Amoxapine

Amoxapine
Clinical data
Trade names Asendin, Asendis, Defanyl, Demolox
AHFS/Drugs.com Monograph
MedlinePlus a682202
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code N06AA17 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability >60%[1]
Protein binding 90%[2]
Metabolism Hepatic (cytochrome P450 system)[1]
Biological half-life 8–10 hours (30 hours for chief active metabolite)[2]
Excretion Renal (60%), faeces (18%)[1]
Identifiers
CAS Number 14028-44-5 YesY
PubChem (CID) 2170
IUPHAR/BPS 201
DrugBank DB00543 YesY
ChemSpider 2085 YesY
UNII R63VQ857OT YesY
KEGG D00228 YesY
ChEBI CHEBI:2675 YesY
ChEMBL CHEMBL1113 YesY
Chemical and physical data
Formula C17H16ClN3O
Molar mass 313.781 g/mol
3D model (Jmol) Interactive image
  (verify)

Amoxapine (pronounced: a-mox-a-peen.[3] Notable brand names include: Asendin, Asendis, Defanyl, Demolox. See here for more brand name information) is a tetracyclic antidepressant of the dibenzoxazepine family, though it is often classified as a secondary amine tricyclic antidepressant. It is the N-demethylated metabolite of loxapine. It first received marketing approval in the US in 1992 (approximately thirty to forty years after most of the other tricyclic antidepressants were introduced in the US).[3]

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.[4][5] In excess of 80% of patients that do respond to amoxapine are reported to respond within a fortnight of the beginning of treatment.[6] It also has properties similar to those of the atypical antipsychotics,[7][8][9] and may behave as one[10][11] 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 psychosis.[12]

Adverse effects

Adverse effects by incidence:[1][13]
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:

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

Uncommon/Rare (<1% incidence) adverse effects include:

  • Diarrhoea
  • Flatulence
  • Hypertension (high blood pressure)
  • Hypotension (low blood pressure)
  • Syncope (fainting)
  • Tachycardia (high heart rate)
  • Menstrual irregularity
  • Disturbance of accommodation
  • Mydriasis (pupil dilation)
  • Orthostatic hypotension (a drop in blood pressure that occurs upon standing up)
  • Seizure
  • Urinary retention (being unable to pass urine)
  • Urticaria (hives)
  • Vomiting
  • Nasal congestion
  • Photosensitization
  • Hypomania (a dangerously elated/irritable mood)
  • Tingling
  • Paresthesias of the extremities
  • Tinnitus
  • Disorientation
  • Numbness
  • Incoordination
  • Disturbed concentration
  • Epigastric distress
  • Peculiar taste in the mouth
  • Increased or decreased libido
  • Impotence (difficulty achieving an erection)
  • Painful ejaculation
  • Lacrimation (crying without an emotional cause)
  • Weight gain
  • Altered liver function
  • Breast enlargement
  • Drug fever
  • Pruritus (itchiness)

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 tricyclic antidepressants (e.g. amitriptyline, clomipramine, doxepin, imipramine and trimipramine).[14] It may also be less cardiotoxic than its predecessors.[15]

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.[1] Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations.[1] Its use is also recommended against in the following disease states:[1]

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. ondansetron, citalopram, pimozide, sertindole, ziprasidone, haloperidol, chlorpromazine, thioridazine, etc.).[1]

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.[4][16]

Overdose

It is considered particularly toxic in overdose,[17] with a high rate of renal failure (which usually takes 2–5 days), rhabdomyolysis, coma, seizures and even status epilepticus.[15] Some believe it to be less cardiotoxic than other tricyclic antidepressants in overdose, although reports of cardiotoxic overdoses have been made.[4][13]

