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Desipramine

Antidepressant

Antidepressant

| Drugs.com = | elimination_half-life = 12–30 hours 58-28-6 (hydrochloride) 62265-06-9 (dibudinate)

Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug has not been considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.

Medical uses

Desipramine is primarily used for the treatment of depression. Evidence of benefit is only in the short term, and with concerns of side effects its overall usefulness is not clear. Desipramine at very low doses is also used to help reduce the pain associated with functional dyspepsia. It has also been tried, albeit with little evidence of effectiveness, in the treatment of cocaine dependence. Evidence for usefulness in neuropathic pain is also poor.

Side effects

Desipramine tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive or memory impairments.

Overdose

Main article: Tricyclic antidepressant overdose

Desipramine is particularly toxic in cases of overdose, compared to other antidepressants. Any overdose or suspected overdose of desipramine is considered to be a medical emergency and can result in death without prompt medical intervention.

Pharmacology

Pharmacodynamics

SiteKi (nM)SpeciesRef
17.6–163Humanvauthors = Tatsumi M, Groshan K, Blakely RD, Richelson Etitle = Pharmacological profile of antidepressants and related compounds at human monoamine transportersjournal = European Journal of Pharmacologyvolume = 340issue = 2–3pages = 249–258date = December 1997pmid = 9537821doi = 10.1016/s0014-2999(97)01393-9 }}
0.63–3.5Human
3,190Human
5-HT1A≥6,400Humanvauthors = Wander TJ, Nelson A, Okazaki H, Richelson Etitle = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitrojournal = European Journal of Pharmacologyvolume = 132issue = 2–3pages = 115–121date = December 1986pmid = 3816971doi = 10.1016/0014-2999(86)90596-0 }}
5-HT2A115–350Human
5-HT2C244–748Ratvauthors = Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala Jtitle = Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptorjournal = Psychopharmacologyvolume = 126issue = 3pages = 234–240date = August 1996pmid = 8876023doi = 10.1007/bf02246453s2cid = 24889381 }}
5-HT3≥2,500Rodentvauthors = Schmidt AW, Hurt SD, Peroutka SJtitle = '[3H]quipazine' degradation products label 5-HT uptake sitesjournal = European Journal of Pharmacologyvolume = 171issue = 1pages = 141–143date = November 1989pmid = 2533080doi = 10.1016/0014-2999(89)90439-1doi-access = free }}
5-HT71,000Ratvauthors = Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DRtitle = Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtypejournal = The Journal of Biological Chemistryvolume = 268issue = 24pages = 18200–18204date = August 1993pmid = 8394362doi = 10.1016/S0021-9258(17)46830-Xdoi-access = free }}
α123–130Human
α2≥1,379Human
β≥1,700Ratvauthors = Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EBtitle = Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivativejournal = Biochemical Pharmacologyvolume = 35issue = 24pages = 4493–4497date = December 1986pmid = 3790168doi = 10.1016/0006-2952(86)90769-0 }}
Cav2.2410Humanvauthors = Benjamin ER, Pruthi F, Olanrewaju S, Shan S, Hanway D, Liu X, Cerne R, Lavery D, Valenzano KJ, Woodward RM, Ilyin VIdisplay-authors = 6title = Pharmacological characterization of recombinant N-type calcium channel (Cav2.2) mediated calcium mobilization using FLIPRjournal = Biochemical Pharmacologyvolume = 72issue = 6pages = 770–782date = September 2006pmid = 16844100doi = 10.1016/j.bcp.2006.06.003 }}
D15,460Humanvauthors = Deupree JD, Montgomery MD, Bylund DBtitle = Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopramjournal = European Journal of Pharmacologyvolume = 576issue = 1–3pages = 55–60date = December 2007pmid = 17850785pmc = 2231336doi = 10.1016/j.ejphar.2007.08.017 }}
D23,400Human
H160–110Humanvauthors = Cusack B, Nelson A, Richelson Etitle = Binding of antidepressants to human brain receptors: focus on newer generation compoundsjournal = Psychopharmacologyvolume = 114issue = 4pages = 559–565date = May 1994pmid = 7855217doi = 10.1007/bf02244985s2cid = 21236268 }}
H21,550Human
H3100,000Human
H49,550Human
66–198Human
M1110Humanvauthors = Stanton T, Bolden-Watson C, Cusack B, Richelson Etitle = Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminicsjournal = Biochemical Pharmacologyvolume = 45issue = 11pages = 2352–2354date = June 1993pmid = 8100134doi = 10.1016/0006-2952(93)90211-e }}
M2540Human
M3210Human
M4160Human
M5143Human
σ11,990–4,000Rodentvauthors = Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JFtitle = 1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugsjournal = Proceedings of the National Academy of Sciences of the United States of Americavolume = 83issue = 22pages = 8784–8788date = November 1986pmid = 2877462pmc = 387016doi = 10.1073/pnas.83.22.8784doi-access = freebibcode = 1986PNAS...83.8784W }}
σ2≥1,611Rat
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Desipramine is a very potent and relatively selective norepinephrine reuptake inhibitor (NRI), which is thought to enhance noradrenergic neurotransmission. Based on one study, it has the highest affinity for the norepinephrine transporter (NET) of any other TCA, and is said to be the most noradrenergic and the most selective for the NET of the TCAs. The observed effectiveness of desipramine in the treatment of ADHD was the basis for the development of the selective NRI atomoxetine and its use in ADHD.

