Tofranil

トフラニール

関

imipramine、imipramine hydrochloride

WordNet

1. a tricyclic antidepressant (trade names Imavate and Tofranil) used to treat clinical depression (同)impramine hydrochloride, Imavate, Tofranil

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/26 22:23:35」(JST)

wiki en

[Wiki en表示]

Imipramine

Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
Clinical data
Trade names	Tofranil
AHFS/Drugs.com	monograph
MedlinePlus	a682389
Pregnancy cat.	C (AU) Known risk of damage to fetus.
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	94-96%
Protein binding	86%
Metabolism	Hepatic (CYP1A2, CYP2C19, CYP2D6) Main active metabolite desipramine
Half-life	20 hours
Excretion	Renal (80%), Faecal (20%) (mostly as inactive metabolites)
Identifiers
CAS number	50-49-7 Y
ATC code	N06AA02
PubChem	CID 3696
IUPHAR ligand	357
DrugBank	DB00458
ChemSpider	3568 Y
UNII	OGG85SX4E4 Y
KEGG	D08070 Y
ChEBI	CHEBI:47499 Y
ChEMBL	CHEMBL11 Y
Chemical data
Formula	C19H24N2
Mol. mass	280.407 g/mol
SMILES c1cc3c(cc1)CCc2c(cccc2)N3CCCN(C)C
InChI InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3 Y Key:BCGWQEUPMDMJNV-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Imipramine (Tofranil), also known as melipramine, is an a tricyclic antidepressant (TCA) of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).

It has also been evaluated for use in panic disorder.

Therapeutic uses

Imipramine is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to decrease the delta-wave stage of sleep where this occurs.

History

Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed (by Ciba). At the first international congress of neuro-pharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania, USA, discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them were diagnosed as 'depressive psychosis'. The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients he reported 'optimal results and in around 20% failure. The side effects noted were classified as ' atropine-like and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders, such as schizophrenia, but proved insufficient. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that Imipramine is also known to cause a high rate of manic and hypomanic reactions, especially in patients with preexisting bipolar disorder. It is estimated that up to 25% of such patients maintained on Imipramine will switch into mania or hypomania. Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.

At the advent of SSRIs, its sometimes intolerable side-effect profile became more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released tricyclics. It is not as commonly used today, but is sometimes used to treat major depression as a second-line treatment. It has also seen limited use in the treatment of migraines, ADHD, and post concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Mechanism of action

Imipramine, tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, ADHD, enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of Imipramine's medicinal action include, but are not limited to, effects on:

• Serotonin (5-HT): Very strong reuptake inhibition. Imipramine has the second highest attraction for the serotonin transporter (SERT) in the tricyclic antidepressant class behind clomipramine. This provides a very strong and proportional effect on the blockade of serotonin reuptake. Moderating this effect, however, is imipramine's continual conversion in the body to its metabolite desipramine, which has extremely strong and relatively selective noradrenergic effects. This blend of imipramine and desipramine circulating together within the body provides a powerful one-two punch in simultaneously blockading both serotonin and norepinephrine reuptake.

• Norepinephrine (NE): Strong reuptake inhibition.

• Dopamine (DA): Reuptake and release at D₁ and D₂ receptors. Similar but less potent than psychostimulants, dopamine agonists, and the atypical antidepressant bupropion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SER and ACh, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine. Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it has only 5% of the potency of amitryptiline or paroxetine, see the table below).^{[citation needed]}

• Acetylcholine (ACh): Imipramine is an anticholinergic. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of Imipramine to cause hallucinations, confusion and delirium in this population. Imipramine is an antagonist at M₂ muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).

• Epinephrine: Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).

• σ receptor and Enkephalinase: Activity on σ-receptors is present, but it is very low (Ki of 520 nM on σ-receptors, see references) and it is about half the power of amitryptiline (300 nM).

• Histamine: Imipramine is an antagonist at histamine H₁ receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imipramine is sometimes prescribed as a sleep aid in low doses.

• BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic Imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promotor, and also reduced expression of hippocampal HDAC5.

• μ receptor: Imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.

