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an antidepressant drug that acts by blocking the reuptake of norepinephrine and serotonin and thus making more of those substances available to act on receptors in the brain (同)tricyclic_antidepressant, tricyclic antidepressant drug
any of a class of drugs used to treat depression; often have undesirable side effects (同)antidepressant_drug

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/11/05 10:00:01」(JST)

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Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were first discovered in the early 1950s and were marketed later in the decade.^[1] They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.^[2]

1 Medical uses
- 1.1 Clinical depression
- 1.2 Attention-deficit hyperactivity disorder
- 1.3 Chronic pain
2 Side effects
- 2.1 Discontinuation
3 Overdose
4 Interactions
5 Pharmacology
- 5.1 Binding profiles
6 Chemistry
7 History
8 Society and culture
- 8.1 Recreational use
9 List of TCAs
10 References
11 Further reading
12 External links

Medical uses

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), Neurological disorders such as attention-deficit hyperactivity disorder (ADHD),^[3] Parkinson's disease^[4] as well as chronic pain, neuralgia or neuropathic pain, and fibromyalgia, headache, or migraine, smoking cessation, tourette syndrome, trichotillomania, irritable bowel syndrome (IBS), interstitial cystitis (IC), nocturnal enuresis (NE),^[5] narcolepsy, insomnia, pathological crying and/or laughing, chronic hiccups, ciguatera poisoning, and as an adjunct in schizophrenia.

Clinical depression

For many years the TCAs were the first choice for pharmacological treatment of clinical depression. Although they are still considered to be highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile, such as the SSRIs and other newer antidepressants such as the novel reversible MAOI moclobemide. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes.^[6] Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethal overdose (see therapeutic index) are far wider in comparison.

Nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants.^[7] They are not considered addictive and are somewhat preferable to the monoamine oxidase inhibitors (MAOIs). The side effects of the TCAs usually come to prominence before the therapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as volition can be increased, possibly giving the patient a greater desire to attempt or commit suicide.^[8]

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD,^[9] though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin, Attentin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the prefrontal cortex of the brain.^[10] Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.^[11] Notably, the TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits, as they help limit hyperactivity and impulsivity, but have little to no benefits on attention.^[12]

Chronic pain

The TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia.^[13]^[14] The precise mechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergic neuromodulation, among other properties.^[15]^[16]^[17] They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

Side effects

Many side effects may be related to the antimuscarinic properties of the TCAs. Such side effects are relatively common and may include dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature.

Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, sexual dysfunction, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose.^[18] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.^[19]

Tolerance to these adverse effects of these drugs often develops if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and then gradually increased, although this may also delay the beneficial effects.

TCAs can behave like class 1A antiarrhythmics, as such, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and increase collateral blood circulation to ischemic heart muscle. Naturally, in overdose, they can be cardiotoxic, prolonging heart rhythms and increasing myocardial irritability.

New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications like TCAs and dementia.^[20] Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops.^[21] Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.

Discontinuation

Antidepressants in general may produce a withdrawal. However, since the term "withdrawal" has been linked to addiction to recreational drugs like opioids, the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."^[22] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.^[23] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.^[24]

Overdose

TCA overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity^[25] and the availability of these in the home when prescribed for bed-wetting and depression. In the event of a known or suspected overdose, medical assistance should be sought immediately.

A number of treatments are effective in a TCA overdose.

An overdose on TCA is especially fatal as it is rapidly absorbed from the GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose. However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying.

Many of the initial signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and emesis (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:^[26]

Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever
Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence) / ECG changes (prolonged QRS, QT, and PR intervals)
CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
Pulmonary effects: hypoventilation resulting from CNS depression
Gastrointestinal effects: decreased or absent bowel sounds

Treatment of TCA overdose depends on severity of symptoms:

Initially, gastric decontamination of the patient is achieved by administering, either orally or via a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract (most useful if given within 2 hours of drug ingestion). Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or (ipecac induced) emesis, are not recommended in TCA poisoning.

If there is metabolic acidosis, intravenous infusion of sodium bicarbonate is recommended by Toxbase.org, the UK and Ireland poisons advice database (TCAs are protein bound and become less bound in more acidic conditions, so by reversing the acidosis, protein binding increases and bioavailability thus decreases – the sodium load may also help to reverse the Na+ channel blocking effects of the TCA).

