Nefazodone

Nefazodone

Systematic (IUPAC) name
1-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-3-ethyl-4-(2-phenoxyethyl)-1H-1,2,4-triazol-5(4H)-one
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a695005
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	20% (variable)
Protein binding	>99%
Metabolism	Hepatic (active metabolites, including mCPP)[1]
Half-life	2–4 hours
Excretion	Urine (55%), Feces (20–30%)
Identifiers
CAS number	83366-66-9 Y
ATC code	N06AX06
PubChem	CID 4449
DrugBank	APRD00402
ChemSpider	4294 Y
UNII	59H4FCV1TF Y
KEGG	D08257 Y
ChEBI	CHEBI:7494 N
ChEMBL	CHEMBL623 Y
Chemical data
Formula	C25H32ClN5O2
Mol. mass	470.01 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C25H32ClN5O2/c1-2-24-27-31(25(32)30(24)18-19-33-23-10-4-3-5-11-23)13-7-12-28-14-16-29(17-15-28)22-9-6-8-21(26)20-22/h3-6,8-11,20H,2,7,12-19H2,1H3 Y Key:VRBKIVRKKCLPHA-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Nefazodone (Serzone, Nefadar) is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity (liver damage), which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years.^[2] On June 14, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States and Canada. Several generic formulations of nefazodone are still available.^[3][4]

Pharmacology

Nefazodone acts primarily as a potent antagonist at the 5-HT_2A receptors (Kd 26 nM).^[5] It also has moderate affinity for the α₁-adrenergic receptor (Kd 48 nM) and 5-HT_1A receptor (Kd 80 nM), and very low affinity for the α₂-adrenergic receptor (Kd 640 nM) and D₂ receptor (Kd 910 nM).^[5] It acts as an antagonist at all of these sites.^[5][6] Nefazodone has low affinity for the serotonin (200 nM), norepinephrine (360 nM), and dopamine (360 nM) transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).^[7] It has negligible affinity for the H₁ receptor (24,000 nM) or muscarinic acetylcholine receptors (11,000 nM), and accordingly lacks any antihistamine or anticholinergic side effects.^[7]

Dosing

Nefazodone doses for adults typically start at 50 mg twice daily uptitrated by 100 mg/day per week to a maximum of 600 mg (300 mg twice daily), according to Food and Drug Administration (FDA) regulations. Some patients with severe depression were treated with more than 600 mg/day. Most patients were treated with 300 mg–600 mg daily.

Side effects

Common and mild side effects of nefazodone reported in clinical trials more often than placebo include dry mouth (25%), sedation/somnolence (25%), nausea (22%), dizziness (17%), blurred/abnormal vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%).^[8] Rare and serious adverse reactions may include allergic reaction, fainting, priapism (painful/prolonged erection), and jaundice.^[9]

Unlike most serotonin reuptake inhibitors, nefazodone has a low incidence of negative effects on libido or sexual function, and is actually sometimes used as an antidote to SSRI or SNRI-induced impotence and anorgasmia in men.^[10] Additionally, unlike mirtazapine, nefazodone is not especially associated with increased appetite and weight gain either.^[11]

Interactions

Nefazodone is a potent inhibitor of CYP3A4, an isozyme of the cytochrome P450 system, and may therefore interact adversely with many commonly-used medications that are metabolized by CYP3A4.^[1][12]

Advantages

Nefazodone's claimed advantages over other antidepressants include reduced possibility of disturbed sleep or sexual dysfunction, and ability to treat some patients who did not respond to other antidepressant drugs.

Nefazodone, though an antidepressant, may also be beneficial in the prophylaxis of migraines due to its antagonistic effects on the 5-HT_2A^[13] and 5-HT_2C receptors.^[14][15] It has a more favorable side effect profile than amitriptyline, a tricyclic antidepressant commonly used for migraine prophylaxis.

See also

• Etoperidone
• Lubazodone
• Trazodone
• Vilazodone

Chemistry

Nefazadone is a piperazine compound incorporating a 1,2,4-triazol-3-one ring. Rxn of the starting propionamide with phosgene leads to the corresponding imino chloride. This intermediate is condensed with hydrazine methylurethane to afford the corresponding guanidine from the displacement of chlorine by basic hydrazine nitrogen. Rxn with sodium methoxide leads first to the ionization of the amine on the side chain; this then cyclizes to a triazolone by displacing the carbamate methoxyl. Alkylation of the anion from rxn of the triazolone with a strong base with chloride affords nefazodone.

References

1. ^ ^{a b} Lexi-Comp (September 2008). "Nefazodone". The Merck Manual Professional. http://www.merck.com/mmpe/lexicomp/nefazodone.html.  Retrieved on November 29, 2008.
2. ^ Rxlist.com: "Nefazodone Prescribing Information", accessed 8 January 2007.]
3. ^ FDA Orange Book, accessed 15 January 2006.
4. ^ About.com: "Serzone Pulled from U.S. Market", accessed 15 January 2006.
5. ^ ^{a b c} Cusack B, Nelson A, Richelson E. (1994). "Binding of Antidepressants to Human Brain Receptors: Focus on Newer Generation Compounds.". Psychopharmacology (Berl). 114 (4): 559–565. doi:10.1007/BF02244985. PMID 7855217. 
6. ^ Sanchez, C; J. Hyttel (1999). "Comparison of the Effects of Antidepressants and Their Metabolites on Reuptake of Biogenic Amines and on Receptor Binding". Celular and Molecular Neurobiology 19 (4): 467–89. doi:10.1023/A:1006986824213. PMID 10379421. 
7. ^ ^{a b} Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological Profile of Antidepressants and Related Compounds at Human Monoamine Transporters.". Eur J Pharmacol. 340 (2–3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821. 
8. ^ "Nefazodone (Serzone) FAQ". http://www.dr-bob.org/tips/nefazodone.html#side-effects. 
9. ^ http://www.drugs.com/serzone.html
10. ^ http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_684.html
11. ^ Sussman N, Ginsberg DL, Bikoff J (April 2001). "Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials". The Journal of Clinical Psychiatry 62 (4): 256–60. doi:10.4088/JCP.v62n0407. PMID 11379839. 
12. ^ Spina E, Santoro V, D'Arrigo C (July 2008). "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update". Clin Ther 30 (7): 1206–27. doi:10.1016/S0149-2918(08)80047-1. PMID 18691982. http://linkinghub.elsevier.com/retrieve/pii/S0149-2918(08)80047-1. 
13. ^ Saper JR, Lake AE, Tepper SJ (May 2001). "Nefazodone for chronic daily headache prophylaxis: an open-label study". Headache 41 (5): 465–74. doi:10.1046/j.1526-4610.2001.01084.x. PMID 11380644. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0017-8748&date=2001&volume=41&issue=5&spage=465. 
14. ^ Mylecharane EJ (1991). "5-HT2 receptor antagonists and migraine therapy". J. Neurol. 238 Suppl 1: S45–52. doi:10.1007/BF01642906. PMID 2045831. 
15. ^ Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID 16433010.