Lowest-Observed-Adverse Effect Level see Levels of Effect in Toxicology Assessment

Lowest-Observed-Effect Level see Levels of Effect in Toxicology Assessment

Loxapine
FL Cantrell, California Poison Control System, San Diego, CA, USA
2014 Elsevier Inc. All rights reserved.
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Name: Loxapine
Chemical Abstracts Service Registry Number: 27833-64-3
Synonyms: Loxapine hydrochloride; Loxapine succinate;
2-Chloro-11-(4-methylpiperazin-1-yl)dibenz[1,4]oxazepine;
Oxilapine; Loxitane
Chemical/Pharmaceutical/Other Class: Dibenzoxazepine
antipsychotic
Molecular Formula: C18H18ClN3O
Chemical Structure:

Environmental Fate and Behavior

Physicochemical Properties
Loxapine has a melting point of 109110  C. The log P,
refractivity, and polarizability of loxapine are 3.6, 95.11, and
34.99, respectively. Loxapine succinate (salt) has a melting
point of 150152  C, boiling point of 458.6  C at 760 mm Hg,
and ash point of 231.1  C.

Exposure Routes and Pathways

N

Loxapine is available in oral liquid, oral capsule, and injectable

dosage forms. The principal exposure pathway is intentional
ingestion by adults or accidental ingestion by children.

NCH3

CI

Toxicokinetics

Loxapine was rst developed in the late 1960s and was introduced into clinical practice in the following decade. It is used
primarily to treat the psychotic symptoms of schizophrenia.
It is a member of the dibenzoxazepine class and is structurally
related to clozapine. The introduction of newer antipsychotic
agents has resulted in the reduced utilization of loxapine over
the last few decades.

Loxapine is readily but incompletely absorbed. Due to rstpass metabolism, oral bioavailability is 30% less than
bioavailability after intramuscular injection. Peak blood
levels occur 1 or 2 h after oral administration and 5 h after
intramuscular injection. Loxapine is extensively metabolized
in the liver through aromatic hydroxylation, N-demethylation, or N-oxidation. The metabolite amoxapine is active
and marketed as an antidepressant. Loxapine is widely
distributed throughout the body, including the central nervous
system. The main metabolites are excreted both in the urine
and feces, and 50% of a single oral dose is eliminated within
24 h. The mean half-lives of oral loxapine and that administered through intramuscular injection are 4 and 12 h,
respectively.

Uses

Mechanism of Toxicity

Loxapine is used to treat and control the psychotic symptoms

of both acute and chronic schizophrenia. Other uses include
treatment of dementia, anxiety neurosis, hostile/aggressive
behavior, and psychotic depression. An inhalation powder of
loxapine (Adasuve) was recently approved in the United
States and the European Union for the acute management of
agitation in patients with bipolar disorder or schizophrenia.

Loxapine has antagonistic action on alpha1 adrenergic,

muscarinic, serotonergic, and dopaminergic receptors. It is
thought to change the level of excitability in subcortical
inhibitory areas of the brain by reducing the ring threshold
of some polysynaptic neurons leading to seizure activity.
Anticholinergic effects are also reported with loxapine
intoxication.

Background

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Loxapine

Acute and Short-Term Toxicity (Animal/Human)

Animal
No specic information is identied. Signs of toxicity are
expected to include sedation, dullness, hypotension, respiratory
depression, anorexia, colic, weakness, fever, icterus, restlessness,
and seizures. Treatment consists of aggressive supportive care
and gastric decontamination. The LD50 (oral) in mice is
65 mg kg 1.

Human
Clinical signs of toxicity most frequently seen include sedation,
coma, seizures, extrapyramidal symptoms, and rarely hypotension and cardiac arrhythmias. Coma and seizures may
develop rapidly following an exposure to loxapine. Cardiac
effects include prolonged QRS, QT intervals, and mild
hypotension; however, the cardiac effects are less pronounced
than those associated with tricyclic antidepressants. Anticholinergic effects, including dry mouth, blurred vision, and
tachycardia, have been seen. Neuroleptic malignant syndrome
has been reported after therapeutic use and acute intoxication.
Hypokalemia has also been noted.