Interactions

The TCAs are highly metabolised by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.^[27] Drugs that prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

Pharmacology

The majority of the TCAs act primarily as SNRIs by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.^[28]^[29] Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).^[28] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.^[30]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT₂^[31] (5-HT_2A^[32] and 5-HT_2C^[32]), 5-HT₆,^[33] 5-HT₇,^[34] α₁-adrenergic,^[31] and NMDA receptors,^[35] and as agonists at the sigma receptors^[36] (σ₁^[36] and σ₂^[37]), some of which may contribute to their therapeutic efficacy, as well as their side effects.^[38] The TCAs also have varying but typically high affinity for antagonising the H₁^[31] and H₂^[39]^[40] histamine receptors, as well as the muscarinic acetylcholine receptors.^[31] As a result, they also act as potent antihistamines and anticholinergics. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.^[41]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.^[42]^[43] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.^[44] It may also be involved in their efficacy as analgesics, however.^[45]

Binding profiles

The binding profiles of various TCAs and some metabolites in terms of their affinities (K_i, nM) for various receptors and transporters are as follows:^[46]

Compound	SERT	NET	DAT	5-HT_1A	5-HT_2A	5-HT_2C	5-HT₆	5-HT₇	α₁	α₂	D₂	H₁	H₂	mACh	σ₁	σ₂
Amineptine	>100,000	10,000	1,000–1,400	>100,000	74,000	ND	ND	ND	>100,000	>100,000	>100,000	≥13,000	ND	>100,000	ND	ND
Amitriptyline	2.8–4.3	19–35	3,250	≥450	18–23	4.0	65–141	93–123	4.4–24	114–690	196–1,460	0.5–1.1	66	9.6	300	ND
Amoxapine	58	16	4,310	ND	0.5	2.0	6.0–50	41	50	2,600	3.6–160	7.9–25	ND	1,000	ND	ND
Butriptyline	≥1,360	5,100	3,940	7,000	380	ND	ND	ND	570	4,800	ND	1.1	ND	35	ND	ND
Clomipramine	0.14–0.28	38–54	≥2,190	≥7,000	27–36	65	54	127	3.2–38	≥535	78–190	13–31	209	37	546	ND
Desipramine	18–163	0.63–3.5	3,190	≥6,400	115–350	244–748	ND	>1,000	23–130	≥1,379	3,400	60–110	1,550	66–198	≥1,990	≥1,610
Dibenzepin	ND	ND	>10,000	>10,000	≥1,500	ND	ND	ND	>10,000	>10,000	>10,000	23	1,950	1,750	ND	ND
Dosulepin	8.6–78	46–70	5,310	4,000	152	ND	ND	ND	419	2,400	ND	3.6–4.0	ND	25–26	ND	ND
Doxepin	68–210	13–58	≥4,600	276	11–27	8.8–200	136	ND	24	28–1,270	360	0.09–1.23	174	23–80	ND	ND
Imipramine	1.3–1.4	20–37	8,500	≥5,800	80–150	120	190–209	>1,000	32	3,100	620–726	7.6–37	550	46	332–520	327–2,100
Iprindole	≥1,620	1,260	6,530	2,800	217–280	206	ND	ND	2,300	8,600	6,300	100–130	200–8,300	2,100	>10,000	ND
Lofepramine	70	5.4	>10,000	4,600	200	ND	ND	ND	100	2,700	2,000	245–360	4,270	67	2,520	ND
Maprotiline	5,800	11–12	1,000	ND	51	122	ND	50	90	9,400	350–665	0.79–2.0	776	570	ND	ND
Norclomipramine	40	0.45	2,100	19,000	130	ND	ND	ND	190	1,800	1,200	450	ND	92	ND	ND
Northiaden	192	25	2,539	2,623	141	ND	ND	ND	950	ND	ND	25	ND	110	ND	ND
Nortriptyline	15–18	1.8–4.4	1,140	294	5.0–41	8.5	148	ND	55	2,030	2,570	3.0–15	646	37	2,000	ND
Opipramol	≥2,200	≥700	≥3,000	>10,000	120	ND	ND	ND	200	6,100	120–300	6.0	4,470	3,300	0.2–50	110
Protriptyline	19.6	1.41	2,100	3,800	70	ND	ND	ND	130	6,600	2,300	7.2–25	398	25	ND	ND
Tianeptine	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000	>10,000
Trimipramine	149–2,110	≥2,450	≥3,780	8,000	32	537	ND	ND	24	680	143–210	0.27–1.5	41	58	ND	ND
Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

With the exception of the sigma receptors, the TCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters.

