Imipramine (sold as
Antideprin,
Deprimin,
Deprinol,
Depsonil,
Dynaprin,
Eupramin,
Imipramil,
Irmin,
Janimine,
Melipramin,
Surplix,
Tofranil) is an
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants , tetracyclic antidepressants , selective serotonin reuptake inhibitors , and serotonin-norepinephrine...
medicationA pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
, a
tricyclic antidepressantTricyclic antidepressants are a class of psychoactive drugs used primarily as antidepressants, which were first discovered in the early 1950s, and subsequently introduced later in the decade...
of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and
enuresisEnuresis refers to an inability to control urination. Use of the term is usually limited to describing individuals old enough to be expected to exercise such control.Types include:* Nocturnal enuresis* Diurnal enuresis...
.
It has also been evaluated for use in
panic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
.
History
Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed (by Ciba-Geigy). It was first tried against psychotic disorders, such as schizophrenia, but proved insufficient. During the clinical studies, its antidepressant qualities were unsurpassed by other antidepressants. To this day, Imipramine is often considered the "gold standard" antidepressant, as its ability to lift the most severe depressive episodes is unsurpassed. It is not surprising, therefore, that Imipramine is also known to cause a high rate of manic and hypomanic reactions, especially in patients with preexisting bipolar disease. It is estimated that up to 25% of such patients maintained on Imipramine will switch into mania or hypomania. Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.
At the advent of SSRIs, its sometimes intolerable side-effect profile became less tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released tricyclics. It is not as commonly used today, but is sometimes used to treat major depression as a second-line treatment. It has also seen limited use in the treatment of
migraineMigraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men. The word migraine was borrowed from Old French migraigne...
s,
ADDAttention-deficit hyperactivity disorder is a neurobehavioral developmental disorder. ADHD is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone." While symptoms may appear to be innocent and merely annoying...
, and post concussive syndrome. Imipramine has additional indications for the treatment of panic attacks,
chronic painChronic pain is defined as pain that persists longer than the temporal course of natural healing, associated with a particular type of injury or disease process....
, and
Kleine-Levin syndromeKleine-Levin Syndrome, or KLS, is a rare neurological disorder characterized by recurring periods of excessive amounts of sleep and altered behavior. At the onset of an episode the patient becomes drowsy and sleeps for most of the day and night , waking only to eat or go to the bathroom...
. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.
Mechanisms Of Action
Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety , ADD/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 medicinal action include, but are not limited to, effects on:
norepinephrineNoradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
,
serotoninSerotonin is a monoamine neurotransmitter. It is found extensively in the gastrointestinal tract of animals, and about 80 to 90 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements...
,
dopamineDopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
,
epinephrineEpinephrine is a hormone and neurotransmitter that participates in the "fight or flight" response of the sympathetic nervous system...
,
sigma receptorThe sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, Ditolylguanidine, Dimethyltryptamine and siramesine.-Classification:...
, enkephalinase,
histamineHistamine is a biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by...
,
muscarineMuscarine, L--muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. It was first isolated from Amanita muscaria in 1869...
, and
acetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division...
. Imipramine has been shown to interact with opioid systems in the central nervous system, possibly explaining some of its pain-relieving properties. It is also becoming apparent that at least some of Imipramine's effects are epigenetic and related to its promotion of histone acetylation of the BDNF promotor in the hippocampus and also downregulation of
histone deacetylaseHistone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferase.-Subtypes:...
(HDAC5).
Effects on:
Norepinephrine (NE)
Reuptake inhibition (strong).
Serotonin (SE)
Reuptake inhibition (moderate to strong). The reuptake inhibition is almost comparable but still less than Imipramine's potency of reuptake inhibition on norepinephrine. Stronger SERT inhibition than most other tricyclic antidepressants with the exception of Clomipramine, making it more akin to the SSRI class of antidepressants (e.g., Prozac (fluoxetine), Zoloft (sertraline)) than its metabolite desipramine, which has almost purely noradrenergic effects.
Acetylcholine (ACh)
Imipramine is an
anticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicyclomine....
. Thus, it is prescribed with caution to the elderly and with extreme caution to those with pyschosis, 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. Imipramine is an antagonist at M2 muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause
euphoriaEuphoria is medically recognized as a mental/emotional state defined as a sense of great elation and wellbeing. Technically, euphoria is an affect, but the term is often colloquially used to define emotion as an intense state of transcendent happiness combined with an overwhelming sense of wellbeing...
, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).
Epinephrine
Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).
Dopamine
Reuptake and release at D1 and D2 receptors, similar to, but less potent than, psychostimulants, dopamine agonists, and atypical antidepressant buproprion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SE and ACe, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine.
Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice.
Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it is 1/20 the potency of amitryptiline and
paroxetineParoxetine is a selective serotonin reuptake inhibitor antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, see references).
Sigma receptor and Enkephalinase
Activity on sigma receptors (sigma ligands) is present, but it is very low (Ki of 520 nM on sigma receptors, see references) and it is about half the power of amitryptiline (300 nM).
Histamine
Imipramine is an antagonist at histamine H1 receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imiparmine is sometimes prescribed as a sleep aid in low doses.
