Imipramine

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Imipramine
Imipramine.svg
Imipramine-3D-balls.png
Clinical data
Trade names Tofranil, Tofranil-PM, others
Other namesMelipramine; G-22355
AHFS/Drugs.com Monograph
MedlinePlus a682389
License data
Pregnancy
category
Routes of
administration 		By mouth, intramuscular injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 94–96% [3]
Protein binding 86% [4]
Metabolism Liver (CYP1A2, CYP2C19, CYP2D6) [4]
Metabolites Desipramine [4]
Elimination half-life 20 hours [4]
Excretion Kidney (80%), fecal (20%) [4]
Identifiers
  • 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.039 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H24N2
Molar mass 280.415 g·mol−1
3D model (JSmol)
  • CN(C)CCCN1c2ccccc2CCc2ccccc21
  • InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3 Yes check.svgY
  • Key:BCGWQEUPMDMJNV-UHFFFAOYSA-N Yes check.svgY
   (verify)

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth.

Contents

Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes. Overdose of the medication can result in death. Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergic receptors.

Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and TCAs other than amitriptyline (which, at least in the U.K., is prescribed comparatively as frequently as selective serotonin reuptake inhibitors [SSRIs]) have decreased in prescription frequency with the rise of SSRIs—which have fewer inherent side effects and are far safer in overdose despite lacking equivalent potency to TCAs.[ citation needed ] Regardless of its caveats, imipramine retains importance in psychopharmacology and pediatrics (e.g., with childhood enuresis) and is considered the "gold standard" for panic disorder. [5] [6]

Medical uses

Imipramine is primarily used for the treatment of depression and certain anxiety disorders, including acute post-traumatic stress reactions. A significant amount of research regarding its efficacy on acute post-traumatic stress in children and adolescents has focused on trauma resulting from burn-injuries. [7] [8] [9] Although evidence for its efficacy in the treatment of chronic post-traumatic stress disorder appears to be less robust, [10] it remains a viable treatment. [11] Here, it may act fairly similarly to monoamine oxidase inhibitor phenelzine.

Caution is needed in prescribing imipramine (and its commercially-available metabolite, desipramine) in children and youth/adolescents (whether they suffer with, e.g., bed-wetting, recurrent panic attacks, acute trauma or, in the case of desipramine, [12] [13] ADHD), owing to possibility of certain side-effects which may be of particular concern in those under a certain age. [14] [15]

In the treatment of depression, it has demonstrated similar efficacy to the MAOI moclobemide. [16] It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. It is also used for separation anxiety in dogs and cats. Blood levels between 150 and 250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy. [17]

Contraindications

Combining it with alcohol consumption may cause more drowsiness, necessitating greater caution when drinking. [18] It may be unsafe during pregnancy. [1]

Many MAOIs are known to have serious interactions with imipramine. It is often contraindicated during their use or in the two weeks following their discontinuation. This category includes medications such as isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, moclobemide, procarbazine, rasagiline, safinamide, and tranylcypromine. [18] [19]

Side effects

These side effects can be contributed to the multiple receptors that imipramine targets such as serotonin, norepinephrine, dopamine, acetylcholine, epinephrine, histamine. Those listed in italics below denote common side effects, separated by the organ systems that are affected. [20] Some side effects may be beneficial in some cases, e.g. reduction of hyperactive gag reflex; reduced random or physical strain-linked urinary leakage.

Overdose

Interactions

Like other tricyclic antidepressants, imipramine has many medication interactions. Many MAOIs have serious interactions with this medication. Other categories of medications that may interact with imipramine include blood thinners, antihistamines, muscle relaxants, sleeping pills, thyroid medications, and tranquilizers. Some medications used for various conditions such as high blood pressure, mental illness, nausea, Parkinson's disease, asthma, colds, or allergies. [18]

Certain medications increase the risk of serotonin syndrome, including selective serotonin reuptake inhibitors (SSRIs), St. John's Wort, and drugs such as ecstasy. Other prescription drugs decrease the body's ability to eliminate imipramine. These include barbiturates, some antiarrhythmic medications, some antiepileptic drugs, and certain HIV drugs (protease inhibitors). Others may cause changes in the heart rhythm, such as QT prolongation. [19]

