Imipramine toxicity

A 51-year-old patient developed imipramine toxicity and increased plasma concentrations associated with the introduction of terbinafine, possibly due to inhibition of CYP2D6 (212). 

There is evidence that oestrogens can sometimes reduce the effects of imipramine, yet at the same time paradoxically cause imipramine toxicity. The general clinical importance of this interaction has yet to be evaluated. 

Treatment with imipramine, the most studied TCA, leaves 45% to 70% of patients panic free. Both desipramine and clomipramine have demonstrated effectiveness in PD as well. Despite their efficacy, TCAs are considered second- or third-line pharmacotherapy due to poorer tolerability and toxicity on overdose.48,49 TCAs are associated with a greater rate of discontinuation from treatment than SSRIs.53 PD patients taking TCAs may experience anticholinergic effects, orthostatic hypotension, sweating, sleep disturbances, dizziness, fatigue, sexual dysfunction, and weight gain. Stimulant-like side effects occur in up to 40% of patients.49... 

Rao et al.20 demonstrated a fluorescence polarization immunoassay for evaluating serum concentrations of tricyclic antidepressants (amitriptyline, imipramine, clomipramine, and doxepin) with respect to nonresponse, compliance, therapeutic window, and influences of age, sex, substance abuse, and toxicity. Abbott Laboratories TDx/TDxFLx Toxicology Tricyclic Assay FPIA (fluorescence polarization immunoassay) was used. This assay of 50 /uL samples contained tricyclic antidepressant antibodies raised in rabbits and fluorescein-labeled tricyclic antidepressant as a tracer. The assay was calibrated with imipramine in the range of 75 to 1000 fig/L (268 to 3571 nmol/L). Intra-assay and inter-assay coefficients of variation for internal quality control samples from the manufacturer were 4.2 and 4.7%, respectively. The limits of detection were 72,71,64, and 72 nmol/L for amitriptyline, imipramine, clomipramine, and doxepin, respectively. This high-throughput immunoassay was easy to use although amitriptyline, dosulepine, desipramine, and nortriptyline showed cross-reactivities ranging from 74 to 100%. 

Additional ADRs linked to diet pills include psychosis myocardial ischemia drug interactions, such as the interaction of fenfluramine with imipramine, fenfluramine with amitriptyline or desipramine, or the toxic reaction between fluoxetine and phentermine and the release of serotonin while inhibiting its reuptake, contributing to hyperserotonin reactions. When the next craze takes hold of patients and their physicians, hopefully physicians and pharmacists will take a more vocal position and recommend restraint, xmtil some proof of efficacy and lack of toxicity is shown for new faddish off-label combinations. 

Of greater concern is the safety of the TCAs. Toxic levels of these medications can produce lethal cardiac arrhythmias, seizures, and suppression of breathing. An overdose of a 1-2 week supply of most TCAs is often fatal, a serious consideration when prescribing medication to depressed patients with suicidal thoughts. Children taking imipramine for treatment of ADHD have died from sudden cardiac death consequently, child psychiatrists seldom use TCAs. Likewise, patients with heart disease or seizure disorders are more likely to have dangerous complications from TCAs and should avoid them. 

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

Tramadol is an opioid analgesic and when given to patients who are also receiving imipramine (a tricyclic antidepressant), there is an increased risk of central nervous system toxicity. The risk of occurrence of sedation is increased. 

All were double-blind controlled evaluations and established iprindole as at least as effective as imipramine, and one study [195] included an examination of the doctor-patient interaction as a factor in such work (a similar discussion was felt necessary, as noted above [179] in the evaluation of oxpertine). In only two [192, 194] of the above reports is it possible to estimate the frequency and severity of anticholinergic side effects, thou in the one case [192] the care taken in the experimental design and the number of patients observed leaves little doubt that the dry mouth, constipation, etc. characteristic of imipramine therapy is either greatly reduced or even absent during iprindole treatment. This point is confirmed in an extension of this team s work to include a 12 month toxicity study [197] which, in addition, failed to produce evidence of haemopoitic, hepatic, cardiac, ocular or renal damage. Similar results followed other work. 

Our understanding of the mechanism of antidepressant action has evolved over time. In the late 1950s, the first molecules introduced for the treatment of MDD were the so-called tricyclic antidepressants (TCAs), represented by imipramine (7). Subsequent experience with TCAs supported the role of both 5-HT and NE, although these drug molecules act on other neuronal systems as well. Despite their elfectiveness, the use of TCAs was limited due to poor tolerability and safety concerns, in particular, severe toxicity when taken in overdose. 

