Loxapine

Loxapine

Names
Trade names	Loxitane, Adasuve, others
IUPAC name 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
Clinical data
Drug class	Typical antipsychotic[1]
Main uses	Psychosis[1]
Side effects	Movement disorders, sleepiness, dry mouth, blurry vision, low blood pressure with standing, fast heart rate[1]
Routes of use	By mouth, powder for inhalation
Typical dose	60 to 100 mg per day[1]
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a682311
Legal
License data	EU EMA: by INN US DailyMed: Loxapine US FDA: Loxapine
Legal status	AU: S4 (Prescription only) US: ℞-only EU: Rx-only
Pharmacokinetics
Protein binding	96.8%[2]
Metabolism	Extensive hepatic; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-gp and is a substrate of CYP1A2, CYP3A4 and CYP2D6[2]
Elimination half-life	4 hours (oral); 7.61 hours (inhalation)[2]
Excretion	Majority are excreted within 24 hours, main route through urine (conjugated metabolites), small amounts through the feces (unconjugated metabolites)
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

Loxapine, sold under the brand names Loxitane among others, is a typical antipsychotic used to treat psychosis including schizophrenia and for agitation.^[1][3] Benefit in people with intellectual disability is unclear.^[1] It is taken by mouth or inhaled.^[1][3]

Common side effects include movement disorders, sleepiness, dry mouth, blurry vision, low blood pressure with standing, and fast heart rate.^[1] Other side effects may include milk production, seizures, sunburns, neuroleptic malignant syndrome, and increased risk of death in those with dementia.^[1] It is believed to work by blocking dopamine D₂ and 5-HT_2A receptors.^[3]

Loxapine was approved for medical use in the United States in 1975.^[1] In the United States 60 pills of 50 mg costs about 38 USD as of 2021.^[4]

Medical uses[edit | edit source]

Bottle containing loxapine capsules

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]

Dosage[edit | edit source]

Loxapine can be taken by mouth as a capsule or a liquid oral concentrate.^[8] It is also available as an intramuscular injection and as a powder for inhalation.^[5][8]

It is generally started at 10 mg twice per day and is typically increased to 60 to 100 mg per day.^[1]

Side effects[edit | edit source]

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),^[9] and movement problems (i.e. extrapyramidal symptoms [EPS]).^[10] At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics.^[11] 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.^[12][13] Abuse of loxapine has been reported.^[14]

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.^[5]

Pharmacology[edit | edit source]

Mechanism of action[edit | edit source]

Loxapine is a "mid-potency" typical antipsychotic.^[13] 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 high potency for the D2 receptor.^[13]

Several researchers have argued that loxapine may behave as an atypical antipsychotic.^[17] Loxapine may be metabolized by N-demethylation to amoxapine, a tricyclic antidepressant.^[18]

Pharmacokinetics[edit | edit source]

Loxapine is metabolized to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine).^[2] Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine.^[19] 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.^[19]

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.^[19]

Chemistry[edit | edit source]

Loxapine is a dibenzoxazepine and is structurally related to clozapine.

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

See also[edit | edit source]

• Amoxapine
• Clotiapine

References[edit | edit source]

External links[edit | edit source]

• Product monograph Archived 2021-11-01 at the Wayback Machine from Medscape (free registration required).