Alcohol and tobacco may interact with imipramine. Tobacco may decrease the medication's effectiveness. [18]

Pharmacology

Pharmacodynamics

Imipramine (and metabolite) [21] [22]
SiteIMI DSI Tooltip DesipramineSpeciesRef
SERT Tooltip Serotonin transporter1.3–1.417.6–163Human [23] [24]
NET Tooltip Norepinephrine transporter20–370.63–3.5Human [23] [24]
DAT Tooltip Dopamine transporter8,5003,190Human [23]
5-HT1A ≥5,800≥6,400Human [25] [26] [27]
5-HT2A 80–150115–350Human [25] [27]
5-HT2C 120244–748Human/rat [28] [29] [26]
5-HT3 970–3,651≥2,500Rodent [26] [30]
5-HT6 190–209NDRat [31]
5-HT7 >1,000>1,000Rat [32]
α1 3223–130Human [25] [33] [24]
α2 3,100≥1,379Human [25] [33] [24]
β >10,000≥1,700Rat [34] [35] [36]
D1 >10,0005,460Human [26] [37]
D2 620–7263,400Human [37] [26] [33]
D3 387NDHuman [26]
H1 7.6–3760–110Human [25] [33] [38]
H2 5501,550Human [38]
H3 >100,000>100,000Human [38]
H4 24,0009,550Human [38]
mACh Tooltip Muscarinic acetylcholine receptor4666–198Human [25] [33]
   M1 42110Human [39]
   M2 88540Human [39]
   M3 60210Human [39]
   M4 112160Human [39]
   M5 83143Human [39]
α3β4 410–970NDHuman [40]
σ1 332–5201,990–4,000Rodent [41] [42] [43]
σ2 327–2,100≥1,611Rat [21] [42] [43]
hERG Tooltip human Ether-à-go-go-Related Gene3,400NDHuman [44]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Imipramine affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of imipramine's actions include, but are not limited to, effects on:

Bethanechol may also be able to alleviate the sexual-dysfunction symptoms which may occur in the context of tricyclic-antidepressant treatment. [51] [52] [53]

Pharmacokinetics

Imipramine has a varied absolute oral bioavailability ranging from 22% to 77%, leading to significant variability in pharmacokinetics. While the drug has rapid and complete absorption after oral administration, much of the drug is affected by first pass metabolism. Food has no effect on absorption, peak drug concentration, or time to peak drug concentration. [56]

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite. [56]

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. [57] Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). [57] [58] Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. [59] [60] Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. [61] [62] The chemical name of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H24N2 with a molecular weight of 280.407 g/mol. [63] The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used. [63] [64] The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8. [63] [64]

History

The parent compound of imipramine, 10,11-dihydro-5H-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. [65] [66] [67] Imipramine was first synthesized in 1951, as an antihistamine. [68] [69] The antipsychotic effects of chlorpromazine were discovered in 1952, [70] and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. [33] [71] The medication was tested in several hundred patients with psychosis, but showed little effectiveness. [72] However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. [33] [71] [73] This was followed by similar observations in other patients and further clinical research. [74] [72] Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. [75] Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants. [73] [74] [72]

In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as "depressive psychosis". The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients experienced dizziness. Imipramine was first tried for treating psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. [76] It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. [77] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.

Before the advent of selective serotonin reuptake inhibitors (SSRIs), its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since SSRIs are superior in terms of inherent side-effect tolerability (although probably inferior in terms of actual efficacy), it has, as of the 1990s, no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression. It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Society and culture

Generic names

Imipramine is the English and French generic name of the drug and its INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, and DCF Tooltip Dénomination Commune Française, while imipramine hydrochloride is its USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, BANM Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [63] [64] [78] [79] Its generic name in Spanish and Italian and its DCIT Tooltip Denominazione Comune Italiana are imipramina, in German is imipramin, and in Latin is imipraminum. [64] [79] The embonate salt is known as imipramine pamoate. [64] [79]

Brand names

Imipramine is marketed throughout the world mainly under the brand name Tofranil. [64] [79] Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection. [64] [79] [80]

Availability

Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, India, Brazil, South Africa, Australia, and New Zealand. [79]

Between 1998 and 2017, along with amitriptyline, imipramine was the most commonly prescribed first antidepressant for children aged 5-11 years in England. [81]

See also

Related Research Articles

<span class="mw-page-title-main">Antidepressant</span> Class of medication used to treat depression and other conditions

Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. 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.

