Trimipramine

Source: Wikipedia, the free encyclopedia.
Trimipramine
Clinical data
Trade namesSurmontil, others
Other namesTrimeproprimine; IF-6120; IL-6001; RP-7162; 2'-Methylimipramine; β-Methylimipramine
AHFS/Drugs.com
MedlinePlusa602010
License data
Pregnancy
category
  • AU: C
Routes of
administration		Oral, intramuscular injection, intravenous
ATC code
Legal status
Legal status
Renal[2][3][4][5]
Identifiers
  • (±)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine
JSmol)
  • c1cc3c(cc1)CCc2c(cccc2)N3CC(C)CN(C)C
  • InChI=1S/C20H26N2/c1-16(14-21(2)3)15-22-19-10-6-4-8-17(19)12-13-18-9-5-7-11-20(18)22/h4-11,16H,12-15H2,1-3H3 checkY
  • Key:ZSCDBOWYZJWBIY-UHFFFAOYSA-N checkY
  (verify)

Trimipramine, sold under the brand name Surmontil among others, is a

antidopaminergic, and anticholinergic activities.[6][7][8][9]

Medical uses

Trimipramine's primary use in medicine is in the treatment of major depressive disorder,[11][12] especially where sedation is helpful due to its prominent sedative effects.[12] The drug is also an effective anxiolytic, and can be used in the treatment of anxiety.[8][9] In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture.[8] In particular, it does not suppress REM sleep, and dreams are said to "brighten" during treatment.[8][13]

Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of

delusional depression, schizoaffective disorder or schizophrenia.[6][7]

A major

certainty of evidence was rated as very low, and no data were available for longer-term treatment (3 months).[14] For comparison, the other sedating antihistamines assessed, doxepin and doxylamine, had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.47 (95% CI 0.06 to 0.89) (moderate certainty evidence), respectively.[14]

The effective dosage of trimipramine in depression is 150 to 300 mg/day.[9] Doses of trimipramine used for insomnia range from 25 to 200 mg/day.[15][16][17] However, it has been advised that doses be kept as low as possible, and a low dose of 25 mg/day has been recommended.[15]

Contraindications

Contraindications include:[2][3][4][5][11][12]

  • Recent myocardial infarction
  • Any degree of heart block or other cardiac arrhythmias
  • Mania
  • Severe liver disease
  • During breastfeeding
  • Hypersensitivity to trimipramine or to any of the excipients

Side effects

The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of

Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.[9]

It is described as being associated with minimal or no

cardiotoxic than other TCAs[7] and cardiotoxicity is said to be minimal, with a "very favorable profile".[9]

Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later.[19] However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.[19]

List of side effects

Common adverse effects include:[2][3][4][5][11][12]

  • Sedation — especially common with trimipramine compared to the other TCAs
  • Anticholinergic effects including:
- dry mouth
- blurred vision
- mydriasis
- decreased lacrimation
- constipation
- urinary hesitancy or retention
- reduced GI motility
- tachycardia (high heart rate)
- anticholinergic delirium (particularly in the elderly and in Parkinson's disease)
  • Weight gain
  • Orthostatic hypotension
  • Sexual dysfunction including impotence, loss of libido and other sexual adverse effects
  • Tremor
  • Dizziness
  • Sweating
  • Anxiety
  • Insomnia
  • Agitation
  • Rash

Adverse effects with an unknown incidence includes:[2][3][4][5][11][12]

  • Confusion
  • Nausea
  • Vomiting
  • Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.)
  • Tinnitus
  • Paraesthesia
  • ECG changes
  • Increased liver function tests

Rare adverse effects include:[2][3][4][5][11][12]

Overdose

Main article: Tricyclic antidepressant overdose

Compared to other TCAs, trimipramine is relatively safe in

serotonin–norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.[20]

Interactions

Trimipramine should not be given with

epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine
.

hyperthyrodism.[2][3][4][5][11][12]

Pharmacology

Pharmacodynamics

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Trimipramine[21]
Site Ki/IC50 (nM) Species Ref
SERTTooltip Serotonin transporter 149–2,110 Human [22][23]
NETTooltip Norepinephrine transporter 2,450–4,990 Human [22][23]
DATTooltip Dopamine transporter ≥3,780 Human [22][23]
5-HT1A 8,000 Human [24]
5-HT1D >10,000 Pig [25]
5-HT2A 32 Human [24]
5-HT2C 537 Pig [25]
5-HT3 9,120 Rat [25]
α1 24 Human [18]
α2 680 Human [18]
D1
 347 Pig [25]
D2
 143–210 Human/undefined [18][26][25]
D3
 ND ND ND
D4
 275 Undefined [25]
H1 0.27–1.48 Human [27][18][28]
H2 41 Human [27]
H3 >100,000 Human [27]
H4 43,700 Human [27]
mAChTooltip Muscarinic acetylcholine receptor 58 Human [18]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

