Loxapine

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Loxapine
Loxapine.svg
Loxapine ball-and-stick model.png
Clinical data
Trade namesLoxitane, Adasuve
AHFS/Drugs.comMonograph
MedlinePlusa682311
License data
Routes of
administration
Oral, powder for inhalation
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Protein binding96.8%[1]
MetabolismExtensive hepatic; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-gp and is a substrate of CYP1A2, CYP3A4 and CYP2D6[1]
Elimination half-life4 hours (oral); 7.61 hours (inhalation)[1]
ExcretionMajority are excreted within 24 hours, main route through urine (conjugated metabolites), small amounts through the feces (unconjugated metabolites)
Identifiers
  • 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.016.215 Edit this at Wikidata
Chemical and physical data
FormulaC18H18ClN3O
Molar mass327.81 g·mol−1
3D model (JSmol)
Melting point109 to 110 °C (228 to 230 °F)
  • Clc2ccc1Oc4c(/N=C(\c1c2)N3CCN(C)CC3)cccc4
  • InChI=1S/C18H18ClN3O/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18/h2-7,12H,8-11H2,1H3 checkY
  • Key:XJGVXQDUIWGIRW-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)
Bottle containing loxapine capsules, a mid-potency typical antipsychotic.

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, 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.[2]

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

Medical uses[edit]

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.[4]

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia.[5] A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.[6]

Available forms[edit]

Loxapine can be taken by mouth as a capsule or a liquid oral concentrate.[7] It is also available as an intramuscular injection and as a powder for inhalation.[4][7]

Side effects[edit]

Loxapine can cause side effects that are generally similar to that of other medications in the typical antipsychotic class of medications. These include, e.g., gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics),[8] and movement problems (i.e. extrapyramidal symptoms [EPS]).[9] At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics.[10] Although it is structurally similar to clozapine, it does not have the same risk of agranulocytosis (which, even with clozapine, is less than 1%); however, mild and temporary fluctuations in blood leukocyte levels can occur.[11][12] Abuse of loxapine has been reported.[13]

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth.[4]

Pharmacology[edit]

Mechanism of action[edit]

Loxapine is a "mid-potency" typical antipsychotic.[12] However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its high potency for the D2 receptor.[12]

Loxapine (and metabolite)[14][15]
Site LOX AMX
5-HT1A 2,460 ND
5-HT1B 388 ND
5-HT1D 3,470 ND
5-HT1E 1,400 ND
5-HT2A 6.6 0.5
5-HT2C 13 2 (rat)
5-HT3 190 ND
5-HT5A 780 ND
5-HT6 31 50
5-HT7 88 40 (rat)
α1A 31 ND
α1B 53 ND
α2A 151 ND
α2B 108 ND
α2C 80 ND
β1 >10,000 ND
β2 >10,000 ND
M1 120 ND
M2 445 ND
M3 211 ND
M4 1,270 ND
M5 166 ND
D1 54 ND
D2 11 21
D3 19 21
D4 8.4 21
D5 75 ND
H1 2.2–4.9 7.9–25
H2 208 ND
H3 55,000 >100,000
H4 5,050–8,710 6,310
SERT >10,000 58
NET 5,700 16
DAT >10,000 58
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Pharmacokinetics[edit]

Loxapine is metabolized to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine).[1] Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine.[16] At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.[16]

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth.[16]

Chemistry[edit]

Loxapine is a dibenzoxazepine and is structurally related to clozapine.

Chemical structures of loxapine and clozapine, with key differences highlighted.

See also[edit]

References[edit]

  1. ^ a b c d 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. ^ a b c "ADASUVE Package Insert" (PDF). Galen US Inc.
  5. ^ "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin. 29 (11): 41–2. May 1991. PMID 1747161.
  6. ^ 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.
  7. ^ a b "LOXITANE Package Insert" (PDF). Watson Laboratories, Inc.
  8. ^ 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
  9. ^ Chakrabarti, Abhijit; Bagnall, Anne-Marie; Chue, Pierre; Fenton, Mark; Palanisamy, Vikram; Wong, Winson; Xia, Jun (17 October 2007). "Loxapine for schizophrenia". Cochrane Database of Systematic Reviews (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMC 7017975. PMID 17943763.
  10. ^ 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. S2CID 39718567.
  11. ^ DePaulo, J. Raymond; Ayd, Frank J. (March 1982). "Loxapine: Fifteen years' clinical expenence". Psychosomatics. 23 (3): 261–271. doi:10.1016/S0033-3182(82)73416-4. PMID 7041162.
  12. ^ a b c Singh, AN; Barlas, C; Singh, S; Franks, P; Mishra, RK (January 1996). "A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes". Journal of Psychiatry & Neuroscience. 21 (1): 29–35. PMC 1188731. PMID 8580115.
  13. ^ 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.
  14. ^ Roth, BL; Driscol, J. "PDSP Ki Database". 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.
  15. ^ 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. S2CID 14274150.
  16. ^ a b c Simpson, George M.; Cooper, Thomas B.; Lee, J. Hillary; Young, Michael A. (1978). "Clinical and plasma level characteristics of intramuscular and oral loxapine". Psychopharmacology. 56 (2): 225–232. doi:10.1007/BF00431855. PMID 417377. S2CID 21795809.

External links[edit]