Therapeutic levels of TCAs are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM.^[47] Plasma protein binding is generally 90% or greater.^[47]

Chemistry

There are two major groups of TCAs in terms of chemical structure, which most, but not all, TCAs fall into.^[48]^[49]^[50] The groupings are based on the tricyclic ring system.^[48]^[49]^[50] They are the dibenzazepines (imipramine, desipramine, clomipramine, trimipramine, lofepramine) and the dibenzocycloheptadienes (amitriptyline, nortriptyline, protriptyline, butriptyline).^[48]^[49] Minor TCA groups based on ring system include the dibenzoxepins (doxepin), the dibenzothiepines (dosulepin), and the dibenzoxazepines (amoxapine).^[48]^[49] In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of substitutions of the side chain amine.^[50]^[51] These groups include the tertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and the secondary amines (desipramine, nortriptyline, protriptyline).^[50]^[51] Lofepramine is technically a tertiary amine, but acts largely as a prodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines.^[51] Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them.^[52]

History

The TCAs were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulenc's chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s.^[53] Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic.^[54] Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was imipramine, a dibenzazepine analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957.^[53] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.^[54] Geigy later became Ciba-Geigy and eventually Novartis.

Dibenzazepine derivatives are described in U.S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline.

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.^[54] This compound has a different three-ring structure than imipramine.

Society and culture

Recreational use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.^[55] According to the US government classification of psychiatric medications, TCAs are "non-abusable"^[56] and generally have low abuse potential.^[57] Nonetheless due to their atypical MOA, amineptine and tianeptine (dopamine reuptake inhibition and μ-opioid receptor agonism, respectively) are the two TCAs with the highest addiction and abuse potential. Several cases of the misuse^[58] of amitriptyline alone^[59]^[60] or together with methadone^[58]^[61] or in other drug dependent patients^[62]^[63] and of dosulepin with alcohol^[64] or in methadone patients^[65] have been reported.

List of TCAs

Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:

Butriptyline† (Evadyne) (relatively weak serotonin reuptake inhibitor)
Clomipramine (Anafranil)
Imipramine (Tofranil, Janimine, Praminil)
Trimipramine (Surmontil) (relatively weak serotonin reuptake inhibitor)

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:

Desipramine (Norpramin, Pertofrane)
Dibenzepin‡ (Noveril, Victoril)
Lofepramine§ (Lomont, Gamanil)
Maprotiline (Ludiomil) – can be classed with the TCAs though more frequently classed with the TeCAs
Nortriptyline (Pamelor, Aventyl, Norpress)
Protriptyline (Vivactil)

Whereas either fairly balanced reuptake inhibitors of serotonin and norepinephrine or unspecified inhibitors include:

Amitriptyline (Elavil, Endep)
Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin)
Amoxapine (Asendin) – can be classed with the TeCAs but more frequently classed with the TCAs
Demexiptiline† (Deparon, Tinoran)
Dimetacrine† (Istonil, Istonyl, Miroistonil)
Dosulepin§ (Prothiaden)
Doxepin (Adapin, Sinequan)
Fluacizine† (Phtorazisin)
Imipraminoxide† (Imiprex, Elepsin)
Melitracen§ (Deanxit, Dixeran, Melixeran, Trausabun)
Metapramine† (Timaxel)
Nitroxazepine‡ (Sintamil)
Noxiptiline‡ (Agedal, Elronon, Nogedal)
Pipofezine‡ (Azafen/Azaphen)
Propizepine† (Depressin, Vagran)
Quinupramine† (Kevopril, Kinupril, Adeprim, Quinuprine)

And the following are TCAs that act via main mechanisms other than serotonin or norepinephrine reuptake inhibition:

Amineptine‡ (Survector, Maneon, Directim) – norepinephrine–dopamine reuptake inhibitor
Iprindole† (Prondol, Galatur, Tetran) – 5-HT₂ receptor antagonist
Opipramol‡ (Insidon, Pramolan, Ensidon, Oprimol) – σ receptor agonist
Tianeptine‡ (Stablon, Coaxil, Tatinol) – atypical μ-opioid receptor agonist

Legend:

† indicates products that have been withdrawn from the market worldwide.
‡ indicates products that are not available in any country in which English is an official language.
§ indicates products that are not available in the United States, but are available in other English-speaking countries such as Australia, Canada, United Kingdom, etc.
Bolded names indicates products that are available in at least three countries in which English is an official language.