The

monoamine reuptake inhibition.[10][7][6] The effects of the drug are thought to be mainly due to receptor antagonism as follows:[18][26][24]

In spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g., amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g., maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g., fluoxetine).[6][7] In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons.[8] Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs.[9] The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.[7]

The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.[23]

Monoamine reuptake inhibition

Trimipramine and MATs
SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter Type Species Tissue Year/Ref
8,200 1,000 6,800 IC50 (nM) Rat Brain 1977[29]
2,500 510 3,400 Ki (nM) Rat Brain 1984[30]
149 2,450 3,780 KD (nM) Human
HEK293
 1997[22]
2,110 4,990 55,600 IC50 (nM) Human HEK293 2011[23]

Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine,

HEK293 cells,[22] but other authors and a more recent study with an improved design have not had the same findings.[23] In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).[23]

Trimipramine, metabolites, and MATs[23]
Compound SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter
Trimipramine 5.675 5.302 >30 μM
Desmethyltrimipramine 5.206 5.535 4.530
2-Hydroxytrimipramine >30 μM 4.960 4.585
Trimipramine-N-oxide 5.445 4.930 5.027
Values are pIC50. The higher the value, the more
strongly the drug binds to the site.

Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition.[23][31] In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right).[23][31] Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake.[23] However, desmethyltrimipramine still showed only very weak inhibition of the NET.[23]

Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150–350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites.[23] However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood–brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery.[23] As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects.[23][31] This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine.[23] That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine,[32] has also been implicated in antidepressant effects.[33][10][34]

In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines.

hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramine's lack of serotonin reuptake inhibition.[7]

Antihistamine activity

See also: Doxepin § As a hypnotic

Trimipramine is a very potent

H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs).[18][35] The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists,[18][35][36] whereas other TCAs and TeCAs are less potent.[10] These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine),[37] and are among the most potent antihistamines available.[36][38]

Trimipramine is also an antagonist of the

duodenal ulcers.[9]

As a hypnotic

Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.[39]

Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects).[6] This includes TCAs (e.g., amitriptyline, nortriptyline), TeCAs (e.g., mianserin, maprotiline), MAOIs (e.g., clorgiline, pargyline), and SSRIs (e.g., fluoxetine, zimelidine, indalpine).[6] Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep.[6][9] Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep.[40] In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic–pituitary–adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.[25]

In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia.[6] It also improved subjectively perceived sleep quality and well-being during daytime.[6] Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.[6]

Antidopaminergic activity

Trimipramine and clozapine[25][6]
Site Trimipramine Clozapine
5-HT2A 7.71 7.84
α1A/B 7.62 8.54
D2
 7.24 7.01
D1
 6.46 6.58
α2B 6.42 7.08
5-HT2C 6.27 8.40
α2A 5.86 7.10
5-HT3 5.04 7.00
5-HT1A <5.00 6.17
5-HT1D <5.00 5.68
Values are pKi (nM). The higher the value,
the more strongly the drug binds to the site.

Trimipramine is a weak but significant antagonist of the dopamine

antidopaminergic actions of trimipramine.[6][23]

Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission.[7] This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene.[7] Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects.[7][40] As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signaling could be involved in the antidepressant effects of trimipramine.[7][40] However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor.[7] Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.[40]

Pharmacokinetics

The

terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma)[7] and as long as 24 hours.[9] In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.[9][7]

Trimipramine is a

L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively.[42] CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.[42]

Chemistry

Trimipramine is a

maleate salt.[50][51] The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.[50][51]

History

Trimipramine was developed by Rhône-Poulenc.[52] It was patented in 1959 and first appeared in the literature in 1961.[52] The drug was first introduced for medical use in 1966, in Europe.[52][53] It was not introduced in the United States until later in 1979 or 1980.[54][55]

Society and culture

Generic names

Trimipramine is the

Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.[51][57]

Brand names

Trimipramine is marketed throughout the world mainly under the brand name Surmontil.[51][57] Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.[51][57]

Availability

Trimipramine is no longer marketed in Australia, though it was previously.[58][59]

In film

The sedative effects of Trimipramine in off-prescription, recreational use are described in the 1987 film Withnail and I where the eponymous character declares "This is the plan. We get in there and get wrecked, then we'll eat a pork pie, then we'll drop a couple of Surmontil-50's each. That means we'll miss out Monday but come up smiling Tuesday morning."[60]

References

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