塩酸トラゾドン

関: trazodone

WordNet

oral antidepressant (trade name Desyrel) that is a nontricyclic drug used as a sedative (同)trazodone_hydrochloride, Desyrel
a complex consisting of an organic base in association with hydrogen chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/08/05 10:17:45」(JST)

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Trazodone (also sold under the brand names Desyrel, Oleptro, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico, and Mesyrel) is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is a phenylpiperazine compound. Trazodone also has anti-anxiety (anxiolytic) and sleep-inducing (hypnotic) effects.^[1] Trazodone has considerably fewer prominent anticholinergic (dry mouth, constipation, tachycardia) and sexual side effects than most of the tricyclic antidepressants (TCAs).

1 History
2 Indications
- 2.1 Off-label and investigational uses
3 Pharmacology
- 3.1 Binding profile
- 3.2 Correspondence to clinical effects
4 Pharmacokinetics
5 Warnings
6 Precautions
7 Pregnancy and lactation
8 Side effects
- 8.1 Serious side effects
  - 8.1.1 Cardiac arrhythmia
  - 8.1.2 Priapism
  - 8.1.3 Other
9 Occupational hazards
10 Laboratory tests
11 Drug interactions
12 Dosage
13 Overdose
- 13.1 Symptoms
- 13.2 Treatment
14 Synthesis
15 See also
16 References
17 External links

History[edit source | edit]

Trazodone was originally discovered and developed in Italy in the 1960s by Angelini Research Laboratories as a second-generation antidepressant. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold.^[2] Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration (FDA) at the end of 1981.

Indications[edit source | edit]

Anxiety disorder
Unipolar depression, with or without anxiety
Bipolar depression, in some circumstances
Insomnia^[3]^[4]^[5] (in some countries, this is an off-label use)
Control of nightmares ^[6]

Off-label and investigational uses[edit source | edit]

Fibromyalgia^[7]
Panic disorder^[8]
Diabetic neuropathy^[9]
Bulimia nervosa^[10]
Obsessive-compulsive disorder (OCD)^[11]^[12]
Alcohol withdrawal^[13]^[14]^[15]
Schizophrenia and other psychoses^[16]^[17]
Complex regional pain syndrome^{[citation needed]}
Hallucinogen intoxication^[18]

Pharmacology[edit source | edit]

Binding profile[edit source | edit]

Trazodone behaves as an antagonist at all of the following receptors except 5-HT_1A where it acts as a partial agonist similarly to buspirone and tandospirone but with greater intrinsic activity in comparison:^[19]^[20]^[21]^[22]^[23]^[24]

5-HT_1A receptor (K_d = 78 nM)
5-HT_2A receptor (K_i = 13 nM)
5-HT_2B receptor (K_i = 74 nM)^[25]
5-HT_2C receptor (K_i = 192 nM)
α₁-adrenergic receptor (K_d = 39 nM)
α₂-adrenergic receptor (K_d = 405 nM)
H₁ receptor (K_d = 725 nM)

It is an inhibitor of the following transporters as well:^[26]

SERT (K_d = 160 nM)

The affinities listed are the means of selected values from the references included.

Correspondence to clinical effects[edit source | edit]

Trazodone acts predominantly as a 5-HT_2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.^[27] Its inhibitory effects on serotonin reuptake and 5-HT_2C receptors are relatively weak (~15-fold lower than for 5-HT_2A) and contribute only lightly to its overall effects.^[27] Hence, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs)^[27] and is not particularly associated with increased appetite and weight gain, unlike other 5-HT_2C antagonists like mirtazapine.^[28]^[29] Moderate 5-HT_1A partial agonism (6-fold lower than 5-HT_2A) is likely to contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.^[23]^[24]^[30]

Trazodone's potent α₁-adrenergic blockade (~3-fold lower relative to 5-HT_2A) may cause some side effects like orthostatic hypotension and sedation.^[31] Conversely, along with 5-HT_2A antagonism, it may underlie its efficacy as a hypnotic. This seems possible as trazodone's antihistamine activity is relatively weak and probably clinically insignificant; hence, it cannot explain trazodone's sleep-inducing/enhancing effects. Trazodone lacks any affinity for the mACh receptors and therefore does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor agonist and serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits.^[32]^[33]^[34] However, scientific research has not supported this hypothesis, and mCPP may actually antagonize trazodone's efficacy as well as produce additional side effects.^[35]^[36]^[37]^[38]^[39]

