Loxapine

The medicine is a member of the dibenzoxazepine class and structurally very similar to clozapine. Several researchers have argued that loxapine, initially classified as a typical antipsychotic, behaves as an atypical antipsychotic.

Loxapine

Clinical data
Trade names	Loxitane, Adasuve
AHFS/Drugs.com	Monograph
MedlinePlus	a682311
License data	EU EMA: by INN US DailyMed: Loxapine US FDA: Loxapine
Routes of administration	By mouth, inhalation, intramuscular
Drug class	Antipsychotic
ATC code	N05AH01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances) US: WARNINGRx-only EU: Rx-only
Pharmacokinetic data
Protein binding	96.8%
Metabolism	Extensive Liver; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-gp and is a substrate of CYP1A2, CYP3A4 and CYP2D6
Elimination half-life	4 hours (oral); 7.61 hours (inhalation)
Excretion	Majority are excreted within 24 hours, main route through urine (conjugated metabolites), small amounts through the feces (unconjugated metabolites)
Identifiers
IUPAC name 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
CAS Number	1977-10-2 Y
PubChem CID	3964
IUPHAR/BPS	205
DrugBank	DB00408 N
ChemSpider	3827 Y
UNII	LER583670J
KEGG	D02340 Y
ChEBI	CHEBI:50841 N
ChEMBL	ChEMBL831 Y
CompTox Dashboard (EPA)	DTXSID7023229
ECHA InfoCard	100.016.215
Chemical and physical data
Formula	C18H18ClN3O
Molar mass	327.81 g·mol−1
3D model (JSmol)	Interactive image
Melting point	109 to 110 °C (228 to 230 °F)
SMILES Clc2ccc1Oc4c(/N=C(\c1c2)N3CCN(C)CC3)cccc4
InChI 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 Y Key:XJGVXQDUIWGIRW-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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

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.

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.

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 5HT_2A 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.

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.

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