Chemistry:Asenapine

From HandWiki
Short description: Medication to treat schizophrenia
Asenapine
Skeletal formula of asenapine
Ball-and-stick model of the asenapine molecule
Clinical data
Trade namesSaphris, Sycrest, Secuado
Other namesORG-5222
AHFS/Drugs.comMonograph
MedlinePlusa610015
License data
Pregnancy
category
  • AU: C
Routes of
administration		Sublingual, transdermal
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability35% (sublingual), <2% (Oral)[3][4][1][5]
Protein binding95%[3][4][1][5]
Metabolismhepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)[3][4][1][5]
Elimination half-life24 hours[3][4][1][5]
ExcretionKidney (50%), Faecal (40%; ~5–16% as unchanged drug in faeces)[3][4][1][5]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H16ClNO
Molar mass285.77 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder as well as the medium to long-term management of bipolar disorder.[2][6]

It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.[7]

It was initially approved in the United States in 2009[8] and approved as a generic medication in 2020.[9]

Medical uses

Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.[8] In Australia asenapine's approved (and also listed on the PBS) indications include the following:[10]

  • Schizophrenia
  • Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
  • Maintenance treatment, as monotherapy, of bipolar I disorder

In the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.[1][5][2]

Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.[11] A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.[12]

Schizophrenia

A Cochrane systematic review found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of asenapine for the treatment of schizophrenia.[13]

Bipolar disorder

For the medium-term and long-term management and control of both depressive and manic features of bipolar disorder asenapine was found be equally effective as olanzapine, but with a substantially superior side effect profile.[6]

In acute mania, asenapine was found to be significantly superior to placebo.[6] As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs such as risperidone and olanzapine (with the exception of ziprasidone). Drop-out rates (in clinical trials) were also unusually high with asenapine.[14] According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.[15]

Adverse effects

Adverse effect incidence[3][4][1][5]

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

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

Uncommon (0.1–1% incidence) adverse effects include:

Rare (0.01–0.1% incidence) adverse effects include:

Unknown incidence adverse effects

  • Allergic reaction
  • Restless legs syndrome
  • Nausea
  • Oral mucosal lesions (ulcerations, blistering and inflammation)
  • Salivary hypersecretion
  • Hyperprolactinaemia

dagger Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).[18] Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis.[18] This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic.[18] The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics.[18]

Discontinuation

For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse.[19] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[20] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[20] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[20] Symptoms generally resolve after a short period of time.[20]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a transient withdrawal symptom.[21] It may also result in recurrence of the condition that is being treated.[22] Rarely tardive dyskinesia can occur when the medication is stopped.[20]

Pharmacology

Pharmacodynamics

Asenapine[23][8]
Site pKi Ki (nM) Action
5-HT1A 8.6 2.5 Partial agonist
5-HT1B 8.4 4.0 Antagonist
5-HT2A 10.2 0.06 Antagonist
5-HT2B 9.8 0.16 Antagonist
5-HT2C 10.5 0.03 Antagonist
5-HT5A 8.8 1.6 Antagonist
5-HT6 9.5 0.25 Antagonist
5-HT7 9.9 0.13 Antagonist
α1 8.9 1.2 Antagonist
α2A 8.9 1.2 Antagonist
α2B 9.5 0.32 Antagonist
α2C 8.9 1.2 Antagonist
D1 8.9 1.4 Antagonist
D2 8.9 1.3 Antagonist
D3 9.4 0.42 Antagonist
D4 9.0 1.1 Antagonist
H1 9.0 1.0 Antagonist
H2 8.2 6.2 Antagonist
mACh <5 8128 Antagonist

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors.[24] At all other targets asenapine is an antagonist.[23]

Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors.[23]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Sycrest 5mg sublingual tablets - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/2807/smpc. 
  2. ↑ 2.0 2.1 2.2 "Sycrest EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/sycrest. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Product Information Saphris (asenapine maleate)" (PDF). TGA eBusiness Services. Merck Sharp & Dohme (Australia) Pty Limited. 14 January 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03052-3. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Saphris (asenapine maleate) tablet". DailyMed. Organon Pharmaceuticals. March 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=17209c32-56eb-4f84-954d-aed7b7a1b18d. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Product information Sycrest – EMEA/H/C/001177 –II/0012". European Medicines Agency. N.V. Organon. 21 February 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001177/WC500096895.pdf. 
  6. ↑ 6.0 6.1 6.2 "Efficacy and tolerability of asenapine for acute mania in bipolar I disorder: meta-analyses of randomized-controlled trials". International Clinical Psychopharmacology 28 (5): 219–227. September 2013. doi:10.1097/YIC.0b013e32836290d2. PMID 23719049. 
  7. ↑ "Evaluation of the clinical efficacy of asenapine in schizophrenia". Expert Opinion on Pharmacotherapy 11 (12): 2107–2115. August 2010. doi:10.1517/14656566.2010.506188. PMID 20642375. 
  8. ↑ 8.0 8.1 8.2 "Saphris (asenapine) prescribing information". Schering Corporation. 2009-08-01. http://www.spfiles.com/pisaphrisv1.pdf. 
  9. ↑ "First Generic Drug Approvals". https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals. 
  10. ↑ Rossi, S, ed (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  11. ↑ "Asenapine: a clinical review of a second-generation antipsychotic". Clinical Therapeutics 34 (5): 1023–1040. May 2012. doi:10.1016/j.clinthera.2012.03.002. PMID 22494521. 
  12. ↑ "Transdermal Asenapine in Schizophrenia: A Systematic Review". Patient Preference and Adherence 14: 1541–1551. 18 March 2020. doi:10.2147/PPA.S235104. PMID 32943849. 
  13. ↑ "Asenapine versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews 2015 (11): CD011458. November 2015. doi:10.1002/14651858.CD011458.pub2. PMID 26599405. 
  14. ↑ "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet 378 (9799): 1306–1315. October 2011. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976. 
  15. ↑ "Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials". BMC Psychiatry 11: 101. June 2011. doi:10.1186/1471-244X-11-101. PMID 21689438. 
  16. ↑ "Which psychotropics carry the greatest risk of QTc prolongation?". Current Psychiatry 11 (10): 36–39. October 2012. http://www.mdedge.com/currentpsychiatry/article/64870/anxiety-disorders/which-psychotropics-carry-greatest-risk-qtc. Retrieved 14 April 2017. 
  17. ↑ The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. 2012. ISBN 978-0-470-97948-8. 
  18. ↑ 18.0 18.1 18.2 18.3 "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  19. ↑ Joint Formulary Committee, BMJ, ed (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse." 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 (in en) Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. 2004. pp. 207–216. ISBN 9780198527480. https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207. 
  21. ↑ "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica 114 (1): 3–13. July 2006. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
  22. ↑ (in en) Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. 2013. p. 85. ISBN 9788847026797. https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85. 
  23. ↑ 23.0 23.1 23.2 "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature". Journal of Psychopharmacology 23 (1): 65–73. January 2009. doi:10.1177/0269881107082944. PMID 18308814. 
  24. ↑ "Electrophysiological characterization of the effects of asenapine at 5-HT(1A), 5-HT(2A), alpha(2)-adrenergic and D(2) receptors in the rat brain". European Neuropsychopharmacology 19 (3): 177–187. March 2009. doi:10.1016/j.euroneuro.2008.11.001. PMID 19116183. 

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Asenapine&oldid=3327158"