Amoxapine

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Albert Flores

Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCAs). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1992 (approximately 30 to 40 years after most of the other TCAs were introduced in the United States).

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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. +more 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. +more Its use is also recommended against in the following disease states:.

* Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation) * Uncorrected narrow angle glaucoma * Acute recovery post-myocardial infarction

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 (e. g. +more ondansetron, citalopram, pimozide, sertindole, ziprasidone, haloperidol, chlorpromazine, thioridazine, etc. ).

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 (that is, those that can either result in permanent injury or are irreversible or are potentially life-threatening) are written in 'bold text.

Very common (>10% incidence) adverse effects include:

* Constipation * Dry mouth * Sedation

Common (1-10% incidence) adverse effects include:

* Anxiety * Ataxia * Blurred vision * Confusion * Dizziness * Headache * Fatigue * Nausea * Nervousness/restlessness * Excessive appetite * Rash * Increased perspiration (sweating) * Tremor * Palpitations * Nightmares * Excitement * Weakness * ECG changes

* Oedema. An abnormal accumulation of fluids in the tissues of the body leading to swelling. +more * Prolactin levels increased. Prolactin is a hormone that regulates the generation of breast milk. Prolactin elevation is not as significant as with risperidone or haloperidol.

Uncommon/Rare (

Overdose

It is considered particularly toxic in overdose, with a high rate of renal failure (which usually takes 2-5 days), 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

SiteKi (nM)SpeciesRef
58Human
16Human
4,310Human
5-HT2A0. 5Human
5-HT2C2. +more0Monkey
5-HT66. 0-50Human
5-HT741Monkey
α150Human
α22,600Human
D23. 6-160Human
D311Human
D42. 0-40Human
H17. 9-25Human
H2
H3>100,000Human
H46,310Human
1,000Human
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
.

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 (or inverse agonist depending on the receptor in question) at all sites. +more 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 (Ki = 2. 5 μM, EC50 = 0. 98 μM) 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 (hr)tmax (hr)CSS (ng/mL)Protein bindingVdExcretion
Amoxapine81-217-93 ng/mL (divided dosing), 13-209 ng/mL (single daily dosing)90%0. 9-1. +more2 L/kgUrine (60%), feces (18%)
8-hydroxyamoxapine305. 3 (single dosing)158-512 ng/mL (divided dosing), 143-593 ng/mL (single dose)???
7-hydroxyamoxapine6. 52. 6-5. 4 (single dosing)????
.

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 (where † denotes discontinued brands):

* Adisen (KR) * Amolife (IN) * Amoxan (JP) * Asendin† (previously marketed in CA, NZ, US) * Asendis† (previously marketed in IE, UK) * Défanyl (FR) * Demolox (DK†, IN, ES†) * Oxamine (IN) * Oxcap (IN)

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