Desipramine has the weakest antihistamine and anticholinergic effects of the TCAs. It tends to be slightly activating/stimulating rather than sedating, unlike most others TCAs. Whereas other TCAs are useful for treating insomnia, desipramine can cause insomnia as a side effect due to its activating properties. The drug is also not associated with weight gain, in contrast to many other TCAs. Secondary amine TCAs like desipramine and nortriptyline have a lower risk of orthostatic hypotension than other TCAs, although desipramine can still cause moderate orthostatic hypotension.

Pharmacokinetics

Desipramine is the major metabolite of imipramine and lofepramine.

Chemistry

Desipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine (N-methyldesipramine), clomipramine, trimipramine, and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Desipramine is a secondary amine TCA, with its N-methylated parent imipramine being a tertiary amine. Other secondary amine TCAs include nortriptyline and protriptyline. The chemical name of desipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C18H22N2 with a molecular weight of 266.381 g/mol. The drug is used commercially mostly as the hydrochloride salt; the dibudinate salt is or has been used for intramuscular injection in Argentina (brand name Nebril) and the free base form is not used. The CAS Registry Number of the free base is 50-47-5, of the hydrochloride is 58-28-6, and of the dibudinate is 62265-06-9.

History

Desipramine was developed by Geigy. It first appeared in the literature in 1959 and was patented in 1962. The drug was first introduced for the treatment of depression in 1963 or 1964.

Society and culture

Generic names

Desipramine is the generic name of the drug and its and , while desipramine hydrochloride is its , , , and . Its generic name in French and its are désipramine, in Spanish and Italian and its are desipramina, in German is desipramin, and in Latin is desipraminum.

Brand names

Desipramine is or has been marketed throughout the world under a variety of brand names, including Irene, Nebril, Norpramin, Pertofran, Pertofrane, Pertrofran, and Petylyl among others.

References

References

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alpha-1-blockers antihistamines cyp2a6-inhibitors cyp2d6-inhibitors dibenzazepines human-drug-metabolites m1-receptor-antagonists m2-receptor-antagonists m3-receptor-antagonists m4-receptor-antagonists m5-receptor-antagonists norepinephrine-reuptake-inhibitors secondary-amines serotonin-receptor-antagonists sodium-channel-blockers stimulants tricyclic-antidepressants wakefulness-promoting-agents
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