Comparison with other antidepressants

Binding Profile of popular TCAs towards their cloned human (unless otherwise specified) molecular targets (K_i in nM)

Drug	SERT	NET	DAT	α1	α2A	D2	H1	M1	M3	5-HT1A	5-HT2A	5-HT2C	5-HT6	5-HT7
imipramine	10.4	51.7	8,500	-	3,100 (Human, Brain)	726	11.0	42	60	>10,000	120 (Rat, Cloned)	120 (Rat, Cloned)	190 (Rat, Cloned)	1,000 (Rat, Cloned)
desipramine	179	2.27	>10,000	130	1,380 (Human, Brain)	1,560	45.6	110	210	>10,000	114 (Rat, Cloned)	496 (Rat, Cloned)	-	1,000 (Rat, Cloned)
amitriptyline	3.13	22.4	4,440	24 (Human, Brain)	690 (Human, Brain)	1,460 (Human, Brain)	0.5	14.7	12.8	450 (Human, Brain)	5.60 (Rat, Cortex)	6.15 (Rat, Cloned)	103	114 (Rat, Cloned)
clomipramine	0.21	45.9	2,610	3.2	525	120	-	-	-	>10,000	35.5	64.6	53.8 (Rat, Cloned)	127 (Rat, Cloned)

Metabolism

Within the body, Imipramine is converted to desipramine, another TCA.

Side effects

Those listed in Italic text below denote common side effects. Those listed in bold text denote life-threatening side effects.

• Central Nervous System: Dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia

• Cardiovascular: Orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias

• Eyes, Ears, Nose and Throat: Blurred vision, tinnitus, mydriasis

• Gastrointestinal:Dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change

• Genitourinary: Urinary retention,

• Hematological: Agranulocytosis, thrombocytopenia, eosinophilia, leukopenia

• Skin: Rash, urticaria, diaphoresis, pruritus, photosensitivity

Dosage

• Hospitalized patients: starting with 3 times 25 mg, increasing to 125 mg. Up to 300 mg may be given in resistant cases. After remission dose is often reduced to 50 to 100 mg daily.
• Ambulatory patients: starting with 25 to 75 mg daily, increasing up to a maximum of 200 mg daily, after remission dose is often reduced to 50–100 mg daily.
• Pediatric patients: starting with 10 mg daily the dose is adjusted according to the severity of the symptoms to be treated, the side-effects encountered and the weight of the patient.

Overdose

Main article: Tricyclic antidepressant overdose

The symptoms and the treatment of an imipramine overdose are largely the same as for the other tricyclic antidepressants. Cardinal symptoms are cardiac (tachycardia, widened QRS complex) and neurological disturbances. Any ingestion by children should be considered as serious and potentially fatal.

See also

• Tricyclic antidepressant

References

External links

• Imipramine - Medicinenet.com
• Neurotransmitter - Neurotransmitter.net
• Imipramine bound to proteins in the PDB

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 三環系抗うつ剤および四環系抗うつ剤：薬理学、投与、および副作用tricyclic and tetracyclic drugs pharmacology administration and side effects [show details]
  …or less of amitriptyline, clomipramine, desipramine, doxepin, imipramine, or trimipramine; most studies involved amitriptyline or imipramine) with placebo in 807 patients for six to eight weeks . Response …
• 2. Anesthesia for electroconvulsive therapyanesthesia for electroconvulsive therapy [show details]
  …antidepressants – Tricyclic antidepressant agents (TCAs) such as amitriptyline, nortriptyline, dosulepin, imipramine, and desipramine inhibit the presynaptic reuptake of serotonin and norepinephrine. They also have…
• 3. Nocturnal enuresis in children: Managementnocturnal enuresis in children management [show details]
  …effective, imipramine is used most often in the treatment of enuresis. It is the only TCA recommended by the NICE guidelines . Imipramine should be administered one hour before bedtime . Imipramine is supplied …
• 4. 小児や青年の不安障害への薬物療法pharmacotherapy for anxiety disorders in children and adolescents [show details]
  …compared imipramine with placebo, finding no difference in the response rate between the two groups (45 versus 44 percent) . Mixed anxiety disorders — Clinical trials have found that imipramine reduced …
• 5. 成人における急性ストレス障害の治療treatment of acute stress disorder in adults [show details]
  …severe burns, compared treatment with imipramine to chloral hydrate . After daily treatment for seven days, patients were more likely to respond in the imipramine group compared with those receiving chloral …

English Journal

• Screening of antidepressant activity and estimation of quercetin from Coccinia indica using TLC densitometry.

• Randhawa K1, Kumar D, Jamwal A, Kumar S.
• Pharmaceutical biology.Pharm Biol.2015 Dec;53(12):1867-74. doi: 10.3109/13880209.2015.1025289. Epub 2015 Apr 7.
• CONTEXT: Coccinia indica Naud (Cucurbitaceae) has been traditionally used for the treatment of depression but these claims have not been validated.OBJECTIVES: The objective of this study is to investigate antidepressant activity of various extracts and fractions of C. indica aerial parts, and to est
• PMID 25845639

• The loss of NDRG2 expression improves depressive behavior through increased phosphorylation of GSK3β.