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^ Gillman PK (July 2007). "Tricyclic antidepressant pharmacology and therapeutic drug interactions updated". British Journal of Pharmacology. 151 (6): 737–48. doi:10.1038/sj.bjp.0707253. PMC 2014120 . PMID 17471183.
^ Rénéric JP, Lucki I (March 1998). "Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test". Psychopharmacology. 136 (2): 190–7. doi:10.1007/s002130050555. PMID 9551776.
^ ^a ^b ^c ^d Cusack B, Nelson A, Richelson E (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–565. doi:10.1007/BF02244985. PMID 7855217.
^ ^a ^b Sánchez C, Hyttel J (August 1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology. 19 (4): 467–89. doi:10.1023/A:1006986824213. PMID 10379421.
^ Branchek TA, Blackburn TP (2000). "5-ht6 receptors as emerging targets for drug discovery". Annual Review of Pharmacology and Toxicology. 40: 319–34. doi:10.1146/annurev.pharmtox.40.1.319. PMID 10836139.
^ Stam NJ, Roesink C, Dijcks F, Garritsen A, van Herpen A, Olijve W (August 1997). "Human serotonin 5-HT7 receptor: cloning and pharmacological characterisation of two receptor variants". FEBS Letters. 413 (3): 489–94. doi:10.1016/S0014-5793(97)00964-2. PMID 9303561.
^ Sills MA, Loo PS (July 1989). "Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate". Molecular Pharmacology. 36 (1): 160–5. PMID 2568580.
^ ^a ^b Narita N, Hashimoto K, Tomitaka S, Minabe Y (June 1996). "Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain". European Journal of Pharmacology. 307 (1): 117–9. doi:10.1016/0014-2999(96)00254-3. PMID 8831113.
^ Volz HP, Stoll KD (November 2004). "Clinical trials with sigma ligands". Pharmacopsychiatry. 37 Suppl 3: S214–20. doi:10.1055/s-2004-832680. PMID 15547788.
^ "Differences between tricyclic antidepressants and SNRIs mechanism of action | Pharmacology Corner".
^ Green JP, Maayani S; Maayani (September 1977). "Tricyclic antidepressant drugs block histamine H2 receptor in brain". Nature. 269 (5624): 163–5. Bibcode:1977Natur.269..163G. doi:10.1038/269163a0. PMID 20581.
^ Tsai BS, Yellin TO (November 1984). "Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa". Biochemical Pharmacology. 33 (22): 3621–5. doi:10.1016/0006-2952(84)90147-3. PMID 6150708.
^ Uher R.; Farmer A.; Henigsberg N.; Rietschel M.; Mors O.; Maier W.; Aitchison K. J. (2009). "Adverse reactions to antidepressants". The British Journal of Psychiatry. 195 (3): 202–210. doi:10.1192/bjp.bp.108.061960. PMID 19721108.
^ Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C (January 1998). "Inhibition of neuronal Na+ channels by antidepressant drugs". The Journal of Pharmacology and Experimental Therapeutics. 284 (1): 208–14. PMID 9435180.
^ Zahradník I, Minarovic I, Zahradníková A (March 2008). "Inhibition of the cardiac L-type calcium channel current by antidepressant drugs". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 977–84. doi:10.1124/jpet.107.132456. PMID 18048694.
^ Harrigan RA, Brady WJ (July 1999). "ECG abnormalities in tricyclic antidepressant ingestion". The American Journal of Emergency Medicine. 17 (4): 387–93. doi:10.1016/S0735-6757(99)90094-3. PMID 10452441.
^ Brian E. Cairns (1 September 2009). Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management. John Wiley & Sons. pp. 66–68. ISBN 978-0-470-52221-9.
^ Roth, BL; Driscol, J. "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
^ ^a ^b Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 267–271. ISBN 978-1-58562-309-9.
^ ^a ^b ^c ^d K. Ghose (11 November 2013). Antidepressants for Elderly People. Springer. pp. 182–. ISBN 978-1-4899-3436-9.
^ ^a ^b ^c ^d J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 7–. ISBN 978-0-444-53266-4.
