Tricyclic antidepressants ( TCA ) are a class of drugs used primarily as antidepressants. TCA was discovered in the early 1950s and was marketed late in the decade. They are named after their chemical structure, which contains three atomic rings. The tetracyclic antidepressant (TeCA), which contains four atomic rings, is a group of closely related antidepressant compounds.
Although TCAs are sometimes prescribed for depressive disorders, they have largely been replaced in clinical use in most of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs ). ). Side effects were found to have similar levels between TCA and SSRI.
Video Tricyclic antidepressant
Medical use
TCA is 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 such as anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), neurological disorders such as attention- deficit hyperactivity disorder (ADHD) Parkinson's and chronic pain, neuralgia or neuropathic pain, and fibromyalgia, headache, or migraine, quit smoking, turretic syndrome, trichotillomania, intestinal irritable syndrome (IBS), interstitial cystitis (IC), nocturnal enuresis (NE), narcolepsy, insomnia, pathological cry and/or laughter, chronic hiccup, ciguatera poisoning, and in addition to schizophrenia.
Clinical depression
Over the years, TCA is the first choice for pharmacologic treatment of clinical depression. Although they are still considered highly effective, they have been increasingly replaced by antidepressants with better safety profiles and side effects, such as SSRIs and other new antidepressants such as the new reversible MAOI moclobemide. However, tricyclic antidepressants may be more effective in treating melancholy depression than other classes of antidepressant medications. Newer antidepressants are thought to have fewer and less severe side effects and are also considered less likely to cause injury or death if used in suicide attempts, because the doses required for clinical care and the likelihood of a lethal overdose (see therapeutic index) are much broader than.
Nevertheless, TCA is sometimes used for drug-resistant depression that fails to respond to therapy with newer antidepressants. They are not considered addictive and somewhat better than monoamine oxidase inhibitors (MAOIs). Side effects of TCA usually become well-known before the therapeutic benefits of depression and/or anxiety, and for this reason, they have the potential to be somewhat dangerous, as willpower may be increased, possibly giving patients greater desire to try or kill themselves.
Attention deficit hyperactivity disorder
The TCAs used in the past in ADHD clinical treatment, although they are not normally used again, have been replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin) and stimulants such as methylphenidate (Ritalin, Focalin, Concerta) , and amphetamines (Adderall, Attentin, Dexedrine, Vyvanse). ADHD is thought to be caused by inadequate activity of dopamine and norepinephrine in the prefrontal cortex of the brain. Most TCAs inhibit norepinephrine reuptake, although not dopamine, and as a result, they show some success in overcoming the disorder. In particular, TCA is more effective at treating ADHD behavioral aspects than cognitive deficits, because TCA helps limit hyperactivity and impulsivity, but has little or no benefit to attention.
Chronic pain
TCA demonstrates efficacy in clinical care of a number of different types of chronic pain, particularly neuralgia or neuropathic pain and fibromyalgia. Appropriate mechanisms of action in the explanation of their analgesic efficacy are unclear, but it is thought that they indirectly modulate opioid systems in the downstream brain through serotonergic and noradrenergic neuromodulations, among other properties. They are also effective in migraine prophylaxis, although not in the instant relief from acute migraine attacks. They may also be effective in preventing chronic tension headaches.
Maps Tricyclic antidepressant
Side effects
Many side effects may be related to antimuscarinic properties of TCA. These side effects are relatively common and may include dry mouth, dry nose, blurred vision, lower gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and elevated body temperature.
Other side effects may include drowsiness, anxiety, emotional dullness (apathy/anhedonia), confusion, anxiety, dizziness, acatisia, hypersensitivity, appetite and weight changes, sweating, sexual dysfunction, muscle twitching, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some toxic effects caused by overdose. Rhabdomyolysis or muscle disorders are rarely reported with this class of drugs.
Tolerance to the ill effects of these drugs often develops when treatment is continued. Side effects may also be less inconvenient if treatment begins with a low dose and then gradually increases, although this may also delay beneficial effects.
TCAs can behave like class 1A antiarrhythmias, thus, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and promote collateral blood circulation to ischemic heart muscle. Of course, in overdose, they can be cardiotoxic, extend heart rhythm and increase myocardial irritability.
The new study also revealed strong evidence of a link between long-term use of anticholinergic drugs such as TCA and dementia. Although many studies have investigated this association, this is the first study to use a long-term (over seven years) approach to find that anticholinergic-associated dementia may not be reversible even years after drug use ceases. Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.
Termination
Antidepressants can generally generate withdrawals. However, since the term "withdrawal" has been linked to recreational drug addictions such as opioids, the medical profession and pharmaceutical public relations prefer that different terms are used, the "termination syndrome." Symptoms of discontinuation can be managed by gradual reduction of dose for several weeks or months to minimize symptoms. In tricyclics, the symptoms of termination syndrome include anxiety, insomnia, headache, nausea, malaise, or motor disorders.
