Tricyclic antidepressant

Chemical structure of the tricyclic antidepressant amitriptyline. Notice its three rings.

Tricyclic antidepressants (TCAs) are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade. They are named after their chemical structure, which contains three rings of atoms. The tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), among others, though they are still sometimes prescribed for certain indications.

Contents

List of TCAs

The TCAs include the following agents which are predominantly serotonin and/or norepinephrine reuptake inhibitors:

  • Amitriptyline (Elavil, Tryptizol, Laroxyl)
  • Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin)
  • Butriptyline (Evadyne)
  • Clomipramine (Anafranil)
  • Demexiptiline (Deparon, Tinoran)
  • Desipramine (Norpramin, Pertofrane)
  • Dibenzepin (Noveril, Victoril)
  • Dimetacrine (Istonil, Istonyl, Miroistonil)
  • Dosulepin/Dothiepin (Prothiaden)
  • Doxepin (Adapin, Sinequan)
  • Imipramine (Tofranil, Janimine, Praminil)
  • Imipraminoxide (Imiprex, Elepsin)
  • Lofepramine (Lomont, Gamanil)
  • Melitracen (Deanxit, Dixeran, Melixeran, Trausabun)
  • Metapramine (Timaxel)
  • Nitroxazepine (Sintamil)
  • Nortriptyline (Pamelor, Aventyl)
  • Noxiptiline (Agedal, Elronon, Nogedal)
  • Pipofezine (Azafen/Azaphen)
  • Propizepine (Depressin, Vagran)
  • Protriptyline (Vivactil)
  • Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine)

As well as the following atypical compounds:

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.[1] 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.[2] 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 Ronald Kuhn in 1957.[1] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[2] 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.[2] This compound has a different three-ring structure from imipramine.

Many patents were filed in the 1950s and 1960s concerning variations on these three-ring structures with applications to psychiatric conditions.

These patents cover the structures of the compounds and their mode of chemical synthesis. Understanding of their mode of action as re-uptake inhibitors and development of the serotonin theory of depression came in the years to follow.

Indications

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and bipolar disorder (BD), especially of the treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalised 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), attention-deficit hyperactivity disorder (ADHD), 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),[3] narcolepsy, insomnia, pathological crying and/or laughing, chronic hiccups, and 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 the SSRIs and other newer antidepressants. Notably, however, a recent Cochrane review of the efficacy of the SSRIs concluded that they were only slightly more effective than placebo[4] for the treatment of people with depression. Other indications of SSRIs were not tested. Newer antidepressants are thought to have fewer and less intense 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.[5] 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.[6]

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD,[7] though they are not typically used anymore on account of being 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). ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the prefrontal cortex of the brain. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.[8] 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.[9]

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.[10][11] 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.[12][13][14] They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack.

Pharmacology

The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the extracellular concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[15][16] Notably, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[15] 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.[17]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[18] (5-HT2A[19] and 5-HT2C[19]), 5-HT6,[20] 5-HT7,[21] α1-adrenergic,[18] and NMDA receptors,[22] and as agonists at the sigma receptors[23] (σ1[23] and σ2[24]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[25] The TCAs also have varying but typically high affinity for antagonising the H1[18] and H2[26][27] histamine receptors, as well as the muscarinic acetylcholine receptors.[18] As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles.[25]

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.[28][29] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[30]

Binding profiles

The affinities (Kd (nM)) of a selection of TCAs have been compared below at an assortment of binding sites:[15][18][31][32]