Pharmacokinetics[edit source | edit]

Trazodone is well absorbed after oral administration with mean peak blood levels obtained at approximately 1 hour after ingestion. Absorption is somewhat delayed and enhanced by food. The mean blood elimination half-life is biphasic: the first phase's half-life is 3–6 hours, and the following phase's half-life is 5–9 hours. The drug is extensively metabolized with 3 or 4 major metabolites having been identified in the human body, particularly mCPP,^[40] which may contribute to the side effect profile of trazodone. mCPP has been shown to activate numerous serotonin receptors, including 5-HT_2C. Approximately 70–75% of ¹⁴C-labelled trazodone was found to be excreted in the urine within 72 hours.^[41] Trazodone is highly protein-bound.

As a consequence of the production of mCPP as a metabolite, patients administered trazodone may test positive on EMIT II urine tests for the presence of MDMA ("ecstasy").^[42]

Warnings[edit source | edit]

If the patient has a known hypersensitivity to trazodone
If the patient is under eighteen years of age and combines with other antidepressant medications it may increase the possibility of suicidal thoughts or actions.^[43]

Precautions[edit source | edit]

Trazodone is metabolized by CYP3A4, a liver enzyme.^[40] Inhibition of this enzyme by various other substances may delay its degradation, leading to high blood levels of trazodone. CYP3A4 may be inhibited by many other medications, herbs, and foods, and as such, trazodone may interact with these substances. One drug-food interaction is grapefruit juice. Drinking grapefruit juice is discouraged in patients taking trazodone. One glass of grapefruit juice occasionally is not likely to have this effect on most people, but drinking large amounts, or drinking it regularly is proven to affect trazodone's clearance.

The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. The number of tablets prescribed at any one time should take into account this possibility, and patients with suicidal ideation should never have access to large quantities of trazodone.

Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with medications to control seizures.^[44]

While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of the SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly.^[45] Care must therefore be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.

Pregnancy and lactation[edit source | edit]

Pregnancy: Sufficient data in humans is lacking. Use should be justified by the severity of the condition to be treated.^{[citation needed]}
Lactation: Sufficient data in humans is also lacking. Additionally, trazodone may be found in the maternal milk in significant concentrations. Women should not breastfeed while taking trazodone.^{[citation needed]}

Side effects[edit source | edit]

Adverse reactions reported include the following:^[46]

Headache or heaviness in head
Nausea, vomiting
Bad taste in mouth
Dry mouth
Stomach pain
Diarrhea or Constipation
Changes in appetite or weight
Weakness or tiredness
Nervousness
Decreased ability to concentrate or remember things
Confusion
Brain fog or "zombie-like" sensations
Nightmares
Muscle pain
Sweating
Blurred vision
Tired, red, or itchy eyes
Tinnitus (Ringing in ears)
Restless leg syndrome

Trazodone can enhance libido and in males, increase erectile function.^[47] Compared to the reversible MAOI antidepressant drug moclobemide there is significantly more impairment on vigilance with trazodone.^[48]

Serious side effects[edit source | edit]

Chest pain (angina)
Fast, pounding, or irregular heartbeat
Shortness of breath
Fever, sore throat, chills, or other signs of infection
Hives
Skin rash
Itching
Difficulty breathing or swallowing (dysphagia)
Swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs (peripheral edema)
Hoarseness
Decreased coordination
Uncontrollable shaking of a part of the body
Numbness, burning, or tingling in the arms, legs, hands, or feet
Dizziness or lightheadedness
Fainting (syncope)
Painful erection that lasts longer than normal (priapism)

Cardiac arrhythmia[edit source | edit]

Recent clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population.^{[citation needed]} Arrhythmia identified include isolated PVC's, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. There have also been several post-marketing reports of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias.^{[citation needed]} Trazodone is not recommended for use during the initial recovery phase of myocardial infarction.^{[citation needed]}

Priapism[edit source | edit]

Trazodone has been associated with the occurrence of priapism, likely due to its antagonism at α-adrenergic receptors.^[49] Priapism is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within four hours.^[46] In approximately 33% of the cases reported, surgical intervention was performed and, in a portion of these cases, permanent impairment of erectile function or impotence resulted.^{[citation needed]}

In women, a similar condition of persistent arousal can be caused and is called persistent genital arousal disorder.^[50]

Other[edit source | edit]

Rare cases of idiosyncratic hepatotoxicity have been observed, possibly due to the formation of reactive metabolites.^[51]

Elevated prolactin concentrations have been observed in patients taking trazodone.^[52]

It has been concluded that trazodone impairs motor healing in brain-injured rats.^[53]

Occupational hazards[edit source | edit]

Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired.