<span class="mw-page-title-main">Sertraline</span> Antidepressant (SSRI class) medication

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The effectiveness of sertraline for depression is similar to that of other antidepressants such as Fluoxetine or Paroxetine. Sertraline is better tolerated than the older tricyclic antidepressants. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder, and obsessive–compulsive disorder (OCD). Although approved for post-traumatic stress disorder (PTSD), findings have shown sertraline leads to only modest improvements in symptoms. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.

<span class="mw-page-title-main">Maprotiline</span> Antidepressant

Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to such-other secondary-amine TCAs as nortriptyline and protriptyline and has similar effects to them, albeit with more distinct anxiolytic effects. Additionally, whereas protriptyline tends to be somewhat more stimulating and in any case is distinctly more-or-less non-sedating, mild degrees of sedation may be experienced with maprotiline.

<span class="mw-page-title-main">Amitriptyline</span> Tricyclic antidepressant

Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headaches. Due to the frequency and prominence of side effects, amitriptyline is generally considered a second-line therapy for these indications.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), and obsessive–compulsive disorder (OCD). SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

<span class="mw-page-title-main">Desipramine</span> Antidepressant

Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.

<span class="mw-page-title-main">Clomipramine</span> Antidepressant

Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyperacusis, panic disorder, major depressive disorder, trichotillomania, body dysmorphic disorder and chronic pain. It has also been notably used to treat premature ejaculation and the cataplexy associated with narcolepsy.

<span class="mw-page-title-main">Nortriptyline</span> Antidepressant medication

Nortriptyline, sold under the brand name Aventyl, among others, is a tricyclic antidepressant. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. Its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18–24 population initiating treatment. Nortriptyline is not a preferred treatment for attention deficit hyperactivity disorder or smoking cessation. It is taken by mouth.

<span class="mw-page-title-main">Trimipramine</span> Antidepressant

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs, however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

<span class="mw-page-title-main">Milnacipran</span> Antidepressant

Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.

<span class="mw-page-title-main">Dosulepin</span> Antidepressant

Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression. Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom, but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs. It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects.

<span class="mw-page-title-main">Dibenzepin</span> Chemical compound

Dibenzepin, sold under the brand name Noveril among others, is a tricyclic antidepressant (TCA) used widely throughout Europe for the treatment of depression. It has similar efficacy and effects relative to other TCAs like imipramine but with fewer side effects.

<span class="mw-page-title-main">Butriptyline</span> Atypical tricyclic antidepressant medication

Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an "atypical" or "second-generation" TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.

<span class="mw-page-title-main">Lofepramine</span> Chemical compound

Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression. The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.

<span class="mw-page-title-main">Iprindole</span> Atypical tricyclic antidepressant

Iprindole, sold under the brand names Prondol, Galatur, and Tertran, is an atypical tricyclic antidepressant (TCA) that has been used in the United Kingdom and Ireland for the treatment of depression but appears to no longer be marketed. It was developed by Wyeth and was marketed in 1967. The drug has been described by some as the first "second-generation" antidepressant to be introduced. However, it was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.

<span class="mw-page-title-main">Metapramine</span> Chemical compound

Metapramine is a tricyclic antidepressant (TCA) developed by Rhone Poulenc that was introduced for the treatment of depression in France in 1984. In addition to its efficacy against affective disorders, it also has analgesic properties, and may be useful in the treatment of pain.

<span class="mw-page-title-main">Amitriptylinoxide</span> Chemical compound

Amitriptylinoxide, or amitriptyline N-oxide, is a tricyclic antidepressant (TCA) which was introduced in Europe in the 1970s for the treatment of depression.

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