Amoxapine

Amoxapine
Systematic (IUPAC) name
2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine
Clinical data
Trade names Asendin, Asendis, Defanyl, Demolox
AHFS/Drugs.com monograph
MedlinePlus a682202
Licence data US FDA:link
  • US: C (Risk not ruled out)
  • AU: Prescription Only (S4)
  • US: ℞-only
Oral
Pharmacokinetic data
Bioavailability >60%[1]
Protein binding 90%[2]
Metabolism Hepatic (cytochrome P450 system)[1]
Half-life 8–10 hours (30 hours for chief active metabolite)[2]
Excretion Renal (60%), faeces (18%)[1]
Identifiers
14028-44-5 Yes
N06AA17
PubChem CID 2170
IUPHAR ligand 201
DrugBank DB00543 Yes
ChemSpider 2085 Yes
UNII R63VQ857OT Yes
KEGG D00228 Yes
ChEBI CHEBI:2675 Yes
ChEMBL CHEMBL1113 Yes
Chemical data
Formula C17H16ClN3O
313.781 g/mol
 Yes (what is this?)  (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]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 "Asendin, (amoxapine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 26 November 2013.
  2. ↑ 2.0 2.1 Kinney, JL; Evans, RL (September–October 1982). "Evaluation of amoxapine". Clinical Pharmacy 1 (5): 417–24. PMID 6764165.
  3. ↑ 3.0 3.1 3.2 "Amoxapine: Indications, Side Effects, Warnings -Drugs.com". Drugs.com. Drugs.com. 6 November 2013. Retrieved 26 November 2013.
  4. ↑ 4.0 4.1 4.2 4.3 Amoxapine. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). 30 January 2013. Retrieved 26 November 2013.
  5. ↑ Ban, TA; Fujimori, M; Petrie, WM; Ragheb, M; Wilson, WH (1982). "Systematic studies with amoxapine, a new antidepressant". International Pharmacopsychiatry 17 (1): 18–27. PMID 7045016.
  6. ↑ Product Information: Asendin(R), amoxapine tablets. Physicians' Desk Reference (electronic version), MICROMEDEX, Inc, Englewood, CO, USA, 1999.
  7. ↑ 7.0 7.1 Cohen, BM; Harris, PQ; Altesman, RI; Cole, JO (September 1982). "Amoxapine: neuroleptic as well as antidepressant?". The American Journal of Psychiatry 139 (9): 1165–7. PMID 6126130.
  8. ↑ Kapur, S; Cho, R; Jones, C; McKay, G; Zipursky, RB (May 1999). "Is amoxapine an atypical antipsychotic? positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy". Biological Psychiatry 45 (9): 1217–1220. doi:10.1016/S0006-3223(98)00204-2. PMID 10331115.
  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.
  13. ↑ 13.0 13.1 "AMOXAPINE TABLET [WATSON LABORATORIES, INC.]". DailyMed. Watson Laboratories, Inc. July 2010. Retrieved 26 November 2013.
  14. ↑ "Side effects of antidepressant medications". UpToDate. Wolters Kluwer Health. Retrieved 26 November 2013.
  15. ↑ 15.0 15.1 Walker, R; Whittlesea, C, ed. (2007) [1994]. Clinical Pharmacy and Therapeutics (4th ed.). Edinburgh: Churchill Livingstone Elsevier. ISBN 978-0-7020-4293-5.
  16. ↑ Gelenberg, AJ; Cooper, DS; Doller, JC; Maloof, F (October 1979). "Galactorrhea and Hyperprolactinemia Associated With Amoxapine Therapy". JAMA 242 (17): 1900–1901. doi:10.1001/jama.1979.03300170046029. PMID 573343.
  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 3550116. 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.
  19. ↑ 19.0 19.1 Pälvimäki EP, Roth BL, Majasuo H et al. (August 1996). "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology 126 (3): 234–40. doi:10.1007/BF02246453. PMID 8876023.