Laboratory tests[edit source | edit]

It is recommended that white blood cell and differential counts should be performed in patients who develop sore throat, fever, or other signs of infection or blood dyscrasia and trazodone should be discontinued if the white blood cell or absolute neutrophil count falls below normal.^{[citation needed]}

Drug interactions[edit source | edit]

Trazodone may enhance the effects of alcohol, barbiturates, and other CNS depressants; patients should be cautioned accordingly as trazodone with the combination of another CNS depressant, can result in extreme tiredness and dizziness.

Increased serum digoxin and phenytoin levels have been reported to occur in patients receiving trazodone concurrently with either of those two drugs. Little is known about the interaction between trazodone and general anesthetics; therefore, prior to elective surgery, trazodone should be discontinued for as long as clinically feasible.

Because it is not known whether an interaction will occur between trazodone and monoamine oxidase inhibitors (MAOI's), administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAOI is given concomitantly or has been discontinued shortly before medication with trazodone is instituted.

Because of the absence of experience, concurrent administration of electroconvulsive therapy should be avoided.

Dosage[edit source | edit]

Trazodone adult and geriatric recommended starting dose is 150 mg once daily, it may be increased by 50 mg every three to four days. The dose may be increased slowly to a maximum of 400 mg daily for outpatients and to 600 mg daily in hospitalized patients. Pediatric initial dose should be 25 – 50 mg and may be increased up to 150 mg if necessary. Adult dosage for sedation and sleep aid is 25 – 50 mg. It is recommended that trazodone be given in a divided dose. If necessary just a single dose, in the evening, may be given.

Overdose[edit source | edit]

Symptoms[edit source | edit]

Overdose of trazodone may cause an increase in incidence or severity of any of the reported adverse reactions, e.g. excessive sedation. Death by deliberate or accidental overdosage has been reported.^[54]^[55] However, trazodone is often used instead of tricyclic antidepressants because it is very difficult to overdose on. Depressed patients are therefore unlikely to complete suicide with trazodone.^[56]

Treatment[edit source | edit]

There is no specific antidote for trazodone. Management of overdosage should, therefore, be symptomatic and supportive. Any person suspected of having taken an overdosage should be evaluated at a hospital as soon as possible. Activated charcoal, gastric lavage, and forced diuresis may be useful in facilitating elimination of the drug.

Synthesis[edit source | edit]

Palazzo, G.; Silvestrini, B.; 1968, U.S. Patent 3,381,009.
B. Silvestrini, G. Palazzo, DE 164594

References[edit source | edit]

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^ Boyeson MG, Harmon RL. (October 1993). "Effects of trazodone and desipramine on motor recovery in brain-injured rats". American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 72 (5): 286–93. doi:10.1097/00002060-199310000-00007. PMID 8398020.
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External links[edit source | edit]

U.S. National Library of Medicine: Drug Information Portal - Trazodone

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5. 成人における単極性うつ病：継続療法および維持療法 unipolar depression in adults continuation and maintenance treatment

English Journal

Pharmacological Management of Borderline Personality Disorder in a Pregnant Woman with a Previous History of Alcohol Addiction: A Case Report.

Gentile S1,2.
Clinical drug investigation.Clin Drug Investig.2015 Sep 18. [Epub ahead of print]
The clinical utilization of psychotropic medications in pregnant women represents a significant challenge. Indeed, the risks of untreated severe mental disorders, particularly when complicated by substance-related and addictive disorders, must be carefully balanced against the potential teratogenic
PMID 26385757

Circadian rhythm in Alzheimer disease after trazodone use.