• Ichikawa T1, Nakahata S1, Tamura T1, Manachai N1, Morishita K2.
• Cellular signalling.Cell Signal.2015 Oct;27(10):2087-98. doi: 10.1016/j.cellsig.2015.07.012. Epub 2015 Jul 21.
• N-myc downstream-regulated gene 2 (NDRG2) is one of the important stress-inducible genes and plays a critical role in negatively regulating PI3K/AKT signaling during hypoxia and inflammation. Through recruitment of PP2A phosphatase, NDRG2 maintains the dephosphorylated status of PTEN to suppress exc
• PMID 26208882

• Chronic imipramine treatment differentially alters the brain and plasma amino acid metabolism in Wistar and Wistar Kyoto rats.

• Nagasawa M1, Otsuka T1, Yasuo S1, Furuse M2.
• European journal of pharmacology.Eur J Pharmacol.2015 Sep 5;762:127-35. doi: 10.1016/j.ejphar.2015.05.043. Epub 2015 May 22.
• In the present study, the amino acids which have the possibility for the therapeutic efficacy of imipramine were explored and compared between Wistar Kyoto rats, an animal model of depression, and Wistar rats as a normal model. The antidepressant-like effect caused by chronic imipramine treatment wa
• PMID 26004533

Japanese Journal

• Extra-Weak Chemiluminescence of Drugs. V. The Extra-Weak Chemiluminescence of Imipramine Hydrochloride Produced by Autoxidation(Pharmaceutical)

• 佐藤 秀昭,江戸 清人,水柿 道直
• Chemical & pharmaceutical bulletin 34(12), 5110-5114, 1986-12-25
• The chemiluminescence (CL) produced by autoxidation of imipramine hydrochloride was investigated. The CL generated from imipramine hydrochloride was strongly enhanced by replacing nitrogen with either …
• NAID 110006280845

• 光眼輪筋反射の late component の発現機序に関する実験的研究

• 服部 裕子
• 関西医科大学雑誌 34(2), 377-426, 1982
• … Barbiturate, chlorpromazine, diazepam and tofranil had inhibitory effect predominantly on all the components of PPR. … ERG was not affected significantly with the administration of such chemicals as barbiturate, chlorpromazine, diazepam, tofranil, cardiazol, amphetamine and CDP-choline.<BR>14. …
• NAID 130004625530

• 末期癌患者の頑痛に対するTofranilの鎮痛効果

• 西村 敏雄 [他]
• 産科と婦人科 38(2), 196-202, 1971-02
• NAID 40017817362

Related Links

• Tofranil (Imipramine) Drug Information: Description, User Reviews ...

Learn about the prescription medication Tofranil (Imipramine), drug uses, dosage , side effects, drug interactions, warnings, reviews and patient labeling.

• Imipramine - Wikipedia, the free encyclopedia

Trade names, Tofranil ... Imipramine (sold as Antideprin, Deprimin, Deprinol, Depsol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil), also known as melipramine, is an antidepressant medication, ...

Related Pictures

---

★リンクテーブル★

リンク元	「イミプラミン」「imipramine hydrochloride」「imipramine」
関連記事	「tofranil」

「イミプラミン」

　　[★]

英

imipramine

化

塩酸イミプラミン imipramine hydrochloride

商

イミドール、トフラニール Tofranil

分類

• 抗うつ薬

• 三環系抗うつ薬

作用機序

• 脳内のセロトニン、ノルエピネフリンの神経終末への取り込み阻害による受容体刺激の増進
• 代謝物のデシプラミンのノルエピネフリン取り込み阻害はイミプラミンより強い

重大な副作用

イミドール糖衣錠(10)／イミドール糖衣錠(25)

• 1. 悪性症候群（Syndrome malin）（頻度不明）

• 無動緘黙，強度の筋強剛，嚥下困難，頻脈，血圧の変動，発汗等が発現し，それに引き続き発熱がみられる場合は，投与を中止し，体冷却，水分補給等の全身管理とともに適切な処置を行う．

本症発症時には，白血球の増加や血清CK（CPK）の上昇がみられることが多く，またミオグロビン尿を伴う腎機能の低下がみられることがある．なお，高熱が持続し，意識障害，呼吸困難，循環虚脱，脱水症状，急性腎不全へと移行し，死亡した例が報告されている．

• 2. セロトニン症候群（頻度不明）

• 不安，焦燥，せん妄，興奮，発熱，発汗，頻脈，振戦，ミオクロヌス，反射亢進，下痢等を主症状とするセロトニン症候群があらわれることがあるので，これらの症状が出現した場合には投与を中止し，水分補給等の全身管理とともに適切な処置を行うこと．