Compound SERT NET DAT 5-HT1A 5-HT2A α1 α2 D2 H1 mACh
Amitriptyline 4.30 35 3,250 320 24 26 815 1,230 1.03 13.8
Butriptyline 1,360 5,100 3,940 7,000 380 570 4,800  ? 1.1 35
Clomipramine 0.28 38 2,190 7,000 27 38 3,200 190 31 37
Desipramine 17.6 0.83 3,190 6,700 315 115 6,350 3,400 85 132
Dosulepin 8.6 46 5,310 2,300 258 470 2,400  ? 3.6 25
Doxepin 68 29.5 12,100 283 26 24 1,185 1,380 0.21 52
Imipramine 1.40 37 8,500 7,650 115 61 3,150 1,310 24 68
Iprindole 1,620 1,262 6,530 2,800 280 2,300 8,600  ? 130 2,100
Lofepramine 70 5.4 18,000 4,600 200 100 2,700 2,000 360 67
Nortriptyline 18 4.37 1,140 302 43 58 2,265 1,885 8.2 94
Protriptyline 19.6 1.41 2,100 3,800 70 130 6,600 2,300 25 25
Trimipramine 149 2,450 3,780 8,000 32 24 680 180 0.27 58

The selected ligands act as antagonists (or inverse agonists depending on the site in question) at all receptors listed and as inhibitors of all transporters listed.[15][18][31][32]

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. Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[33]

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 Antiarrythmics, 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.

Discontinuation

Antidepressants in general may produce a discontinuation syndrome. This is not the same as drug withdrawal.[34] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[35]

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.[36] 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.

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[37] and the availability of these in the home when prescribed for bed wetting and depression.

A number of treatments are effective in a TCA overdose.

An overdose on TCA is especially fatal as they are rapidly absorbed from 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[38]:

  1. Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever
  2. 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)
  3. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
  4. Pulmonary effects: hypoventilation resulting from CNS depression
  5. Gastrointestinal effects: decreased or absent bowel sounds

Treatment depends on severity of symptoms. If there is a metabolic acidosis, infusion of Sodium Bicarbonate is recommended by Toxbase (UK poisons advice website). Two mechanisms are postulated for its therapeutic effect. Tricyclics are protein bound and become less bound in more acidic conditions. By reversing the acidosis, protein binding increases and bioavailability thus decreases. An alternative explanation is that the sodium load helps to reverse the Na+ channel blocking effects of the TCA. Treatment is otherwise supportive.

Recreational use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[39] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[40] and generally have low abuse potential.[41] Several cases of the misuse[42] of amitriptyline alone[43][44] or together with methadone[42][45] or in other drug dependent patients[46][47] and of dothiepin with alcohol[48] or in methadone patients[49] have been reported.