^ ^a ^b ^c ^d Patricia K. Anthony (2002). Pharmacology Secrets. Elsevier Health Sciences. pp. 39–. ISBN 1-56053-470-2.
^ ^a ^b ^c Philip Cowen; Paul Harrison; Tom Burns (9 August 2012). Shorter Oxford Textbook of Psychiatry. OUP Oxford. pp. 532–. ISBN 978-0-19-162675-3.
^ Alan F. Schatzberg, M.D.; Charles B. Nemeroff, M.D., Ph.D. (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition. American Psychiatric Pub. pp. 306–. ISBN 978-1-58562-523-9.
^ ^a ^b A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, D. G. Cunningham Owens, http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf
^ ^a ^b ^c Rose, Nikolas (2004). "Becoming Neurochemical Selves". In Stehr, Nico. Biotechnology: Between Commerce and Civil Society. New Brunswick, NJ: Transaction Publishers. pp. 90–91. ISBN 978-0-7658-0224-8.
^ Wills, Simon (2005). Drugs Of Abuse, 2nd Edition. London: Pharmaceutical Press. p. 213. ISBN 0-85369-582-2.
^ "Exhibit 4-3 Abuse Potential of Common Psychiatric Medications". Health Services/Technology Assessment Text (HSTAT). U.S. National Library of Medicine. Retrieved 2007-05-25.
^ "Figure 3-4: Abuse Potential of Common Psychiatric Medications". Health Services/Technology Assessment Text (HSTAT). U.S. National Library of Medicine. Retrieved 2007-05-25.
^ ^a ^b Wills, Simon (2005). Drugs Of Abuse, 2nd Edition. London: Pharmaceutical Press. pp. 215–216. ISBN 0-85369-582-2.
^ Wohlreich MM, Welch W (1993). "Amitriptyline abuse presenting as acute toxicity". Psychosomatics. 34 (2): 191–3. doi:10.1016/S0033-3182(93)71918-0. PMID 8456167. The patient denied any alcohol or substance abuse, and no signs of withdrawal were noted in the hospital...On examination, Ms. B. denied suicidal ideation or intent but did admit to taking over 800 mg of amitriptyline per day for the past 3 years after being started on the drug for depression. She clearly described a euphoria associated with amitriptyline, noting that it gave her a “buzz” and that she felt “numbed up” and calm about 30 minutes after ingestion. The patient expressed fears of being addicted to the amitriptyline and desired inpatient hospitalization for medication adjustment and education.
^ Singh GP, Kaur P, Bhatia S (June 2004). "Dothiepin dependence syndrome". Indian J Med Sci. 58 (6): 253–4. PMID 15226578.
^ Cohen MJ, Hanbury R, Stimmel B (September 1978). "Abuse of amitriptyline". JAMA. 240 (13): 1372–3. doi:10.1001/jama.240.13.1372. PMID 682328.
^ Delisle JD (October 1990). "A case of amitriptyline abuse". Am J Psychiatry. 147 (10): 1377–8. PMID 2400006. Ms. A, a 24-year-old abuser of alcohol and cannabis, consulted her family physician because of anxiety, depression, and insomnia. Unaware of her drug abuse, he prescribed amitriptyline, 200 mg. About 30 minutes after taking each dose, she would experience relief from her symptoms that lasted about 2 hours. By increasing the dose, she found she could intensify these effects and prolong them for up to several hours. Her “high” consisted of feelings of relaxation, giddiness, and contentment.Frequently, this progressed to incoordination, slurred speech, and confusion. Sometimes she would forget how much she had taken and ingest up to 2 g.
^ Sein Anand J, Chodorowski Z, Habrat B (2005). "Recreational amitriptyline abuse". Prz. Lek. 62 (6): 397–8. PMID 16225078.
^ Lepping P, Menkes DB (July 2007). "Abuse of dosulepin to induce mania". Addiction. 102 (7): 1166–7. doi:10.1111/j.1360-0443.2007.01828.x. PMID 17567406.
^ Dorman A, Talbot D, Byrne P, O'Connor J (December 1995). "Misuse of dothiepin". BMJ. 311 (7018): 1502. doi:10.1136/bmj.311.7018.1502b. PMC 2543748 . PMID 8520352.