  20. ↑ Glusa E, Pertz HH (June 2000). "Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT2B receptors". British Journal of Pharmacology 130 (3): 692–8. doi:10.1038/sj.bjp.0703341. PMC 1572101. PMID 10821800.
  21. ↑ 21.0 21.1 21.2 Gozlan H, Saddiki-Traki F, Merahi N, Laguzzi R, Hamon M (December 1991). "[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats]". L'Encéphale (in French). 17 Spec No 3: 415–22. PMID 1666997.
  22. ↑ 22.0 22.1 Roth BL, Craigo SC, Choudhary MS et al. (March 1994). "Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors". The Journal of Pharmacology and Experimental Therapeutics 268 (3): 1403–10. PMID 7908055.
  23. ↑ 23.0 23.1 23.2 23.3 23.4 Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics 230 (1): 94–102. PMID 6086881.
  24. ↑ 24.0 24.1 Burstein ES, Ma J, Wong S et al. (December 2005). "Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist". The Journal of Pharmacology and Experimental Therapeutics 315 (3): 1278–87. doi:10.1124/jpet.105.092155. PMID 16135699.
  25. ↑ 25.0 25.1 25.2 Wei HB, Niu XY (1990). "[Comparison of the affinities of amoxapine and loxapine for various receptors in rat brain and the receptor down-regulation after chronic administration]". Yao Xue Xue Bao = Acta Pharmaceutica Sinica (in Chinese) 25 (12): 881–5. PMID 1966571.
  26. ↑ Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R (September 2005). "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist". The Journal of Pharmacology and Experimental Therapeutics 314 (3): 1310–21. doi:10.1124/jpet.105.087965. PMID 15947036.
  27. ↑ Harald Sitte; Michael Freissmuth (2 August 2006). Neurotransmitter Transporters. Springer Science & Business Media. pp. 472–. ISBN 978-3-540-29784-0.
  28. ↑ Onali P, Dedoni S, Olianas MC (January 2010). "Direct agonist activity of tricyclic antidepressants at distinct opioid receptor subtypes". J. Pharmacol. Exp. Ther. 332 (1): 255–65. doi:10.1124/jpet.109.159939. PMID 19828880.
  29. ↑ Midha KK, Hubbard JW, McKay G, Rawson MJ, Hsia D (September 1999). "The role of metabolites in a bioequivalence study II: amoxapine, 7-hydroxyamoxapine, and 8-hydroxyamoxapine". International Journal of Clinical Pharmacology and Therapeutics 37 (9): 428–38. PMID 10507241.
  30. ↑ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Aug 3]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from:http://pdsp.med.unc.edu/pdsp.php
  31. ↑ Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  32. ↑ 32.0 32.1 Jue, SG; Dawson, GW; Brogden, RN (July 1982). "Amoxapine: A Review of its Pharmacology and Efficacy in Depressed States". Drugs 24 (1): 1–23. doi:10.2165/00003495-198224010-00001. PMID 7049659.
  33. ↑ Calvo, B; García, MJ; Pedraz, JL; Mariño, EL; Domínguez-Gil, A (April 1985). "Pharmacokinetics of amoxapine and its active metabolites". International journal of clinical pharmacology, therapy, and toxicology 23 (4): 180–185. PMID 3997304.
  34. ↑ Takeuchi, H; Yokota, S; Shimada, S; Ohtani, Y; Miura, S; Kubo, H (April 1993). "Pharmacokinetics of amoxapine and its active metabolites in healthy subjects". Current Therapeutic Research 53 (4): 427–434. doi:10.1016/S0011-393X(05)80202-4.
  35. ↑ "Amoxapine Monograph for Professionals - Drugs.com". Drugs.com. Bethesda, MD, USA: American Society of Health-System Pharmacists, Inc. 1 October 2007. Retrieved 30 November 2013.
  36. ↑ "Amoxapine -Drugs.com". Drugs.com. Drugs.com. 2013. Retrieved 26 November 2013.