Overdose
TCA overdose is a significant cause of fatal drug poisoning. The associated morbidity and mortality associated with this drug are well documented for their cardiovascular and neurological toxicities. In addition, this is a serious problem in the pediatric population due to the inherent toxicity and availability of these at home when prescribed for bedwetting and depression. If there is a known or suspected overdose, medical assistance should be sought immediately.
A number of treatments are effective in TCA overdose.
Overdose in TCA is fatal because it is rapidly absorbed from the digestive tract in the alkaline conditions of the small intestine. As a result, poisoning often becomes apparent in the first hour after an overdose. However, symptoms may take several hours to appear if a mixed overdose causes delayed gastric emptying.
Many of the early signs are associated with the anticolinergic effects of TCA such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and vomiting (or vomiting). Because of the location of norepinephrine receptors throughout the body, many physical signs are also associated with TCA overdose:
- Anticholinergic effects: changes in mental status (eg, agitation, confusion, lethargy, etc.), sinus tachycardia, dry mouth, midriasis (dilated pupils), fever
- Heart effects: hypertension (premature and temporary, untreated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequences)/ECG changes (QRS, QT and PR extension)
- CNS effects: syncope, seizures, coma, myoclonus, hyperreflexia
- Pulmonary effects: hypoventilation due to CNS depression
- Gastrointestinal effects: missing or missing bowel sounds
TCA overdose treatment depends on the severity of the symptoms:
Initially, the patient's gastric decontamination is achieved by administration, either orally or via a nasogastric tube, activated pre-mixed with water, adsorbing the drug in the gastrointestinal tract (most useful if administered within 2 hours after ingestion). Other decontamination methods such as abdominal pumps, gastric lavage, total intestinal irrigation, or ipecac-induced emec, are not recommended in TCA poisoning.
If there is a metabolic acidosis, intravenous sodium bicarbonate infusion recommended by Toxbase.org, UK and Ireland poisoned the suggestion database (TCA is a bound protein and becomes less bound in more acidic conditions, thus by reversing acidosis, increasing protein binding and bioavailability thus decreasing - sodium can also help reverse the Na channel blocking effect of TCA).
Interactions
TCA is highly metabolized by the liver enzyme P450 cytochrome. Drugs that inhibit cytochrome P450 (eg cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) can result in a decrease in TCA metabolism, leading to an increase in blood concentration and associated toxicity. Drugs that extend QT intervals include antiarrhythmics such as quinidine, antihistamine astemizole and terfenadine, and some antipsychotics may increase the likelihood of ventricular dysrhythmias. TCA can improve response to alcohol and other barbiturate and CNS depressant effects. Side effects can also be enhanced by other drugs that have antimuscarinic properties.
Pharmacology
The majority of TCAs act primarily as SNRIs by blocking serotonin transporters (SERT) and norepinephrine (NET) transporters, respectively, resulting in increased synaptic concentrations of these neurotransmitters, and therefore increased neurotransmissions. In particular, with the only exception of amineptine, TCA has a negligible affinity for dopamine transporters (DAT), and therefore has no efficacy as dopamine reuptake inhibitors (DRIs). Both serotonin and norepinephrine have been heavily involved in depression and anxiety, and have shown that the facilitation of their activity has a beneficial effect on this mental disorder.
In addition to reuptake inhibition, many TCAs also have high affinity as antagonists at 5-HT 2 (5-HT 2A and 5-HT 2C ), 5-HT 6 , 5-HT 7 ,? 1 -adrenergic, and NMDA receptors, and as an agonist on receptor sigma ( 1 and 2 ), some of which may contribute to the efficacy therapeutic, and side effects. TCA also has a varied but usually high affinity for histamine receptor antagonists H 1 and H 2 , as well as acetylcholine muscarinic receptors. As a result, they also act as powerful antihistamines and anticholinergics. These properties are often useful in antidepressants, especially with comorbid anxiety, because it provides a sedative effect.
Most, if not all, of the TCAs also potentially inhibit the sodium and calcium channels L , and therefore act as a channel blocker of sodium and calcium channel blockers, respectively. The former property is responsible for the high mortality rate in the overdose seen with TCA through cardiotoxicity. It may also be involved in their efficacy as an analgesic.
Bind profile
Binding profiles of various TCAs and some metabolites in terms of their affinity ( K i , nM ) for various receptors and transporters are as follows:
With the exception of sigma receptors, TCA acts as an inverse antagonist or agonist of the receptor and as a carrier inhibitor. Tianeptine is included in this list because it is technically a TCA, but with very different pharmacology.
TCA therapeutic levels are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM. Plasma protein bonds are generally 90% or greater.