External links

Tricyclic Antidepressive Agents at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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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
2. 三環系抗うつ剤中毒 tricyclic antidepressant poisoning
3. Overview of the treatment of chronic non-cancer pain
4. 成人における抗うつ薬の切り替え switching antidepressant medications in adults
5. 小児や青年の不眠症への薬物療法：エビデンスに基づいた治療法 pharmacotherapy for insomnia in children and adolescents a rational approach

English Journal

Clinical management of perinatal anxiety disorders: A systematic review.

Marchesi C1, Ossola P2, Amerio A3, Daniel BD4, Tonna M5, De Panfilis C6.
Journal of affective disorders.J Affect Disord.2016 Jan 15;190:543-50. doi: 10.1016/j.jad.2015.11.004. Epub 2015 Nov 4.
BACKGROUND: In the last few decades, there has been a growing interest in anxiety disorders (AnxD) in the perinatal period. Although AnxD are diagnosed in 4-39% of pregnant women and in up to 16% of women after delivery, evidence on their clinical management is limited.METHODS: A systematic review w
PMID 26571104

The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication.

Basol N1, Erbas O2.
Human & experimental toxicology.Hum Exp Toxicol.2016 Jan;35(1):29-34. doi: 10.1177/0960327115574920. Epub 2015 Feb 27.
BACKGROUND AND OBJECTIVE: Amitriptyline, a frequently used tricyclic antidepressant agent, has powerful cardiotoxic effects especially in high doses. Serum and urine levels of amitriptyline dosages are not correlated with severity of toxicity; therefore, it increases the importance of electrocardiog
PMID 25724422

Involvement of the catecholaminergic system on the antidepressant-like effects of Alpinia zerumbet in mice.

Bevilaqua F1, Mocelin R1,2, Grimm C Jr1, da Silva Junior NS1, Buzetto TL1, Conterato GM1,2, Roman WA Jr1,3, Piato AL1,2.
Pharmaceutical biology.Pharm Biol.2016 Jan;54(1):151-6. doi: 10.3109/13880209.2015.1025287. Epub 2015 Apr 17.
CONTEXT: The traditional uses of Alpinia zerumbet (Pers.) B.L.Burtt & R.m.SM (Zingiberaceae), popularly known as colonia or pacová, suggest that the species has antihypertensive, diuretic, and sedative properties. We previously reported that an ethanol extract of Alpinia zerumbet (HEA) signific
PMID 25885936

Japanese Journal

症例報告経皮的心肺補助により救命した三環系抗うつ薬中毒の2症例

小林かおり,宮島衛,田中敏春 [他]
中毒研究 24(1), 46-50, 2011
NAID 40018756125

症例三環系抗うつ薬から選択的セロトニン再取り込み阻害薬へ置換した後に認知機能が改善したうつ病の1例

豊島邦義,清水祐輔,三井信幸 [他]
精神科 18(2), 238-243, 2011-02
NAID 40018703252

Related Pictures

★リンクテーブル★

リンク元	「三環系抗うつ薬」「TCA」「tricyclic antidepressive agent」

「三環系抗うつ薬」

Tricyclic antidepressant
	Drug class
	Chemical structure of the prototypical and first marketed tricyclic antidepressant imipramine. Notice its three rings.
Class identifiers
Chemical class	Tricyclic
External links
MeSH	D000929
	In Wikidata

　　[★]

英: tricyclic antidepressant, tricyclic anti-depressant agent
関: 抗うつ薬、四環系抗うつ薬; イミプラミン

概念

環状の構造を三つ持つ抗うつ薬
治療効果発現には2-3週間必要

種類

作用機序

ノルアドレナリン、セロトニンのシナプス前ニューロンへの再取り込みを抑制
シナプス前膜のα₂受容体の脱感作。ネガティブフィードバックが解除され、モノアミンの放出が促進される

副作用

抗コリン作用

視力障害、口渇、便秘、尿閉

頻脈

α₁ブロック作用

起立性低血圧

血中ノルアドレナリンの上昇

抗ヒスタミン作用

鎮静、眠気

「TCA」

　　[★]

tricarboxylic acid cycle クエン酸サイクル

「tricyclic antidepressive agent」

　　[★]

三環系抗うつ薬、三環系抗うつ剤

関: tricyclic antidepressant

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[27] "Clinical Pharmacology of SSRI's: Why Are CYP Enzymes Important When Considering SSRIs?". preskorn.com.