See also

References

  1. ↑ 1.0 1.1 A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, D. G. Cunningham Owens, http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf
  2. ↑ 2.0 2.1 2.2 Becoming Neurochemical Selves, Nikolas Rose, p.3
  3. ↑ Glazener C, Evans J, Peto R (2003). "Tricyclic and related drugs for nocturnal enuresis in children". Cochrane Database Syst Rev (3): CD002117. doi:10.1002/14651858.CD002117. PMID 12917922. 
  4. ↑ Moncrieff et al. (2003). Active placebos versus antidepressants for depression. Cochrane databases.
  5. ↑ Broquet K (1999). "Status of treatment of depression.". South Med J 92 (9): 846–56. PMID 10498158. 
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  7. ↑ Biederman J, Baldessarini R, Wright V, Knee D, Harmatz J (1989). "A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy". J Am Acad Child Adolesc Psychiatry 28 (5): 777–84. doi:10.1097/00004583-198909000-00022. PMID 2676967. 
  8. ↑ Biederman J, Spencer T (1999). "Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder". Biol Psychiatry 46 (9): 1234–42. doi:10.1016/S0006-3223(99)00192-4. PMID 10560028. 
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  10. ↑ Micó J, Ardid D, Berrocoso E, Eschalier A (2006). "Antidepressants and pain.". Trends Pharmacol Sci 27 (7): 348–54. doi:10.1016/j.tips.2006.05.004. PMID 16762426. 
  11. ↑ McQuay H, Tramèr M, Nye B, Carroll D, Wiffen P, Moore R (1996). "A systematic review of antidepressants in neuropathic pain.". Pain 68 (2-3): 217–27. doi:10.1016/S0304-3959(96)03140-5. PMID 9121808. 
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  15. ↑ 15.0 15.1 15.2 15.3 Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters.". Eur J Pharmacol. 340 (2-3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821. 
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  17. ↑ 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. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 Cusack B, Nelson A, Richelson E. (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds.". Psychopharmacology (Berl). 114 (4): 559–565. doi:10.1007/BF02244985. PMID 7855217. 
  19. ↑ 19.0 19.1 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. 
  20. ↑ 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. 
  21. ↑ 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. 
  22. ↑ 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. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2568580. 
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  28. ↑ 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. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9435180. 
  29. ↑ 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. 
  30. ↑ 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. 
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  35. ↑ van Broekhoven F, Kan CC, Zitman FG (June 2002). "Dependence potential of antidepressants compared to benzodiazepines". Progress in Neuro-psychopharmacology & Biological Psychiatry 26 (5): 939–43. doi:10.1016/S0278-5846(02)00209-9. PMID 12369270. 
  36. ↑ http://www.preskorn.com/books/ssri_s7.html
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  38. ↑ California Poison Control 1-800-876-4766
  39. ↑ Wills, Simon (2005). Drugs Of Abuse, 2nd Edition. London: Pharmaceutical Press. pp. 213. ISBN 0-85369-582-2. 
  40. ↑ "Exhibit 4-3 Abuse Potential of Common Psychiatric Medications". Health Services/Technology Assessment Text (HSTAT). U.S. National Library of Medicine. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.36258. Retrieved 2007-05-25. 
  41. ↑ "Figure 3-4: Abuse Potential of Common Psychiatric Medications". Health Services/Technology Assessment Text (HSTAT). U.S. National Library of Medicine. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.table.67504. Retrieved 2007-05-25. 
  42. ↑ 42.0 42.1 Wills, Simon (2005). Drugs Of Abuse, 2nd Edition. London: Pharmaceutical Press. pp. 215–216. ISBN 0-85369-582-2. 
  43. ↑ Wohlreich MM, Welch W (1993). "Amitriptyline abuse presenting as acute toxicity". Psychosomatics 34 (2): 191–3. 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.". 
  44. ↑ Singh GP, Kaur P, Bhatia S (June 2004). "Dothiepin dependence syndrome". Indian J Med Sci 58 (6): 253–4. PMID 15226578. http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2004;volume=58;issue=6;spage=253;epage=254;aulast=Singh. 
  45. ↑ 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. 
  46. ↑ 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.". 
  47. ↑ Sein Anand J, Chodorowski Z, Habrat B (2005). "Recreational amitriptyline abuse". Prz. Lek. 62 (6): 397–8. PMID 16225078. 
  48. ↑ 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. 
  49. ↑ Dorman A, Talbot D, Byrne P, O'Connor J (December 1995). "Misuse of dothiepin". BMJ 311 (7018): 1502. PMID 8520352. 

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MCH1 antagonists
ATC-0175 • SNAP-94847
mGluR2/3 Agonists
Eglumegad
mGluR5 NAMs
Fenobam
TSPO agonists
DAA-1097 • DAA-1106 • Emapunil • FGIN-127 • FGIN-143
σ1 agonists
Afobazole • Opipramol
Others
Benzoctamine • Carbetocin • Demoxytocin • Mephenoxalone • Mepiprazole • Oxanamide • Oxytocin • Promoxolane • Tofisopam • Trimetozine • WAY-267,464
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