• 3. てんかん発作（頻度不明）

• てんかん発作があらわれることがあるので，観察を十分に行い，異常が認められた場合には投与を中止し，適切な処置を行うこと．

• 4. 無顆粒球症（頻度不明）

• 無顆粒球症（前駆症状として，発熱，咽頭痛，インフルエンザ様症状等）があらわれることがあるので，定期的に血液検査を実施するなど観察を十分に行い，異常が認められた場合には投与を中止し，適切な処置を行うこと．

• 5. 麻痺性イレウス（頻度不明）

• 腸管麻痺（食欲不振，悪心・嘔吐，著しい便秘，腹部の膨満あるいは弛緩及び腸内容物のうっ滞等の症状）を来し，麻痺性イレウスに移行することがあるので，腸管麻痺があらわれた場合には投与を中止すること．なお，この悪心・嘔吐は，本剤の制吐作用により不顕性化することもあるので注意すること．

• 6. 間質性肺炎，好酸球性肺炎（頻度不明）

• 発熱，咳嗽，呼吸困難，肺音の異常（捻髪音）等が認められた場合には投与を中止し，速やかに胸部X線等の検査を実施し，副腎皮質ホルモン剤の投与等の適切な処置を行うこと．

• 7. 心不全（頻度不明）

• 心不全があらわれることがあるので，観察を十分に行い，異常が認められた場合には投与を中止し，適切な処置を行うこと．

• 8. QT延長，心室頻拍（Torsades de pointesを含む）（頻度不明）

• 定期的に心電図検査を行うなど観察を十分に行い，異常が認められた場合には投与を中止し，適切な処置を行うこと．

• 9. 抗利尿ホルモン不適合分泌症候群（SIADH）（頻度不明）

• 症状として低ナトリウム血症，低浸透圧血症，尿中ナトリウム排泄量の増加，高張尿，痙攣，意識障害等があらわれることがあるので，このような場合には投与を中止し，水分摂取の制限等適切な処置を行うこと1）．

• 10. 肝機能障害，黄疸（頻度不明）

• AST（GOT），ALT（GPT），γ-GTPの上昇等を伴う肝機能障害，黄疸があらわれることがあるので，観察を十分に行い，異常が認められた場合には投与を中止し，適切な処置を行うこと．

禁忌

イミドール糖衣錠(10)／イミドール糖衣錠(25)

• 1. 緑内障の患者〔抗コリン作用により眼圧を上昇させるおそれがある．〕
• 2. 本剤の成分又は三環系抗うつ剤に対し過敏症の既往歴のある患者
• 3. 心筋梗塞の回復初期の患者〔症状を悪化させるおそれがある．〕
• 4. 尿閉（前立腺疾患等）のある患者〔抗コリン作用により症状が悪化することがある．〕
• 5. モノアミン酸化酵素阻害剤（セレギリン）を投与中あるいは投与中止後2週間以内の患者〔発汗，不穏，全身痙攣，異常高熱，昏睡等があらわれるおそれがある．〕（「相互作用」の項参照）
• 6. QT延長症候群のある患者〔心室性不整脈を起こすおそれがある．〕

効能又は効果

イミドール糖衣錠(10)／イミドール糖衣錠(25)

• 精神科領域におけるうつ病・うつ状態
• 遺尿症（昼，夜）

薬効薬理

イミドール糖衣錠(10)／イミドール糖衣錠(25)

動物での作用

• (1) ラットを用いたin vivo の実験で，脳内ノルアドレナリン及びセロトニンの再取り込みを抑制する4）．
• (2) ラットを用いた実験で，レセルピンによる眼瞼下垂及び下痢に対して拮抗作用が認められている5）．またラットのテトラベナジンによるカタレプシーに対しても拮抗作用が認められている5）．
• (3) マウスを用いた実験で，メタンフェタミン投与による運動亢進作用を有意に増強する6）．
• (4) ラットの脳を用いたin vitro の実験で，脳内のイミプラミン特異的結合部位に対して親和性を示す6）．

添付文書

• イミドール糖衣錠(10)／イミドール糖衣錠(25)

http://www.info.pmda.go.jp/go/pack/1174006F1027_4_10/1174006F1027_4_10?view=body

「imipramine hydrochloride」

　　[★]

• 塩酸イミプラミン

関

imipramine、Tofranil

「imipramine」

　　[★] イミプラミン

同

Tofranil

　

「tofranil」

　　[★]

同

Tofranil

関

Imipramine