BDNF
Brain derived neurotrophic factor (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 promotor, and also reduced expression of hippocampal histone deacetylase (hdac5).
Comparison with other antidepressants
The potency (affinity) of imipramine and other antidepressant on various transporters and receptors are summarized below. Data are from "Pharmacology of antidepressant", Mayo Clin Proc, May 2001, Vol 76.
Potency (affinity) data are expressed as the inverse of equilibrium dissocation constant multiplied by a factor of 10^-7. So, the higher the number, the higher the blocking power.
| Drug |
NE Transporter |
SE Transporter |
DE transporter |
alpha1 blockade |
D2 blockade |
H1 blockade |
muscarinic blockade |
5HT2 blockade |
| imipramine |
2.7 |
70 |
0.012 |
1.5 |
0.05 |
9.1 |
1.1 |
1.2 |
| desipramine (also an imipramine metabolite) |
128 |
5.7 |
0.024 |
0.77 |
0.03 |
0.91 |
0.5 |
0.38 |
| amitriptyline |
2.9 |
23 |
0.023 |
3.7 |
0.1 |
91 |
5.6 |
3.4 |
| clomipramine |
2.7 |
360 |
0.045 |
2.6 |
0.53 |
3.2 |
2.7 |
3.7 |
| paroxetine |
2.5 |
800 |
0.2 |
0.025 |
0.003 |
0.03 |
0.93 |
0.005 |
| citalopram |
0.035 |
98 |
0.0038 |
0.053 |
0 |
0.21 |
0.045 |
0.34 |
Metabolism
Imipramine is converted to
desipramineDesipramine is a tricyclic antidepressant that inhibits the reuptake of norepinephrine. It is sold under the brand names Norpramin and Pertofrane. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
, another
TCATricyclic antidepressants are a class of psychoactive drugs used primarily as antidepressants, which were first discovered in the early 1950s, and subsequently introduced later in the decade...
, in the body.
Contraindications and precautions
(See Tricyclic antidepressants)
Side-effects
After taking the medicine this drug may cause some side-effects in some patients, particularly with the first few doses.
Allergy: isolated cases of
pneumonitisPneumonitis is a general term that refers to inflammation of lung tissue.Pneumonia is pneumonitis combined with consolidation and exudation....
(fever, chills, cough, difficulty with breathing, unusual weight loss, feeling sick, puffy, swollen face, tongue or body) have been reported. These reactions may be severe, causing shortness of breath, swelling, shock and collapse.
Isolated changes in blood cells.
Arrhythmias: irregular heart rhythms.
Weight gain has been reported frequently. Disturbances in sexual function have been reported occasionally. Isolated cases of enlarged mammary glands, production or over-production of breast milk, increased or decreased blood sugar levels and weight loss have been reported. Low levels of salt in the blood have been reported, usually in elderly patients.
Tremor has been reported frequently. Headache, confusion, orthostatic hypotension (resulting in dizziness upon standing), numbness/tingling, agitation, anxiety, restlessness, mood swings, exaggerated behaviour, delusions and hallucinations have been reported occasionally and are more common in the elderly or in patients on high doses. Aggressiveness, weakness, lack of co-ordination, sudden muscle spasms, difficulty speaking have been reported in isolated cases.
Imipramine also enhances the CNS effects of both stimulants and alcohol, and blocks the parasympathomimetic effects of stimulants while enhancing the cortical excitation. This can be dangerous in some cases and result in seizures and coma.
Ringing or buzzing in the ears.
Feeling or being sick and loss of appetite have been reported occasionally. Isolated cases of tongue lesions and inflammation of the mucus membranes in the mouth have been reported. Extreme dry mouth or "cotton mouth" has been reported. Mild to severe constipation has also been reported.
Changes in liver function have been reported occasionally.
HepatitisHepatitis implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
and
jaundiceJaundice, also known as icterus , is a yellowish discoloration of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia...
(yellowing of the skin and/or whites of the eyes) have been reported in isolated cases.
Allergic reactions such as an itchy skin rash have been reported occasionally. Isolated cases of swelling, sensitivity to the sun or sun lamps, hair loss, small purple red spots and itching have been reported.
If the medicine is stopped too quickly, there is the possibility the user may suffer from feeling or being sick, stomach pains, diarrhea, headache, sleeplessness, nervousness, anxiety, irritability and increased sweating.
Dosage
- Hospitalized patients: starting with 3 times 25 mg, increasing to 125 mg. Up to 300 mg may be given in resistant cases. After remission dose is often reduced to 50 to 100 mg daily.
- Ambulatory patients: starting with 25 to 75 mg daily, increasing up to a maximum of 200 mg daily, after remission dose is often reduced to 50–100 mg daily.
- Pediatric patients: starting with 10 mg daily the dose is adjusted according to the severity of the symptoms to be treated, the side-effects encountered and the weight of the patient.
Overdose
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants. Cardinal symptoms are cardiac (tachycardia, widened QRS complex) and neurological disturbances. Any ingestion by children should be considered as serious and potentially fatal.
External links