At the advent of SSRIs, its sometimes intolerable side effect profile became evident. Subsequently, it was 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 migraines, ADD 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.
Imipramine, a tertiary amine, affects numerous neurotransmitter systems know 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 all include, but are not limited to effects on; norepinephrine, serotonin, dopamine, epinephrine, opiates, enkephalinase, histamine, muscarine, and acetylcholine.
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, 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 anticholinergic. 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 anti-cholinergices 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 euphoria, 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 the psychostimulants, dopamine agonists and atypical antidepressant buproprion on dopaminergic mechanisms. (increase in release and blockade of reutpake inhibition). While this effect is much less than the primary effects on NE, SE and ACe, it is none-the-less 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. In regards of dopamine uptake, imipramine is far less potent then most of other antidepressant (for example is 1/20 in potency of amitryptiline and paroxetine, see references)
Opiates and Enkephalinase Activity on opiate (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.
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 ere 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|
|desipramine (also an imipramine metabilite)||128||5.7||0.024||0.77||0.03||0.91||0.5||0.38|
Imipramine should not be given in conjunction with, or within 14 days of treatment with a MAO inhibitor. Combined therapy of this type could lead to the appearance of serious interactions such as hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions or coma and death may occur.
Imipramine is contraindicated in patients with existing severe hepatic or renal damage, and those with a history of blood dyscrasias.
Imipramine is contraindicated in patients who have shown hypersensitivity to the drug or hypersensitivity to tricyclic antidepressants belonging to the dibenzazepine group.
Imipramine is contraindicated for use during the acute recovery phase following a myocardial infarction.
It should not be used in patients with convulsive disorders or glaucoma.
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.