slightly higher melting point.

Other Information

history

Alprazolam was developed by Upjohn (later taken over by Pfizer ) and launched on the German market in 1984 under the name Tafil. Its patent protection ended in 1993.

Trade names

Monopreparations

Tafil (D), Xanax, Xanax retard (CH, USA), Xanor (A), numerous generics (D, A), Zolam (EGY)

literature

  • Andreas Russ, Stefan Endres (editor): Medicines Pocket Plus , Böhm Bruckmeier Verlag (2006), 2nd edition, ISBN 3-89862-256-8

Web links

Individual evidence

  1. ^ A b c The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; Pp. 1350-1351, ISBN 978-0-911910-00-1 .
  2. ↑ a b c d e M. R. Caira, B. Easter, S. Honiball, A. Horne, LR Nassimbeni: Structure and Thermal Stability of Alprazolam and Selected Solvates in J. Pharm. Sci. 84 (1995) pp. 1379-1384.
  3. ↑ Entry on alprazolam. In: Römpp Online . Georg Thieme Verlag, accessed on June 27, 2019.
  4. ↑ a b c Alprazolam data sheet from Sigma-Aldrich , accessed on March 20, 2011 ( PDF ).
  5. ↑ FDA approved labeling for Xanax revision 08/23/2011 (PDF) Federal Drug Administration. August 23, 2011. Retrieved September 14, 2011.
  6. ↑ a b c d e f g h i j Fachinformation Xanor , AGES PharmMed, as of: September 2008, accessed: June 2010.
  7. ↑ a b c d e f g h i j Specialist information Xanax , Swiss Medicines Compendium, status: December 2004, accessed: June 2010.
  8. ^ H. van Marwijk, G. Allick, F. Wegman, A. Bax, II Riphagen: Alprazolam for depression. In: The Cochrane database of systematic reviews. Number 7, July 2012, p. CD007139, doi : 10.1002 / 14651858.CD007139.pub2 , PMID 22786504 .
  9. ↑ a b c d e f g h i Fachinformation Tafil , Rote Liste, status: September 2008, accessed: June 2010.
  10. ^ B. Wolf, RR Griffiths: Physical dependence on benzodiazepines: differences within the class. Drug Alcohol Depend 1991; 29 (2): pp. 153-156, PMID 1686752 .
  11. ↑ Furugen A, Nishimura A, Kobayashi M, Umazume T, Narumi K, Iseki K: Quantification of eight benzodiazepines in human breastmilk and plasma by liquid-liquid extraction and liquid-chromatography tandem mass spectrometry: Application to evaluation of alprazolam transfer into breastmilk. , J Pharm Biomed Anal. 2019 May 10; 168: 83-93, PMID 30798209
  12. ↑ Mazzarino M, Cesarei L, de la Torre X, Fiacco I, Robach P, Botrè F ' A multi-targeted liquid chromatography-mass spectrometry screening procedure for the detection in human urine of drugs non-prohibited in sport commonly used by the athletes . , J Pharm Biomed Anal. 2016 Jan 5; 117: 47-60, PMID 26342446
  13. ↑ Stamper B, Gul W, Godfrey M, Gul SW, ElSohly MA: LC-MS-MS Method for Analysis of Benzodiazepines in Wastewater During Football Games IV , J Anal Toxicol. 2017 Apr 1; ​​41 (3): 205-213, PMID 27979928
  14. ↑ Jiménez JJ, Sánchez MI, Muñoz BE, Pardo R: Persistence of alprazolam in river water according to forced and non-forced degradation assays: adsorption to sediment and long-term degradation products. , Drug Test Anal. 2017 Aug; 9 (8): 1204-1213, PMID 27992663
  15. ↑ espsy.de: Psychopharmaka (time table) Status: April 21, 2008.