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[pmid17471183-29] Gillman PK (July 2007). "Tricyclic antidepressant pharmacology and therapeutic drug interactions updated". British Journal of Pharmacology. 151 (6): 737–48. doi:10.1038/sj.bjp.0707253. PMC 2014120 . PMID 17471183.

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[pmid10379421-32] Sánchez C, Hyttel J (August 1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology. 19 (4): 467–89. doi:10.1023/A:1006986824213. PMID 10379421.

[pmid10836139-33] Branchek TA, Blackburn TP (2000). "5-ht6 receptors as emerging targets for drug discovery". Annual Review of Pharmacology and Toxicology. 40: 319–34. doi:10.1146/annurev.pharmtox.40.1.319. PMID 10836139.

[pmid9303561-34] Stam NJ, Roesink C, Dijcks F, Garritsen A, van Herpen A, Olijve W (August 1997). "Human serotonin 5-HT7 receptor: cloning and pharmacological characterisation of two receptor variants". FEBS Letters. 413 (3): 489–94. doi:10.1016/S0014-5793(97)00964-2. PMID 9303561.

[pmid2568580-35] Sills MA, Loo PS (July 1989). "Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate". Molecular Pharmacology. 36 (1): 160–5. PMID 2568580.

[pmid8831113-36] Narita N, Hashimoto K, Tomitaka S, Minabe Y (June 1996). "Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain". European Journal of Pharmacology. 307 (1): 117–9. doi:10.1016/0014-2999(96)00254-3. PMID 8831113.

[pmid15547788-37] Volz HP, Stoll KD (November 2004). "Clinical trials with sigma ligands". Pharmacopsychiatry. 37 Suppl 3: S214–20. doi:10.1055/s-2004-832680. PMID 15547788.

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[pmid20581-39] Green JP, Maayani S; Maayani (September 1977). "Tricyclic antidepressant drugs block histamine H2 receptor in brain". Nature. 269 (5624): 163–5. Bibcode:1977Natur.269..163G. doi:10.1038/269163a0. PMID 20581.

[pmid6150708-40] Tsai BS, Yellin TO (November 1984). "Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa". Biochemical Pharmacology. 33 (22): 3621–5. doi:10.1016/0006-2952(84)90147-3. PMID 6150708.

[41] Uher R.; Farmer A.; Henigsberg N.; Rietschel M.; Mors O.; Maier W.; Aitchison K. J. (2009). "Adverse reactions to antidepressants". The British Journal of Psychiatry. 195 (3): 202–210. doi:10.1192/bjp.bp.108.061960. PMID 19721108.

[pmid9435180-42] Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C (January 1998). "Inhibition of neuronal Na+ channels by antidepressant drugs". The Journal of Pharmacology and Experimental Therapeutics. 284 (1): 208–14. PMID 9435180.

[pmid18048694-43] Zahradník I, Minarovic I, Zahradníková A (March 2008). "Inhibition of the cardiac L-type calcium channel current by antidepressant drugs". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 977–84. doi:10.1124/jpet.107.132456. PMID 18048694.

[pmid10452441-44] Harrigan RA, Brady WJ (July 1999). "ECG abnormalities in tricyclic antidepressant ingestion". The American Journal of Emergency Medicine. 17 (4): 387–93. doi:10.1016/S0735-6757(99)90094-3. PMID 10452441.

[Cairns2009-45] Brian E. Cairns (1 September 2009). Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management. John Wiley & Sons. pp. 66–68. ISBN 978-0-470-52221-9.

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[Ghose2013-48] K. Ghose (11 November 2013). Antidepressants for Elderly People. Springer. pp. 182–. ISBN 978-1-4899-3436-9.

[Aronson2009-49] J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 7–. ISBN 978-0-444-53266-4.

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[M.D.Ph.D.2017-52] Alan F. Schatzberg, M.D.; Charles B. Nemeroff, M.D., Ph.D. (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition. American Psychiatric Pub. pp. 306–. ISBN 978-1-58562-523-9.