Grippe TC1, Gonçalves BS2, Louzada LL1, Quintas JL1, Naves JO1,3, Camargos EF1,4, Nóbrega OT1,4.
Chronobiology international.Chronobiol Int.2015 Sep 16:1-4. [Epub ahead of print]
A circadian rhythm is a cycle of approximately 24 h, responsible for many physiological adjustments, and ageing of the circadian clock contributes to cognitive decline. Rhythmicity is severely impaired in Alzheimer disease (AD) and few therapeutic attempts succeeded in improving sleep disorders in
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Interventions for Neuropsychiatric Symptoms in Neurocognitive Impairment Due to Alzheimer's Disease: A Review of the Literature.

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Harvard review of psychiatry.Harv Rev Psychiatry.2015 Sep-Oct;23(5):377-93. doi: 10.1097/HRP.0000000000000097.
Neurocognitive impairment due to Alzheimer's disease (previously termed Alzheimer's dementia) (AD) is the most common form of cognitive impairment worldwide. Given the anticipated increase in the population aged 65 and over, the prevalence of persons with AD is expected to increase exponentially dur
PMID 26332220

Japanese Journal

症例報告自殺目的で塩酸セルトラリン,スルピリド,塩酸ドスレピン,フマル酸クエチアピン,塩酸トラゾドンを含む多剤大量服用後,悪性症候群もしくはセロトニン症候群を併発した1例

防衛衛生 55(4), 71-74, 2008-04
NAID 40015997038

Sensitive Extractive Spectrophotometric Methods for the Determination of Trazodone Hydrochloride in Pharmaceutical Formulations

Chemical & pharmaceutical bulletin 54(7), 968-971, 2006-07-01
NAID 110004836417

In Vitro Study of the Adsorption Characteristics of Drugs(Medicinal Chemistry)

Biological & pharmaceutical bulletin 28(5), 841-844, 2005-05-01
NAID 10016663278

Related Pictures

★リンクテーブル★

リンク元	「トラゾドン」
関連記事	「hydrochloride」

「トラゾドン」

Trazodone
Systematic (IUPAC) name
	2-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a681038
Pregnancy cat.	C (US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	High
Metabolism	Hepatic
Half-life	3-6 hours
Excretion	20% feces,; 80% urine
Identifiers
CAS number	19794-93-5
ATC code	N06AX05
PubChem	CID 5533
IUPHAR ligand	213
DrugBank	DB00656
ChemSpider	5332
UNII	YBK48BXK30
KEGG	D08626
ChEBI	CHEBI:9654
ChEMBL	CHEMBL621
Chemical data
Formula	C19H22ClN5O
Mol. mass	371.864 g/mol
	SMILES Clc4cccc(N3CCN(CCCN1/N=C2/C=C\C=C/N2C1=O)CC3)c4;
	InChI InChI=1S/C19H22ClN5O/c20-16-5-3-6-17(15-16)23-13-11-22(12-14-23)8-4-10-25-19(26)24-9-2-1-7-18(24)21-25/h1-3,5-7,9,15H,4,8,10-14H2 ; Key:PHLBKPHSAVXXEF-UHFFFAOYSA-N ;
(what is this?) (verify);

　　[★]

英: trazodone
化: 塩酸トラゾドン trazodone hydrochloride
商: アンデプレ、デジレル、レスリン、Desyrel
関: 抗うつ薬、薬理学。SSRI

トリアゾピリジン骨格を有する抗うつ薬。
鎮静作用の強い非定型抗うつ薬
日本初のSSRI
抗コリン作用が弱く、心機能抑制は低い。
セロトニン再取り込み阻害作用はノルアドレナリンの26倍という高い選択性
長期投与により、うつ病患者で亢進しているノルアドレナリン受容体やセロトニン受容体の感受性を低下させる。

KPS.1209

1-2時間で血中濃度が最高濃度となる
半減期は6-11時間
活性代謝物はm-クロロフェニルピペラジン
肝臓代謝。代謝産物の75%は尿から排泄される。
選択的セロトニン歳取り込み阻害作用、多少のシナプス後セトロニン活性、α1アドレナリン拮抗作用、抗ヒスタミン作用を有する。
トラゾドンの長期投与によりシナプス後セトロニン受容体2A型(5-HT2A)とβアドレナリン受容体数を減少させる。
副作用：起立性低血圧(α1アドレナリン拮抗作用)、胃炎、持続勃起症(α1アドレナリン拮抗作用)、弱い骨格筋弛緩作用

「hydrochloride」

　　[★] 塩酸塩、ハイドロクロライド　

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[18] Serotonin receptors—from molecular biology to clinical applications

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案内

trazodone hydrochloride