Chemistry
There are two large groups of TCAs in terms of chemical structure, which most, but not all, TCAs fall into. The grouping is based on the tricyclic ring system. They are dibenzazepine (imipramine, desipramine, clomipramine, trimipramine, lofepramine) and dibenzocycloheptadienes (amitriptyline, nortriptyline, protriptyline, butriptyline). The minor TCA groups based on the ring system include dibenzoxepins (doxepin), dibenzothiepines (dosulepin), and dibenzoxazepines (amoxapine). In addition to the classification based on the ring system, TCA can also be grouped by the amount of substitution of the amine side chain. These groups include tertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepine, dosulepine) and secondary amines (desipramine, nortriptyline, protriptyline). Lofepramine is technically a tertiary amine, but largely acts as a prodrug desipramine, a secondary amine, and is therefore more similar in the secondary amine profile than the tertiary amine. Amoxapine does not have a TCA side chain and therefore is not a tertiary or secondary amine, although it is often grouped with secondary amines because it shares more in common with them.
History
TCA was developed in the middle of the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of chlorpromazine in December 1950 by the head of RhÃÆ'Â'ne-Poulenc chemistry, Paul Charpentier, of synthetic antihistamines developed by RhÃÆ'Â'ne-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely used psychiatric drug, in 1955, had produced significant income as an antipsychotic. Chemical researchers are rapidly beginning to explore other chlorpromazine derivatives.
The first TCA reported for the treatment of depression was imipramine, a dibenzazepine analogue of chlorpromazine code called G22355. It was initially not targeted for the treatment of depression. The tendency of the drug to induce a bead effect is "then described as 'in some patients, quite severe'". Paradoxical observations of the mania that drive the sedative cause testing with depressed patients. The first trial of imipramine occurred in 1955 and the first report of the antidepressant effect was published by the Swiss psychiatrist Roland Kuhn in 1957. Some of the imipramine Geigy tests, later known as Tofranil, took place at the MÃÆ'¼nsterlingen Hospital near Konstanz. Geigy then becomes Ciba-Geigy and finally Novartis.
The dibenzazepine derivative is described in US patent 3,074,931 issued 1963-01-22 with an assignment to Smith Kline & amp; French Laboratory. The described compounds share a different tricyclic backbone from the TCA amitriptyline spine.
Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961. It has a distinct three-ring structure of imipramine.
Society and culture
Use of recreation
A small number of cases involving the use of non-medical antidepressants have been reported for the past 30 years. According to the US government classification of psychiatric drugs, the TCA is "incurable" and generally has a low potential for abuse. However, because of the atypical MOA, amineptine and tianeptine (inhibition of dopamine reuptake and opioid receptor agonists), both are TCAs with the highest addiction and abuse potential. Several cases of amitriptyline abuse alone or along with methadone or other drug dependency patients and dosulepine with alcohol or methadone patients have been reported.
TCA List
Those who specifically inhibit serotonin reuptake (at least 10 times that of norepinephrine) include:
- Butriptyline (Evadyne) (relatively weak serotonin reuptake rejuvenator)
- Clomipramine (Anafranil)
- Imipramine (Tofranil, Janimine, Praminil)
- Trimipramine (Surmontil) (relatively weak serotonin reuptake rejuvenator)
Those that exclusively inhibit the reuptake of norepinephrine (at least 10 times that of serotonin) include:
- Desipramine (Norpramin, Pertofrane)
- Dibenzepin? (Noveril, Victoril)
- LofepramineÃ,§ (Lomont, Gamanil)
- Maprotiline (Ludiomil) - can be classified with TCA although more often classified with TeCAs
- Nortriptyline (Pamelor, Aventyl, Norpress)
- Protriptyline (Vivactil)
While serotonin and norepinephrine reuptake inhibitors or non-specific inhibitors include:
And the following are TCAs that act through the main mechanisms other than inhibition of serotonin or norepinephrine reuptake:
- Amineptine? (Survector, Maneon, Directim) - norepinephrine-dopamine reuptake inhibitor
- Iprindole (Prondol, Galatur, Tetran) - 5-HT 2 receptor antagonist
- Opipramol? (Insidon, Pramolan, Ensidon, Oprimol) -? receptor agonists
- Tianeptine? (Stablon, Coaxil, Tatinol) - atypical? Receptor -opioid agonist
Legend:
References
Further reading
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Gillman PK (2007). "Tricyclic antidepressant pharmacology and therapeutic drug interactions are updated". Br. J. Pharmacol . 151 (6): 737-48. doi: 10.1038/sj.bjp.0707253. PMCÃ, 2014120 . PMID 17471183. Ã,
External links
- Tricyclic Antidepressant Agent at US National Library of Medicine's Medical Subject Headings (MeSH)
Source of the article : Wikipedia
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