Imipramine

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.

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 SSRIs) have decreased in prescription frequency with the rise of SSRIs—which have fewer inherent side effects and are far safer in overdose.Template:Cn Regardless of its caveats, imipramine retains importance in psychopharmacology and pediatrics (e.g., with childhood enuresis).<ref name="pmid2002125">Template:Cite journal</ref><ref name="pmid15638761">Template:Cite journal</ref>

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.<ref name="pmid10405506">Template:Cite journal</ref><ref name="pmid16276335">Template:Cite journal</ref><ref name="pmid18675519">Template:Cite journal</ref> Although evidence for its efficacy in the treatment of chronic post-traumatic stress disorder appears to be less robust,<ref name="pmid8878310">Template:Cite journal</ref> it remains a viable treatment.<ref name="pmid31819037">Template:Cite journal</ref> 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,<ref name="pmid32982805">Template:Cite journal</ref><ref name="pmid23914752">Template:Cite journal</ref> ADHD), owing to possibility of certain side-effects which may be of particular concern in those under a certain age.<ref name="pmid15707813">Template:Cite journal</ref><ref name="pmid7079058">Template:Cite journal</ref>

In the treatment of depression, it has demonstrated similar efficacy to the MAOI moclobemide.<ref name="pmid8557884">Template:Cite journal</ref> 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.<ref name="Orsulak Review TDM">Template:Cite journal</ref>

Contraindications

Combining it with alcohol consumption may cause more drowsiness, necessitating greater caution when drinking.<ref name='medline'>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It may be unsafe during pregnancy.<ref name="Drugs.com pregnancy" />

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.<ref name='medline' /><ref name='webmd'>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>Template:Cite book</ref> Some side effects may be beneficial in some cases, e.g. reduction of hyperactive gag reflex; reduced random or physical strain-linked urinary leakage.

• Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia
• Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias
• Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis
• Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change
• Genitourinary: urinary retention
• Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia
• Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity

Overdose

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Interactions

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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.<ref name='medline' />

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.<ref name='webmd' />

Alcohol and tobacco may interact with imipramine. Tobacco may decrease the medication's effectiveness.<ref name='medline' />

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref><ref name="PDSP DSI">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>
Site	Template:Abbr	Template:Abbrlink	Species	Ref
Template:Abbrlink	1.3–1.4	17.6–163	Human	<ref name="pmid9537821">Template:Cite journal</ref><ref name="pmid9400006">Template:Cite journal</ref>
Template:Abbrlink	20–37	0.63–3.5	Human	<ref name="pmid9537821" /><ref name="pmid9400006" />
Template:Abbrlink	8,500	3,190	Human	<ref name="pmid9537821" />
5-HT1A	≥5,800	≥6,400	Human	<ref name="pmid7855217" /><ref name="pmid9686407" /><ref name="pmid3816971">Template:Cite journal</ref>
5-HT2A	80–150	115–350	Human	<ref name="pmid7855217" /><ref name="pmid3816971" />
5-HT2C	120	244–748	Human/rat	<ref name="pmid16712488">Template:Cite journal</ref><ref name="pmid8876023">Template:Cite journal</ref><ref name="pmid9686407">Template:Cite journal</ref>
5-HT3	970–3,651	≥2,500	Rodent	<ref name="pmid9686407" /><ref name="pmid2533080">Template:Cite journal</ref>
5-HT6	190–209	Template:Abbr	Rat	<ref name="pmid7680751">Template:Cite journal</ref>
5-HT7	>1,000	>1,000	Rat	<ref name="pmid8394362">Template:Cite journal</ref>
α1	32	23–130	Human	<ref name="pmid7855217" /><ref name="pmid6086881" /><ref name="pmid9400006" />
α2	3,100	≥1,379	Human	<ref name="pmid7855217" /><ref name="pmid6086881" /><ref name="pmid9400006" />
β	>10,000	≥1,700	Rat	<ref name="pmid2530094">Template:Cite journal</ref><ref name="pmid3790168">Template:Cite journal</ref><ref name="pmid10379421">Template:Cite journal</ref>
D1	>10,000	5,460	Human	<ref name="pmid9686407"/><ref name="pmid17850785">Template:Cite journal</ref>
D2	620–726	3,400	Human	<ref name="pmid17850785" /><ref name="pmid9686407" /><ref name="pmid6086881" />
D3	387	Template:Abbr	Human	<ref name="pmid9686407" />
H1	7.6–37	60–110	Human	<ref name="pmid7855217">Template:Cite journal</ref><ref name="pmid6086881">Template:Cite journal</ref><ref name="pmid22033803">Template:Cite journal</ref>
H2	550	1,550	Human	<ref name="pmid22033803" />
H3	>100,000	>100,000	Human	<ref name="pmid22033803" />
H4	24,000	9,550	Human	<ref name="pmid22033803" />
Template:Abbrlink	46	66–198	Human	<ref name="pmid7855217" /><ref name="pmid6086881" />
M1	42	110	Human	<ref name="pmid8100134">Template:Cite journal</ref>
M2	88	540	Human	<ref name="pmid8100134" />
M3	60	210	Human	<ref name="pmid8100134" />
M4	112	160	Human	<ref name="pmid8100134" />
M5	83	143	Human	<ref name="pmid8100134" />
α3β4	410–970	Template:Abbr	Human	<ref name="pmid20117161">Template:Cite journal</ref>
σ1	332–520	1,990–4,000	Rodent	<ref name="pmid2877462">Template:Cite journal</ref><ref name="pmid20373470">Template:Cite journal</ref><ref name="pmid21911285">Template:Cite journal</ref>
σ2	327–2,100	≥1,611	Rat	<ref name="PDSP" /><ref name="pmid20373470" /><ref name="pmid21911285" />
Template:Abbrlink	3,400	Template:Abbr	Human	<ref name="pmid10510461">Template:Cite journal</ref>
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:

• Serotonin: very strong reuptake inhibition. Imipramine is a tertiary TCA, and is a potent inhibitor of serotonin reuptake, and to a greater extent than secondary amine TCAs such as nortriptyline and despiramine.<ref>Imipramine hydrochloride | DrugBank Online</ref>
• Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine.
• Dopamine: imipramine blocks D₂ receptors.<ref>Template:Cite journal</ref> Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (K_i = 8,500 and >10,000 nM, respectively).<ref>Template:Cite journal</ref>
• Acetylcholine: imipramine is, to a certain extent, an antimuscarinic, specifically a relative antagonist of the muscarinic acetylcholine receptors. The attendant side-effects (e.g., blurry vision, dry mouth, constipation), however, are somewhat less common with imipramine than amitriptyline and protriptyline, which tend to cause antimuscarinic side-effects more often. All-in-all, however, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population. "Anti-cholinergic" side-effects, including urinary hesitancy/retention, may be treated/reversed with bethanechol and/or other acetylcholine-agonists.<ref name="pmid2901489">Template:Cite journal</ref><ref name="pmid1166898">Template:Cite journal</ref><ref name="pmid8101048">Template:Cite journal</ref>

Bethanechol may also be able to alleviate the sexual-dysfunction symptoms which may occur in the context of tricyclic-antidepressant treatment.<ref name="pmid3957884">Template:Cite journal</ref><ref name="pmid3631333">Template:Cite journal</ref><ref name="pmid15654489">Template:Cite journal</ref>

• Epinephrine: imipramine antagonizes adrenergic receptors, thus sometimes causing orthostatic hypotension.
• Sigma receptor: activity on sigma receptors is present, but it is very weak (K_i = 520 nM) and it is about half that of amitriptyline (K_i = 300 nM).Template:Citation needed
• Histamine: imipramine is an antagonist of the histamine H₁ receptors.
• BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pharmacokinetics

Template:Expand section 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.<ref name=":0">Template:Cite journal</ref>

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.<ref name=":0" />

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.<ref name="Ritsner2013">Template:Cite book</ref> Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).<ref name="Ritsner2013" /><ref name="LemkeWilliams2008">Template:Cite book</ref> Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.<ref name="CutlerSramek1994">Template:Cite book</ref><ref name="AnzenbacherZanger2012">Template:Cite book</ref> Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine.<ref name="Anthony2002">Template:Cite book</ref><ref name="CowenHarrison2012">Template:Cite book</ref> 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.<ref name="Elks2014" /> 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.<ref name="Elks2014" /><ref name="IndexNominum2000" /> 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.<ref name="Elks2014" /><ref name="IndexNominum2000" />

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.<ref name="pmid2882911">Template:Cite journal</ref><ref name="pmid11383974">Template:Cite journal</ref><ref name="JørgensenAndersen1999">Template:Cite journal</ref> Imipramine was first synthesized in 1951, as an antihistamine.<ref name=Wal2012>Template:Cite book</ref><ref name="WatanabeWada1991">Template:Cite book</ref> The antipsychotic effects of chlorpromazine were discovered in 1952,<ref name="Bennett2014">Template:Cite book</ref> and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia.<ref name="pmid6086881"/><ref name="MitchellTriggle2009">Template:Cite book</ref> The medication was tested in several hundred patients with psychosis, but showed little effectiveness.<ref name="Kim2018">Template:Cite book</ref> 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.<ref name="pmid6086881"/><ref name="MitchellTriggle2009" /><ref name="pmid29803629">Template:Cite journal</ref> This was followed by similar observations in other patients and further clinical research.<ref name="SteinWilkinson2007">Template:Cite book</ref><ref name="Kim2018" /> Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959.<ref name="Lowry2012">Template:Cite book</ref> 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.<ref name="pmid29803629" /><ref name="SteinWilkinson2007" /><ref name="Kim2018" />

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.<ref>Template:Cite book</ref> 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.<ref name="urlSpringerLink – Journal Article">Template:Cite journal</ref> 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 Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink, while imipramine hydrochloride is its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink.<ref name="Elks2014">Template:Cite book</ref><ref name="IndexNominum2000">Template:Cite book</ref><ref name="MortonHall2012">Template:Cite book</ref><ref name="Drugs.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Its generic name in Spanish and Italian and its Template:Abbrlink are imipramina, in German is imipramin, and in Latin is imipraminum.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> The embonate salt is known as imipramine pamoate.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

Brand names

Imipramine is marketed throughout the world mainly under the brand name Tofranil.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="Pies2007">Template:Cite book</ref>

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.<ref name="Drugs.com" />

Prescription trends

Between 1998 and 2017, along with amitriptyline, imipramine was the most commonly prescribed first antidepressant for children aged 5-11 years in England.<ref>Template:Cite journal</ref>

See also

• List of antidepressants

Further reading

• Template:Cite book