Loxapine

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.

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

Available forms

Loxapine can be taken by mouth. It is also available as an intramuscular injection and as a powder for inhalation.

Side effects

Loxapine can cause side effects that are generally similar to that of other antipsychotic medications. These include, e.g., gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), and movement problems (i.e. extrapyramidal symptoms [EPS]). At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. Although it is structurally similar to clozapine, it has much lower risk of agranulocytosis (which, even with clozapine, is 0.8%); however, mild and temporary fluctuations in blood leukocyte levels can occur. Abuse of loxapine has been reported.

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.

Pharmacology

Mechanism of action

Some scientists say loxapine is a "mid-potency" typical antipsychotic. 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 higher affinity for the D2 receptor compared to clozapine, which has one of the lowest binding affinities at the D2 receptor of any antipsychotic.

Use as an inhaled agitation medication

Loxapine has a relatively strong safety profile compared to similar antipsychotic drugs, such as quetiapine, olanzapine, and clozapine, with a relatively lower incidence of metabolic side-effects (although higher extrapyramial side-effects). Given its strong safety profile and speed/efficacy when given intramuscularly for acute agitation, an inhaled version of the drug (Adasuve) has been developed to be applied nasally for agitated patients needing to be rapidly de-escalated.

Pharmacokinetics

Loxapine is metabolized to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. 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.

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.

Chemistry

Loxapine is a dibenzoxazepine and is structurally very similar to clozapine, an atypical antipsychotic.

References

References

1. (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
2. Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
3. (2015-04-01). "Revisiting loxapine: a systematic review". Annals of General Psychiatry.
4. (1999). "Does loxapine have "atypical" properties? Clinical evidence". The Journal of Clinical Psychiatry.
5. (March 1991). "Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography". Journal of Chromatography.
6. (May 1991). "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin.
7. (October 2007). "Loxapine for schizophrenia". The Cochrane Database of Systematic Reviews.
8. "LOXITANE Package Insert". Watson Laboratories, Inc..
9. (2012). "The Maudsley prescribing guidelines in psychiatry". Wiley-Blackwell.
10. (October 2007). "Loxapine for schizophrenia". The Cochrane Database of Systematic Reviews.
11. (2012). "Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: An update". Neuropsychiatry.
12. (March 1982). "Loxapine: fifteen years' clinical experience". Psychosomatics.
13. (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.
14. (March 1984). "Loxapine abuse". The New England Journal of Medicine.
15. "ADASUVE Package Insert". Galen US Inc.
16. "PDSP K_i Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.
17. (February 2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology.
18. (2019-09-14). "Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis". Lancet.
19. (2023-12-19). "Efficacy and Safety of Loxapine in Acute Agitation: A Systematic Review of Interventional Studies". The Primary Care Companion for CNS Disorders.
20. (2015). "Revisiting loxapine: a systematic review". Annals of General Psychiatry.
21. (March 1978). "Clinical and plasma level characteristics of intramuscular and oral loxapine". Psychopharmacology.