Imipramine Explained

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 the other TCAs (besides amitriptyline, which, at least in the U.K., remains at least just as commonly-prescribed as SSRIs) have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which, although generally significantly less potent in terms of clinical efficacy per-se, have fewer inherent side effects and are far safer in overdose. Irrespective of these caveats, however, imipramine has an invaluable place in psychiatry and other fields of medicine (e.g., with childhood enuresis), and is considered the "gold standard" for panic disorder.[1] [2]

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.[3] [4] [5] Although evidence for its efficacy in the treatment of chronic post-traumatic stress disorder appears to be less robust,[6] it remains a viable treatment.[7] 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, panic attacks, acute trauma or, in the case of desipramine,[8] [9] ADHD), owing to possibility of certain side-effects which may be of particular concern in those under a certain age.[10] [11]

In the treatment of depression, it has demonstrated similar efficacy to the MAOI moclobemide.[12] 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.[13]

Contraindications

Combining it with alcohol consumption may cause more drowsiness, necessitating greater caution when drinking.[14] 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.[15]

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.[16]

Overdose

See main article: Tricyclic antidepressant 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

See also: Pharmacology of antidepressants.

Imipramine (and metabolite)[17] [18]
Site Species Ref
1.3–1.4 17.6–163 Human [19] [20]
20–37 0.63–3.5 Human
8,500 3,190 Human
≥5,800 ≥6,400 Human [21]
80–150 115–350 Human
120 244–748 Human/rat [22] [23] [24]
970–3,651 ≥2,500 Rodent [25]
190–209 Rat [26]
>1,000 >1,000 Rat [27]
32 23–130 Human
3,100 ≥1,379 Human
>10,000 ≥1,700 Rat [28] [29] [30]
>10,000 5,460 Human [31]
620–726 3,400 Human
387 Human
7.6–37 60–110 Human [32] [33] [34]
550 1,550 Human
>100,000 >100,000 Human
24,000 9,550 Human
46 66–198 Human
42 110 Human [35]
88 540 Human
60 210 Human
112 160 Human
83 143 Human
410–970 Human [36]
332–520 1,990–4,000 Rodent [37] [38] [39]
327–2,100 ≥1,611 Rat
3,400 Human [40]
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.[47] [48] [49]

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.[52]

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.[53] Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).[54] Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.[55] [56] Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine.[57] [58] 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.[59] [60] [61] Imipramine was first synthesized in 1951, as an antihistamine.[62] [63] The antipsychotic effects of chlorpromazine were discovered in 1952,[64] and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia.[33] [65] The medication was tested in several hundred patients with psychosis, but showed little effectiveness.[66] 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] [67] This was followed by similar observations in other patients and further clinical research.[68] Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959.[69] 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.

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.[70] 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.[71] 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,, and, while imipramine hydrochloride is its,,, and .[72] [73] [74] [75] Its generic name in Spanish and Italian and its are imipramina, in German is imipramin, and in Latin is imipraminum. The embonate salt is known as imipramine pamoate.

Brand names

Imipramine is marketed throughout the world mainly under the brand name Tofranil. Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.[76]

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.

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.[77]

See also

Further reading

Notes and References

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