Loxapine

Loxapine (several trade names worldwide[1]) is a typical antipsychotic medication used primarily in the treatment of schizophrenia. The drug is a member of the dibenzoxazepine class and structurally related to clozapine. Several researchers have argued that loxapine may behave as an atypical antipsychotic.[3]

Loxapine
Clinical data
Trade namesSeveral trade names worldwide[1]
AHFS/Drugs.comMonograph
MedlinePlusa682311
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral, powder for inhalation
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding96.8%[2]
    MetabolismExtensive hepatic; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-gp and is a substrate of CYP1A2, CYP3A4 and CYP2D6[2]
    Elimination half-life4 hours (oral); 7.61 hours (inhalation) [2]
    ExcretionMajority are excreted within 24 hours, main route through urine (conjugated metabolites), small amounts through the feces (unconjugated metabolites)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.016.215
    Chemical and physical data
    FormulaC18H18ClN3O
    Molar mass327.81 g·mol−1
    3D model (JSmol)
    Melting point109 to 110 °C (228 to 230 °F)
     NY (what is this?)  (verify)
    Bottle containing loxapine capsules, a mid-potency typical antipsychotic.

    Loxapine may be metabolized by N-demethylation to amoxapine, a tricyclic antidepressant.[4]

    Medical uses

    The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.[5]

    A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia.[6] A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.[7]

    Precautions

    This drug is unrelated to the habit-forming benzodiazepines, and misuse is rare.[8] The risks and side effect profile are comparable to other antipsychotics.

    Side effects
    Further information: Typical antipsychotic

    Note: Percentages given after possible adverse effects refer to the incidence of said adverse effects, according to DrugPoint.[2]

    Common side effects of loxapine (≥1% incidence) when inhaled include
    [2]
    • Taste sense altered (14%)
    • Sedated (12%)
    • Pharyngitis (3%)
    Common side effects of orally-administered loxapine include
    [2]
    • Constipation
    • Dry mouth
    • Akathisia
    • Dizziness
    • Intense sleeping
    • Slurred speech
    • Extrapyramidal symptoms (dose-dependent. At lower dosages its propensity for causing extrapyramidal side effects appears to be similar to that of atypical antipsychotics[9]
    • Blurred vision
    • Urinary retention
    • Somnolence (which appears to be moderate in severity compared to other antipsychotic drugs[10])
    • Dyspnoea
    • Nasal congestion
    Rare side effects include
    [2]

    Pharmacology
    Loxapine (and metabolite)[11][12]
    SiteLOXAMX
    5-HT1A2,460ND
    5-HT1B388ND
    5-HT1D3,470ND
    5-HT1E1,400ND
    5-HT2A6.60.5
    5-HT2C132 (rat)
    5-HT3190ND
    5-HT5A780ND
    5-HT63150
    5-HT78840 (rat)
    α1A31ND
    α1B53ND
    α2A151ND
    α2B108ND
    α2C80ND
    β1>10,000ND
    β2>10,000ND
    M1120ND
    M2445ND
    M3211ND
    M41,270ND
    M5166ND
    D154ND
    D21121
    D31921
    D48.421
    D575ND
    H12.2–4.97.9–25
    H2208ND
    H355,000>100,000
    H45,050–8,7106,310
    SERT>10,00058
    NET5,70016
    DAT>10,00058
    Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

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

    See also

    References
    1. Drugs.com International names for loxapine Page accessed March 3, 2016
    2. Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
    3. Glazer WM (1999). "Does loxapine have "atypical" properties? Clinical evidence". The Journal of Clinical Psychiatry. 60 (Suppl 10): 42–6. PMID 10340686.
    4. 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.
    5. Harrison, Pam: Inhalant Approved for Agitation in Bipolar I, Schizophrenia. Medscape. Dec 24, 2012.
    6. "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin. 29 (11): 41–2. May 1991. PMID 1747161.
    7. Chakrabarti A, Bagnall A, Chue P, et al. (2007). Chakrabarti A (ed.). "Loxapine for schizophrenia". Cochrane Database of Systematic Reviews (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMC 7017975. PMID 17943763.
    8. 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.
    9. 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: Nordstrom, Kimberly (2012). "Archived copy". Neuropsychiatry. 2 (3): 253–260. doi:10.2217/npy.12.23.
    10. 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
    11. Roth, BL; Driscol, J. "PDSP Ki Database" (HTML). Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
    12. Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn Schmiedebergs Arch. Pharmacol. 385 (2): 145–70. doi:10.1007/s00210-011-0704-0. PMID 22033803.
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