In the late 1950s, imipramine was noted to be effective for the symptomatic treatment of depression. A number of chemical congeners of imipramine have been synthesized and tested for antidepressant properties they are collectively known as TCAs. The TCAs are no longer considered first-line agents in the treatment of depression because of their prominent side effects and the need to monitor drug blood levels to avoid toxicity. 

Though not used clinically, the therapeutic serum level for imipramine is 225 to 300 ng/ml the toxic serum level is greater than 500 ng/ml... 

Chuang DM, Gao X-M, Paul SM N-methyl-D-aspartate exposure blocks glutamate toxicity in cultured cerebellar granule cells. Mol Pharmacol 42 210-216, 1992 Chugh Y, Saha N, Sankaranarayanan A, et al Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of S-HTj antagonist ICS 205-930. Pharmacol Toxicol 69 105-106, 1991 Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146, 1981 Ciraulo DA, Barnhill JG, Jaffe JH Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers. Pharmacol Ther 43 539-548, 1988... 

D PP, Tam YK, Young LT, et al Dthium decreases Gs, Gi-1 and Gi-2 alpha-subunit mRNA levels in rat cortex. Eur J Pharmacol 206 165-166, 1991 Debhch I, Yirmiya R Naltrexone reverses a long term depressive effect of a toxic lithium injection on saccharin preference. Physiol Behav 39 547-550, 1987 DebowitzMR Social phobia. Mod Probl Pharmacopsychiatry 22 141-173, 1987 Debowitz MR, Quitkin EM, Stewart JW, et al Phenelzine vs. imipramine in atypical depression a preliminary report. Arch Gen Psychiatry 41 669-677, 1984 liebowitz MR, Quitkin EM, Stewart JW, et al Antidepressant specificity in atypical depression. Arch Gen Psychiatry 45 129-137, 1988 Liebowitz MR, Schneier F, Campeas R, et al Phenelzine vs atenolol in social phobia. Arch Gen Psychiatry 49 290-300, 1992... 

Paul lA, Layer RT, Skolnick P, et al Adaptation of the N-methyl-D-aspartate receptor complex in rat front cortex following chronic treatment with electroconvulsive shock or imipramine. Eur J Pharmacol 247 305-312, 1993 Paul SM, Purdy RH Neuroactive steroids. FASEB J 6 2311-2322, 1992 Paul V, Balasubramaniam E, Kazi M The neurobehavioural toxicity of endosulfan in rats a serotonergic involvement in learning impairment. Eur J Pharmacol 270 1-7, 1994... 

Another important situation occurs when the parent drug is biotransformed into a less efficacious and possibly more toxic metabolite. For example, if the concentration of the hydroxylated metabolite of imipramine (2-hydroxyimipramine) were increased, this TCA could lose its effectiveness while simultaneously increasing in toxicity (38). 

This agent did not show a curvilinear relationship between concentration and antidepressant response in adult patients, with a threshold relationship best fitting the data. Based on the Perry et. al. analysis of the adult studies (326), the upper end for optimal antidepressant response to imipramine was close to the threshold for CNS and cardiac toxicity. 

Thus, the upper limit to the therapeutic range is a function of toxicity rather than reduced efficacy in contrast to the other TCAs. Perry et al. ( 326) proposed a minimal threshold for this tertiary amine TCA of 265 ng/mL (imipramine plus desimipramine) with a remission rate of 42% above this threshold versus 15% below it. Of note, this threshold for optimal antidepressant response is closer to the threshold for CNS and cardiac toxicity than for any other TCA. Preskorn and colleagues ( 327) found a lower optimal threshold for imipramine plus desimipramine (125 ng/mL) when it was used to treat clinical depression in children and adolescents than when used in adults. 

CBZ s molecular structure is similar to imipramine. It is primarily metabolized by the liver and, like lithium, has a narrow therapeutic index, predisposing to toxicity with elevated serum levels. 

All SSRIs have an antipanic effect. Their advantages are limited adverse effects and lack of toxicity. Because of more acceptable adverse effect profiles, the SSRIs are usually the drugs of choice. Several studies consistently indicate that SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, as well as agents such as clomipramine and trazodone, all possess antipanic efficacy, although the last may be less effective than imipramine ( 24, 105, 106, 107, 108 and 109). 

Imipramine, a tricyclic antidepressant drug with strong antimuscarinic actions, has long been used to reduce incontinence in institutionalized elderly patients. It is moderately effective but causes significant CNS toxicity. Propiverine, a newer antimuscarinic agent, has been approved for this purpose. 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

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