Loxapine

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Loxapine
Loxapine2DACS.svg
Loxapine3Dan.gif
Systematic (IUPAC) name
2-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a682311
Licence data EMA:Link, US Daily Med:link
Pregnancy cat. C (US)
Legal status Prescription Only (S4) (AU) -only (US)
Routes Inhalation, Oral
Pharmacokinetic data
Protein binding 96.8%[1]
Metabolism Liver, extensive; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-glycoprotein and is a substrate of CYP1A2, CYP3A4 and CYP2D6[1]
Half-life Oral, 4 hours; Inhalation, 7.61 hours [1]
Excretion Majority are excreted within 24 hours. Main route through urine(conjugated metabolites); Small amounts through the faeces(unconjugated metabolites)
Identifiers
CAS number 1977-10-2 YesY
ATC code N05AH01
PubChem CID 3964
IUPHAR ligand 205
DrugBank DB00408
ChemSpider 3827 YesY
UNII LER583670J YesY
KEGG D02340 YesY
ChEBI CHEBI:50841 N
ChEMBL CHEMBL831 YesY
Chemical data
Formula C18H18ClN3O 
Mol. mass 327.808 g/mol
Physical data
Melt. point 109–110 °C (228–230 °F)
 N (what is this?)  (verify)

Loxapine (Loxapac, Loxitane) is a typical antipsychotic medication, used primarily in the treatment of schizophrenia. It is a member of the dibenzoxazepine class and structurally related to clozapine (which belongs to the chemically akin class of dibenzodiazepines). Several researchers have argued that Loxapine may behave as an atypical antipsychotic.[2]

Loxapine may be metabolized by N-demethylation to amoxapine, a tetracyclic antidepressant.[3]

Precautions[edit]

This drug is unrelated to the habit-forming benzodiazepines, and loxapine succinate abuse is rare.[4] The risks and side effect profile are comparable to other antipsychotics.

Side effects[edit]

Note: Percentages given after possible adverse effects refer to the incidence of said adverse effects, according to DrugPoint.[1]

Common side effects of loxapine (≥1% incidence) when inhaled include
[1]
  • Taste sense altered (14%)
  • Sedated (12%)
  • Pharyngitis (3%)
Common side effects of orally-administered loxapine include
[1]
  • Constipation
  • Dry mouth
  • Akathisia
  • Dizziness
  • Extrapyramidal disease (dose-dependent. At lower dosages its propensity for causing extrapyramidal side effects appears to be similar to that of atypical antipsychotics[5]
  • Blurred vision
  • Urinary retention
  • Somnolence (which appears to be moderate in severity compared to other antipsychotic drugs[6])
  • Dyspnoea
  • Nasal congestion
Rare side effects include
[1]

Therapeutic Uses and Dosages[edit]

The typical starting dosage is 10 mg twice daily; usual dose range 30–50 mg twice daily; maximum recommended dosage is 250 mg per day. The US Food and Drug Administration (FDA) has approved loxapine ( Adasuve, Alexza Pharmaceuticals) inhalation powder 10 mg for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. [7]

A brief review of loxapine[8] found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.[9]

Loxapine was one of five antipsychotics used in a study on the structure of neurons in parts of the brain thought to be involved in schizophrenia. Only Loxapine was linked to the development of new connections between neurons.[10]

Pharmacology[edit]

The data in the following table was obtained from the PDSP Ki database and they are for binding towards human cloned proteins (receptor and transporter) unless otherwise specified.[11]

Molecular Target Binding Affinity (Ki [nM]) for Loxapine Binding Affinity (Ki [nM]) for Amoxapine
5-HT1A 2456 -
5-HT1B 388 -
5-HT1D 3468 -
5-HT1E 1399 -
5-HT2A 6.63 0.5
5-HT2C 13.3 2 (Cloned rat receptor protein)
5-HT3 190 -
5-HT5A 776 -
5-HT6 31.0 50
5-HT7 87.6 40.2 (Rat, Cloned)
α1A 31 -
α1B 53 -
α2A 150.9 -
α2B 107.8 -
α2C 80.0 -
β1 >10000 -
β1 >10000 -
M1 119.5 -
M2 445 -
M3 211.3 -
M4 1266 -
M5 166 -
D1 54 -
D2 11 20.8
D3 19.33 21
D4 8.4 21
D5 75 -
H1 4.9 -
H2 208 -
H4 5048 -
SERT >10000 58
NET 5698 16
DAT >10000 58

Chemistry[edit]

Loxapine synthesis.png

Schmutz, J.; Kunzle, F.; Hunziker, F.; Gauch, R.; Helv. Chim. Acta 1967, 50, 245.

References[edit]

  1. ^ a b c d e f g Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2. ^ Glazer WM (1999). "Does loxapine have "atypical" properties? Clinical evidence". The Journal of Clinical Psychiatry 60 (Suppl 10): 42–6. PMID 10340686. 
  3. ^ Cheung SW, Tang SW, Remington G (March 1991). "Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography". Journal of Chromatography 564 (1): 213–21. doi:10.1016/0378-4347(91)80083-O. PMID 1860915. 
  4. ^ Sperry L, Hudson B, Chan CH (March 1984). "Loxapine abuse". The New England Journal of Medicine 310 (9): 598. doi:10.1056/NEJM198403013100920. PMID 6694719. 
  5. ^ Nordstrom K. Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: an update. Neuropsychiatry [Internet]. 2012 Jun [cited 2013 Sep 21];2(3):253–60. Available from: http://www.futuremedicine.com/doi/abs/10.2217/npy.12.23
  6. ^ Taylor D, Paton C, Kapur S, Taylor D, South London and Maudsley NHS Trust. The Maudsley prescribing guidelines in psychiatry [Internet]. Chichester, West Sussex: John Wiley & Sons; 2012 [cited 2013 Sep 21]. Available from: http://site.ebrary.com/lib/uqat/Doc?id=10531429
  7. ^ Harrison, Pam: Inhalant Approved for Agitation in Bipolar I, Schizophrenia. Medscape. Dec 24, 2012.
  8. ^ "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin 29 (11): 41–2. May 1991. PMID 1747161. 
  9. ^ Chakrabarti A, Bagnall A, Chue P, et al. (2007). "Loxapine for schizophrenia". In Chakrabarti, Abhijit. Cochrane Database of Systematic Reviews (Online) (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMID 17943763. 
  10. ^ Brennand, Kristen; Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yangling Mu, Gong Chen, Diana Yu, Shane McCarthy, Jonathan Sebat & Fred H. Gage (13 April 2011). "Modelling schizophrenia using human induced pluripotent stem cells". Nature 473 (7346): 221–5. doi:10.1038/nature09915. PMID 21490598. 
  11. ^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Aug 3]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php

External links[edit]