[assets.cambridge.org-53] A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, D. G. Cunningham Owens, http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf

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v t e Tricyclics
Classes	Acridine Anthracene Dibenzazepine Dibenzocycloheptene Dibenzodiazepine Dibenzothiazepine Dibenzothiepin Dibenzoxazepine Dibenzoxepin Phenothiazine Pyridazinobenzoxazine Pyridinobenzodiazepine Thioxanthene
Antidepressants (TCAs and TeCAs)	7-OH-Amoxapine Amezepine Amineptine Amitriptyline Amitriptylinoxide Amoxapine Aptazapine Azepindole Azipramine Batelapine Butriptyline Cianopramine Ciclazindol Ciclopramine Cidoxepin Clomipramine Cotriptyline Cyanodothiepin Demexiptiline Depramine (balipramine) Desipramine (desmethylimipramine) Desmethylclomipramine Desmethyltrimipramine Dibenzepin Dimetacrine Dosulepin (dothiepin) Doxepin Enprazepine Esmirtazapine Fantridone Fluotracen Hepzidine Homopipramol Imipramine Imipraminoxide Intriptyline Iprindole Ketipramine Litracen Lofepramine Losindole Loxapine Maprotiline Mariptiline Mazindol Melitracen Metapramine Mezepine Mianserin Mirtazapine Monometacrine Naranol Nitroxazepine Norbutriptyline Nordoxepin Northiaden (nordosulepin) Nortriptyline (noramitriptyline) Noxiptiline Octriptyline Opipramol Oxaprotiline Pipofezine Pirandamine Propizepine Protriptyline Quinupramine Setiptiline (teciptiline) Spiroxepin Tandamine Tampramine Tianeptine Tienopramine Trimipramine
Antihistamines	Azatadine Clobenzepam Cyproheptadine Dacemazine Deptropine Desloratadine Epinastine Etymemazine Fenethazine Hydroxyethylpromethazine Isopromethazine Isothipendyl Ketotifen Latrepirdine Loratadine Mebhydrolin Mequitazine Methdilazine Olopatadine Oxomemazine Phenindamine Pimethixene Promethazine Propiomazine Rupatadine Thiazinamium
Antipsychotics	Acetophenazine Alimemazine Amoxapine Asenapine Butaclamol Butaperazine Carfenazine (carphenazine) Carpipramine Chlorpromazine Chlorprothixene Ciclindole Citatepine Clocapramine Clomacran Clorotepine Clotiapine Clozapine Cyanothepin Doclothepin Docloxythepin Erizepine Flucindole Flumezapine Fluotracen Flupentixol Fluphenazine Gevotroline Homopipramol Isofloxythepin Levomepromazine/Methotrimeprazine Loxapine Maroxepin Meperathiepin Mesoridazine Metiapine Metitepine Metoxepin Mosapramine Naranol Octomethothepin Olanzapine Oxyclothepin Oxyprothepin Pentiapine Peradithiepin Perathiepin Perazine Perphenazine Periciazine Pinoxepin Piperacetazine Pipotiazine Piquindone Prochlorperazine Promazine Prothipendyl Quetiapine Savoxepin/Cipazoxapine Sulforidazine Tenilapine Thiethylperazine Thiopropazate Thioridazine Thiothixene Tilozepine Traboxopine Trifluoperazine Triflupromazine Trifluthepin Zotepine Zuclopenthixol
Anticonvulsants	Carbamazepine Dizocilpine Eslicarbazepine Eslicarbazepine acetate Etazepine Licarbazepine Oxcarbazepine Oxitriptyline Rispenzepine
Others	Adosopine Aminopromazine Atiprosin Beloxepin Benzoctamine Carvedilol Cidoxepin Cyclobenzaprine Damotepine Darenzepine Elanzepine Fluradoline Methylene blue Monatepil Nuvenzepine Oxetorone Perlapine P7C3 Pinadoline Pirenzepine Pirolate Pitrazepin Pizotifen Profenamine Serazapine Siltenzepine Telenzepine Tipindole Tropatepine Zolenzepine

Tricyclic antidepressant
Drug class
Chemical structure of the prototypical and first marketed tricyclic antidepressant imipramine. Notice its three rings.
Class identifiers
Chemical class	Tricyclic
External links
MeSH	D000929
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tricyclic antidepressant