Amoxapine


Amoxapine, sold under the brand name Asendin among others, is a tetracyclic antidepressant. It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1992.

Medical uses

Amoxapine is used in the treatment of major depressive disorder. Compared to other antidepressants it is believed to have a faster onset of action, with therapeutic effects seen within four to seven days. In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment. It also has properties similar to those of the atypical antipsychotics, and may behave as one and may be used in the treatment of schizophrenia off-label. Despite its apparent lack of extrapyramidal side effects in patients with schizophrenia it has been found to exacerbate motor symptoms in patients with Parkinson's disease and psychosis.

Contraindications

As with all FDA-approved antidepressants it carries a black-box warning about the potential of an increase in suicidal thoughts or behaviour in children, adolescents and young adults under the age of 25. Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations. Its use is also recommended against in the following disease states:
Its use is also advised against in individuals concurrently on monoamine oxidase inhibitors or if they have been on one in the past 14 days and in individuals on drugs that are known to prolong the QT interval.

Lactation

Its use in breastfeeding mothers not recommended as it is excreted in breast milk and the concentration found in breast milk is approximately a quarter that of the maternal serum level.

Side effects

Adverse effects by incidence:

Note: Serious are written in bold text.
Very common adverse effects include:
Common adverse effects include:
Uncommon/Rare adverse effects include:
Unknown incidence or relationship to drug treatment adverse effects include:
It tends to produce less anticholinergic effects, sedation and weight gain than some of the earlier TCAs. It may also be less cardiotoxic than its predecessors.

Overdose

It is considered particularly toxic in overdose, with a high rate of renal failure, rhabdomyolysis, coma, seizures and even status epilepticus. Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made.

Pharmacology

Pharmacodynamics

Amoxapine possesses a wide array of pharmacological effects. It is a moderate and strong reuptake inhibitor of serotonin and norepinephrine, respectively, and binds to the 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D2, α1-adrenergic, D3, D4, and H1 receptors with varying but significant affinity, where it acts as an antagonist at all sites. It has weak but negligible affinity for the dopamine transporter and the 5-HT1A, 5-HT1B, D1, α2-adrenergic, H4, mACh, and GABAA receptors, and no affinity for the β-adrenergic receptors or the allosteric benzodiazepine site on the GABAA receptor. Amoxapine is also a weak GlyT2 blocker, as well as a weak δ-opioid receptor partial agonist.
7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy, whereas 8-hydroxyamoxapine is a norepinephrine reuptake inhibitor but a stronger serotonin reuptake inhibitor and helps to balance amoxapine's ratio of serotonin to norepinephrine transporter blockade.

Pharmacokinetics

Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine.
Compoundt1/2 tmax CSS Protein bindingVdExcretion
Amoxapine81-217-93 ng/mL, 13-209 ng/mL 90%0.9-1.2 L/kgUrine, feces
8-hydroxyamoxapine305.3 158-512 ng/mL, 143-593 ng/mL ???
7-hydroxyamoxapine6.52.6-5.4 ????

Where:
- t1/2 is the elimination half life of the compound.

- tmax is the time to peak plasma levels after oral administration of amoxapine.

- CSS is the steady state plasma concentration.

- protein binding is the extent of plasma protein binding.

- Vd is the volume of distribution of the compound.

Society and culture

Brand names

Brand names for amoxapine include :