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Clinical Management
Basic and advanced life-support measures should be utilized
as needed. There is no antidote for loxapine exposure. In
patients presenting within 1 h of ingestion, activated charcoal
should be administered. Benzodiazepines are the drug of
choice for seizures. Initial treatment of conduction disturbances should include electrolyte normalization and intravenous sodium bicarbonate. Antidysrhythmic class 1A agents
should be avoided. Dystonic reactions respond well to intravenous benztropine or diphenhydramine. Oral therapy with
diphenhydramine or benztropine should be continued for
2 days to prevent recurrence of the dystonic reaction. For
patients with neuroleptic malignant syndrome, rapid external
cooling and aggressive muscle relaxation with benzodiazepines
or nondepolarizing neuromuscular blocking agents and quality
supportive care are the mainstay of therapy. Bromocriptine has
been used in conjunction with other supportive measures.
Hemodialysis and hemoperfusion have not been shown to be
effective.

See also: Alpha Blockers; Phenothiazines; Poisoning

Emergencies in Humans; Tricyclic Antidepressants.

Chronic Toxicity
Human
Adverse reactions following therapeutic use include sedation,
dizziness, insomnia, agitation, tardive dyskinesia, dysphoria,
dystonic reactions, tachycardia, syncope, anorexia, nausea,
vomiting, constipation, diarrhea, and dyspepsia. The most
frequently reported dystonic reactions include akathisia, stiff
neck, stiff or protruding tongue, and tremor. Gynecomastia can
occur with chronic use as well.

Reproductive Toxicity
No teratogenicity was observed in studies of loxapine in pregnant rats, dogs, or rabbits. In rats treated from midpregnancy
with 0.6 and 1.8 mg kg 1 renal papillary abnormalities were
seen in their offspring. Neonates that are exposed to loxapine
during the third trimester may be at risk for extrapyramidal
symptoms and possibly withdrawal symptoms after delivery.
Agitation, hyper and hypotonia, tremors, somnolence, respiratory difculties, and poor feeding in neonates exposed to
loxapine in utero. Loxapine has been shown to be transported
into milk from nursing dogs. It is not known if it is excreted
in human milk. Nursing mothers should avoid loxapine if
possible.

Further Reading
Chakrabarti, A., Bagnall, A., Chue, P., Fenton, M., Palaniswamy, V., Wong, W., Xia, J.,
October 17, 2007. Loxapine for schizophrenia. Cochrane Database Syst. Rev. 4,
CD001943.
Glazer, W.M., 1999. Does loxapine have atypical properties? Clinical evidence.
J. Clin. Psychiatry 60 (Suppl. 10), 4248.
Juckel, G., 2013. Inhalative loxapine: old tried and trusted medication with new
indications. Nervenarzt 84 (9), 11131116.
Keating, G.M., 2013. Loxapine inhalational powder: a review of its use in the acute
treatment of agitation in patients with bipolar disorder or schizophrenia. CNS Drugs
27 (6), 479489.
Mazzola, C.D., Miron, S., Jenkins, A.J., October 2000. Loxapine intoxication: case
report and literature review. J. Anal. Toxicol. 24 (7), 638641.
Peterson, C.D., August 1981. Seizures induced by acute loxapine overdose.
Am. J. Psychiatry 138 (8), 10891091.

Relevant Websites
http://www.emedicinehealth.com/drug-loxapine/page3_em.htm emedicinehealth
webpage with information on loxapine for patients and prescribers.
http://www.medicalnewstoday.com/articles/254474.php Medical News Today (MNT)
Adusave inhalation powder approved for schizophrenia or bipolar agitation.