Pharmacodynamics

Amoxapine possesses a wide array of pharmacological effects. It is a moderate and strong reuptake inhibitor of serotonin and norepinephrine, respectively,[18] and binds to the 5-HT2A,[19] 5-HT2B,[20] 5-HT2C,[19] 5-HT3,[21] 5-HT6,[22] 5-HT7,[22] D2,[23] α1-adrenergic,[23] D3,[24] D4,[24] and H1 receptors[23] with varying but significant affinity, where it acts as an antagonist (or inverse agonist depending on the receptor in question) at all sites. It has weak but negligible affinity for the dopamine transporter and the 5-HT1A,[21] 5-HT1B,[21] D1,[25] α2-adrenergic,[23] H4,[26] mACh,[23] and GABAA receptors,[25] and no affinity for the β-adrenergic receptors or the allosteric benzodiazepine site on the GABAA receptor.[25] Amoxapine is also a weak GlyT2 blocker,[27] as well as a weak (Ki = 2.5 μM, EC50 = 0.98 μM) δ-opioid receptor partial agonist.[28]

7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy,[7] 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.[29]

The data in the following table from obtained from the PDSP Ki database.[30][31]

Molecular Target Binding Affinity (Ki [nM]) Source
5-HT2A 0.5 Human, Cloned
5-HT2C 2 Rat, Cloned
5-HT6 50 Human, Cloned
5-HT7 40.2 Rat, Cloned
D2 20.8 Human, Cloned
D3 21 Human, Cloned
D4 21 Human, Cloned
H1 25 Human, Cloned
α1 50 Human, Cloned
mAChRs 1000 Human, Cloned
DAT 4310 Human, Cloned
NET 16 Human, Cloned
SERT 58 Human, Cloned

Pharmacokinetics

Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine.[32]

Amoxapine
7-hydroxyamoxapine
8-hydroxyamoxapine
Compound[32][33][34] t1/2 (hr)[35] tmax (hr) CSS (ng/mL) Protein binding[1] Vd[1] Excretion[1]
Amoxapine 8 1-2 17-93 ng/mL (divided dosing), 13-209 ng/mL (single daily dosing) 90% 0.9-1.2 L/kg Urine (60%), faeces (18%)
8-hydroxyamoxapine 30 5.3 (single dosing) 158-512 ng/mL (divided dosing), 143-593 ng/mL (single dose) ? ? ?
7-hydroxyamoxapine 6.5 2.6-5.4 (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.

Brand names

Brand names for amoxapine include (where † denotes discontinued brands):[4][36]

See also

References

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  2. 1 2 Kinney, JL; Evans, RL (September–October 1982). "Evaluation of amoxapine". Clinical Pharmacy. 1 (5): 417–24. PMID 6764165.
  3. 1 2 "Amoxapine: Indications, Side Effects, Warnings -Drugs.com". Drugs.com. Drugs.com. 6 November 2013. Retrieved 26 November 2013.
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  6. Product Information: Asendin(R), amoxapine tablets. Physicians' Desk Reference (electronic version), MICROMEDEX, Inc, Englewood, CO, USA, 1999.
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  9. Wadenberg, M-LG; Sills, TL; Fletcher, PJ; Kapur, S (April 2000). "Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats". Biological Psychiatry. 47 (7): 670–676. doi:10.1016/S0006-3223(99)00267-X. PMID 10745061.
  10. Apiquian, R; Fresan, A; Ulloa, RE; de la Fuente-Sandoval, C; Herrera-Estrella, M; Vazquez, A; Nicolini, H; Kapur, S (December 2005). "Amoxapine as an atypical antipsychotic: a comparative study vs risperidone". Neuropsychopharmacology. 30 (12): 2236–2244. doi:10.1038/sj.npp.1300796. PMID 15956984.
  11. Chaudhry, IB; Husain, N; Khan, S; Badshah, S; Deakin, B; Kapur, S (December 2007). "Amoxapine as an Antipsychotic: Comparative Study Versus Haloperidol". Journal of Clinical Psychopharmacology. 27 (6): 575–581. doi:10.1097/jcp.0b013e31815a4424. PMID 18004123.
  12. Sa, DS; Kapur, S; Lang, AE (July–August 2001). "Amoxapine Shows an Antipsychotic Effect but Worsens Motor Function in Patients with Parkinson's Disease and Psychosis". Clinical Neuropharmacology. 24 (4): 242–244. doi:10.1097/00002826-200107000-00010. PMID 11479398.
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  17. White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type" (PDF). Journal of Medical Toxicology. 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116Freely accessible. PMID 19031375.
  18. Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–58. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
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