Loxapine

Bottle containing loxapine capsules, a mid-potency antipsychotic.

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is a tricyclic<ref>Template:Cite journal</ref> antipsychotic medication used primarily in the treatment of schizophrenia. 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.<ref name="Glazer_1999">Template:Cite journal</ref>

Loxapine may be metabolized by N-demethylation to amoxapine, a tricyclic antidepressant.<ref name="Cheung_1991">Template:Cite journal</ref>

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.<ref name="ADASUVE PI" />

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with schizophrenia.<ref name="pmid1747161">Template:Cite journal</ref> A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.<ref name="Chakrabarti_2007">Template:Cite journal</ref>

Available forms

Loxapine can be taken by mouth.<ref name="LOXITANE PI">Template:Cite web</ref> It is also available as an intramuscular injection and as a powder for inhalation.<ref name="ADASUVE PI" /><ref name="LOXITANE PI" />

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),<ref name="Taylor_2012">Template:Cite book</ref> and movement problems (i.e. extrapyramidal symptoms [EPS]).<ref name="Chakrabarti Cochrane 2007">Template:Cite journal</ref> At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics.<ref name="Nordstrom_2012">Template:Cite journal</ref> 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.<ref name="DePaulo review 1982">Template:Cite journal</ref><ref name="Singh et al 1996">Template:Cite journal</ref> Abuse of loxapine has been reported.<ref name="Sperry et al 1984">Template:Cite journal</ref>

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.<ref name="ADASUVE PI">Template:Cite web</ref>

Pharmacology

Mechanism of action

Some scientists say loxapine is a "mid-potency" typical antipsychotic.<ref name="Singh et al 1996" /> 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.<ref name="Singh et al 1996" />

Loxapine (and metabolite)<ref name="PDSP">Template:Cite web</ref><ref name="Appl_2012">Template:Cite journal</ref>

Site	Template:Abbr	Template:Abbrlink
5-HT1A	2460	Template:Abbr
5-HT1B	388	Template:Abbr
5-HT1D	3470	Template:Abbr
5-HT1E	1400	Template:Abbr
5-HT2A	6.6	0.5
5-HT2C	13	2 (rat)
5-HT3	190	Template:Abbr
5-HT5A	780	Template:Abbr
5-HT6	31	50
5-HT7	88	40 (rat)
α1A	31	Template:Abbr
α1B	53	Template:Abbr
α2A	151	Template:Abbr
α2B	108	Template:Abbr
α2C	80	Template:Abbr
β1	10000+	Template:Abbr
β2	10000+	Template:Abbr
M1	120	Template:Abbr
M2	445	Template:Abbr
M3	211	Template:Abbr
M4	1270	Template:Abbr
M5	166	Template:Abbr
D1	54	Template:Abbr
D2	11	21
D3	19	21
D4	8.4	21
D5	75	Template:Abbr
H1	2.2–4.9	7.9–25
H2	208	Template:Abbr
H3	55000	>100,000
H4	5050–8710	6,310
Template:Abbrlink	10000+	58
Template:Abbrlink	5700	16
Template:Abbrlink	10000+	58
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

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).<ref>Template:Cite journal</ref> Given its strong safety profile and speed/efficacy when given intramuscularly for acute agitation,<ref>Template:Cite journal</ref> an inhaled version of the drug (Adasuve) has been developed to be applied nasally for agitated patients needing to be rapidly de-escalated.<ref>Template:Cite journal</ref>

Pharmacokinetics

Loxapine is metabolized to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine).<ref name="DrugPoint" /> Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine.<ref name="Simpson et al 1978">Template:Cite journal</ref> 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.<ref name="Simpson et al 1978" />

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.<ref name="Simpson et al 1978" />

Chemistry

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

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

External links

• Template:Cite web