Amoxapine

Amoxapine

Clinical data
Pronunciation	A-mox-a-peen[1]
Trade names	Asendin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682202
License data	US  FDA: Amoxapine
Routes of administration	Oral
ATC code	N06AA17 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[3] US: WARNING[2]Rx-only
Renal (60%), feces (18%)[4]
Identifiers
IUPAC name 2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine
JSmol)	Interactive image
SMILES Clc2ccc1Oc4c(/N=C(\c1c2)N3CCNCC3)cccc4
InChI InChI=1S/C17H16ClN3O/c18-12-5-6-15-13(11-12)17(21-9-7-19-8-10-21)20-14-3-1-2-4-16(14)22-15/h1-6,11,19H,7-10H2 Y Key:QWGDMFLQWFTERH-UHFFFAOYSA-N Y
(verify)

Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximately 10 to 20 years after most of the other TCAs were introduced in the United States.^[6]

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.^[7][8] In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment.^[9] It also has properties similar to those of the atypical antipsychotics,^[10][11][12] and may behave as one^[13][14] and thus 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 worsen motor function in a study of three patients with Parkinson's disease and psychosis.^[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.^[4] Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations.^[4] Its use is also recommended against in the following disease states:^[4]

• 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

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.[7]^[16]

Side effects

Adverse effects by incidence:^[4][17]
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:

• Oedema
  . An abnormal accumulation of fluids in the tissues of the body leading to swelling.
• 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 (<1% incidence) adverse effects include:

• Vasculitis a disorder where blood vessels are destroyed by inflammation. Can be life-threatening if it affects the right blood vessels.
• Galactorrhoea
  (lactation that is not associated with pregnancy or breast feeding)
• Delayed micturition (that is, delays in urination from when a conscious effort to urinate is made)
• Hyperthermia (elevation of body temperature; its seriousness depends on the extent of the hyperthermia)
• hypocalcaemia
  (low blood calcium) which can be life-threatening.
• Agranulocytosis a drop in white blood cell counts. The white blood cells are the cells of the immune system that fight off foreign invaders. Hence agranulocytosis leaves an individual open to life-threatening infections.
• Leukopaenia the same as agranulocytosis but less severe.
• Neuroleptic malignant syndrome (a potentially fatal reaction to antidopaminergic agents, most often antipsychotics. It is characterised by hyperthermia, diarrhoea, tachycardia, mental status changes [e.g. confusion], rigidity, extrapyramidal side effects)
• Tardive dyskinesia a most often irreversible neurologic reaction to antidopaminergic treatment, characterised by involuntary movements of facial muscles, tongue, lips, and other muscles. It develops most often only after prolonged (months, years or even decades) exposure to antidopaminergics.
• Extrapyramidal side effects. Motor symptoms such as tremor, parkinsonism
  , involuntary movements, reduced ability to move one's voluntary muscles, etc.

Unknown incidence or relationship to drug treatment adverse effects include:

• Paralytic ileus (paralysed bowel)
• Atrial arrhythmias including atrial fibrillation
• Myocardial infarction (heart attack)
• Stroke
• Heart block
• Hallucinations
• Purpura
• Petechiae
• Parotid swelling
• Changes in blood glucose levels
• Pancreatitis swelling of the pancreas
• Hepatitis swelling of the liver
• Urinary frequency
• Testicular swelling
• Anorexia (weight loss)
• Alopecia
  (hair loss)

• Thrombocytopenia a significant drop in platelet count that leaves one open to life-threatening bleeds.
• Eosinophilia an elevated level of the eosinophils of the body. Eosinophils are the type of immune cell that's job is to fight off parasitic invaders.
• Jaundice yellowing of the skin, eyes and mucous membranes due to an impaired ability of the body to clear the by product of haem breakdown, bilirubin, most often the result of liver damage as it is the liver's responsibility to clear bilirubin.

It tends to produce less

anticholinergic effects, sedation and weight gain than some of the earlier TCAs (e.g. amitriptyline, clomipramine, doxepin, imipramine, trimipramine).^[18] It may also be less cardiotoxic than its predecessors.^[19]

Overdose

Main article: Tricyclic antidepressant overdose

It is considered particularly toxic in overdose,

renal failure (which usually takes 2–5 days), rhabdomyolysis, coma, seizures and even status epilepticus.^[19] Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made.^[7][17]

Pharmacology

Pharmacodynamics

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles

Amoxapine^[21]

Site	Ki (nM)	Species	Ref
SERTTooltip Serotonin transporter	58	Human	[22]
NETTooltip Norepinephrine transporter	16	Human	[22]
DATTooltip Dopamine transporter	4,310	Human	[22]
5-HT2A	0.5	Human	[23]
5-HT2C	2.0	Monkey	[24]
5-HT6	6.0–50	Human	[24][25]
5-HT7	41	Monkey	[24]
α1	50	Human	[26]
α2	2,600	Human	[26]
D2	3.6–160	Human	[27][23][26]
D3	11	Human	[23]
D4	2.0–40	Human	[23]
H1	7.9–25	Human	[28][26]
H2	ND	ND	ND
H3	>100,000	Human	[28]
H4	6,310	Human	[28]
mAChTooltip Muscarinic acetylcholine receptor	1,000	Human	[26]
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

benzodiazepine site on the GABA_A receptor.^[32] Amoxapine is also a weak GlyT2 blocker,^[34] as well as a weak (K_i = 2.5 μM, EC₅₀ = 0.98 μM) δ-opioid receptor partial agonist.^[35]

7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy,^[10] 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.^[36]

Pharmacokinetics

Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine.^[37]

Compound[37][38][39]	t1/2 (hr)[40]	tmax (hr)	CSS (ng/mL)	Protein binding[4]	Vd[4]	Excretion[4]
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%), feces (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:

• t_1/2 is the elimination half life of the compound.
• t_max is the time to peak plasma levels after oral administration of amoxapine.
• C_SS is the steady state plasma concentration.
• protein binding is the extent of plasma protein binding.
• V_d is the volume of distribution of the compound.

Society and culture

Brand names

Brand names for amoxapine include (where † denotes discontinued brands):^[7][41]

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

See also

• Loxapine

References

1. ^ "Amoxapine: Indications, Side Effects, Warnings -Drugs.com". Drugs.com. 6 November 2013. Retrieved 26 November 2013.
2. FDA
   . Retrieved 22 October 2023.
3. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
4. ^ ^{a b c d e f g h i j k} "Asendin, (amoxapine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 26 November 2013.
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6. ^ National Center for Drugs and Biologics (U.S.) (1984). Approved Prescription Drug Products with Therapeutic Equivalence Evaluations (5th, Cumulative Supplement 3 ed.). Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration. p. IV-9.
7. ^ ^{a b c d} Amoxapine. London, UK: Pharmaceutical Press. 30 January 2013. Retrieved 26 November 2013. {{cite book}}: |work= ignored (help)
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9. ^ Product Information: Asendin(R), amoxapine tablets. Physicians' Desk Reference (electronic version), MICROMEDEX, Inc, Englewood, CO, USA, 1999.
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11. S2CID 21407817
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    ISBN 978-0-7020-4293-5
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    S2CID 2247093
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    S2CID 253747520
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31. ^
    PMID 1666997
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    PMID 1966571
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33. S2CID 24248896
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35. S2CID 18893305
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36. PMID 10507241
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37. ^
    S2CID 7279867
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40. ^ "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.
41. ^ "Amoxapine -Drugs.com". Drugs.com. 2013. Retrieved 26 November 2013.