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 generally have more tolerable side effect and are far safer in overdose.Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry. 1998;59 Suppl 15:42-8. PMID: 9786310. Regardless of such caveats, imipramine retains importance in psychopharmacology and pediatrics (e.g., with childhood enuresis).
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. Although evidence for its efficacy in the treatment of chronic post-traumatic stress disorder appears to be less robust, it remains a viable treatment. Here, it may share a similar efficacy with the 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, ADHD), owing to possibility of accidental overdose, which may be of particular concern in children.
In the treatment of depression, it has demonstrated similar efficacy to the MAOI moclobemide. 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.
Contraindications Combining it with alcohol consumption may cause more drowsiness, necessitating greater caution when drinking. It may be unsafe during 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.
Side effects These side effects can be attributed 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. 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
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.
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.
Alcohol and tobacco may interact with imipramine. Tobacco may decrease the medication's effectiveness.
Pharmacology
Pharmacodynamics
+ Imipramine (and metabolite) Site Species Ref 1.3–1.4 17.6–163 Human 20–37 0.63–3.5 Human 8500 3190 Human 5-HT1A 5800+ 6400+ Human 5-HT2A 80–150 115–350 Human 5-HT2C 120 244–748 Human/rat 5-HT3 970–3651 2500+ Rodent 5-HT6 190–209 Rat 5-HT7 1000+ 1000+ Rat α1 32 23–130 Human α2 3100 1379+ Human β 10000+ 1700+ Rat D1 10000+ 5460 Human D2 620–726 3400 Human D3 387 Human H1 7.6–37 60–110 Human H2 550 1550 Human H3 100000+ 100000+ Human H4 24000 9550 Human 46 66–198 Human M1 42 110 Human M2 88 540 Human M3 60 210 Human M4 112 160 Human M5 83 143 Human α3β4 410–970 Human σ1 332–520 1990–4000 Rodent σ2 327–2100 1611 Rat 3400 Human 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.Imipramine hydrochloride | DrugBank Online Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine. Dopamine: imipramine blocks D2 receptors. Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively). 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. Bethanechol may also be able to alleviate the sexual-dysfunction symptoms which may occur in the context of tricyclic-antidepressant treatment. Epinephrine: imipramine antagonizes adrenergic receptors, thus sometimes causing orthostatic hypotension. Sigma receptor: activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM). 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.
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.
Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.
Chemistry Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. 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. 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. 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.
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. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. 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. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. 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.