mepr

dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)
Hypnotics/Sedatives (N05C)
GABAA receptor
Ultrashort-acting
Methohexital • Thiamylal • Thiopental
Short/intermediate-
acting
Allobarbital • Amobarbital • Butabarbital • Butobarbital • Pentobarbital • Secobarbital • Talbutal
Long-acting
Barbital • Mephobarbital • Phenobarbital
Ungrouped
Cyclobarbital • Ethallobarbital • Heptabarbital • Hexobarbital • Proxibarbal • Reposal • Vinylbital • Vinbarbital
Short-acting
Brotizolam • Cinolazepam • Doxefazepam • Loprazolam • Midazolam • Triazolam
Intermediate-acting
Estazolam • Flunitrazepam • Lormetazepam • Nimetazepam • Temazepam
Long-acting
Flurazepam • Flutoprazepam • Nitrazepam • Quazepam
Dialkylphenols
Fospropofol • Propofol • Thymol
Nonbenzo-
diazepines
CL-218,872 • Eszopiclone • Indiplon • Lirequinil • Necopidem • Pazinaclone • ROD-188 • Saripidem • Suproclone • Suriclone • SX-3228 • U-89843A • U-90042 • Zaleplon • Zolpidem • Zopiclone
Piperidinediones
Glutethimide • Methyprylon • Pyrithyldione • Piperidione
Quinazolinones
Afloqualone • Cloroqualone • Diproqualone • Etaqualone • Mebroqualone • Mecloqualone • Methaqualone • Methylmethaqualone • Nitromethaqualone
Neuroactive
steroids
Acebrochol • Allopregnanolone • Alphadolone • Alphaxolone • Eltanolone • Ganaxolone • Hydroxydione • Minaxolone • Org 20599 • Org 21465 • Tetrahydrodeoxycorticosterone
Alpha-2 adrenergic
receptor
Alpha-adrenergic agonists
4-NEMD • Clonidine • Dexmedetomidine • Lofexidine • Medetomidine • Romifidine • Tizanidine • Xylazine
Melatonin receptor
Agomelatine • Melatonin • Ramelteon • Tasimelteon
Histamine receptor &
Acetylcholine receptor
Antihistamines &
Anticholinergics
Amitriptyline • Dimenhydrinate • Doxylamine • Hydroxyzine • Diphenhydramine • Bromodiphenhydramine • Carbinoxamine • Doxepin • Esmirtazapine • Orphenadrine • Mianserin • Mirtazapine • Phenyltoloxamine • Propiomazine • Pyrilamine • Scopolamine
5-HT2A &
α1-adrenergic
Selective 5-HT2A & α1-adrenergic antagonists
Etoperidone • Nefazodone • Niaprazine • Trazodone
GABAB receptor /
GHB receptor
GHB Type
1,4-Butanediol • Aceburic acid • GABOB • gamma-Hydroxybutyric acid • GBL • gamma-Valerolactone
Orexin receptors
Orexin antagonists
Almorexant • SB-334,867 • SB-408,124 • SB-649,868 • TCS-OX2-29
Other receptors/
ungrouped
Acetylglycinamide chloral hydrate • Chloral hydrate • Chloralodol • Dichloralphenazone • Paraldehyde • Petrichloral
Centalun • Ethchlorvynol • Ethinamate • Hexapropymate • Methylpentynol
Carbamates
Meprobamate • Carisoprodol • Tybamate • Methocarbamol • Procymate
Other
2-Methyl-2-butanol • Acecarbromal • Acetophenone • Apronal • Bromides • Bromisoval • Carbromal • Chloralose • Clomethiazole • Embutramide • Etomidate • Evoxine • Fenadiazole • Gaboxadol • Loreclezole • Mephenoxalone • Sulfonmethane • Trichloroethanol • Triclofos • Valerian • Valnoctamide
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

mepr

dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)
Drugs used for the treatment of fibromyalgia and neuropathic pain
Antidepressants
SNRIs
Desvenlafaxine • Duloxetine • Milnacipran • Venlafaxine
TCAs
Amitriptyline • Clomipramine • Desipramine • Imipramine
Others
Anticonvulsants
Carbamazepine • Divalproex sodium • Gabapentin • Lacosamide • Lamotrigine • Oxcarbazepine • Phenytoin • Pregabalin • Sodium valproate • Topiramate • Valproic acid
Miscellaneous
Nabilone • THC (found in Cannabis)
NMDAR antagonists
Botulinum toxin • Capsaicin • Glyceryl trinitrate • Lidocaine
Others
Mexiletine • Tramadol

Serotonergics Tricyclics