Phenothiazines Imipramine

Imipramine and its derivatives produce blue, phenothiazines blue, violet, red or orange to skin-colored chromatogram zones, that fade relatively quickly, on a colorless background (Fig. 1). 

Fig 1 Chromatogram of imipramine and phenothiazine derivatives after staining with Forrest reagent [4] 1 = imipramine, 2 = desipramine, 3 = clomipramine, 4 = lofepramine, 5 = trimipramine, 6 = thioridazine, 7 = chlorphenethazine, 8 = periciazine, 9 = promazine, 10 = promethazine. 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

Allopurinol, aspirin, carbamazepine, chlorpropamide, clomipramine, clozapine, colchicine, desipramine, gold salts, imipramine, levodopa, penicillamine, phenothiazines, phenytoin, propylthiouracil, and sulfonylureas... 

Some phenothiazine derivatives (tranquilizers) can be hallucinogenic at high doses (e.g., imipramine (Tofranil) at oral dose of about 1 g and Ethopropazine (Parsidol) at 100 mg). 

Imipramine (Tofranil) [Antidepressant/TCA] WARNING Close observation for suicidal thinking or unusual changes in behavior Uses Depres-sion, enuresis, panic attack, chronic pain Action TCA t CNS synaptic serotonin or norepinephrine Dose Adults. Hospitalized Initial 100 mg/24 h PO in doses T over several wk 300 mg/d max Output Maint 50-150 mg PO hs, 300 mg/24 h max Peds. Antidepressant 1.5-5 mg/kg/24 h daUy-qid Enuresis >6 y 10-25 mg PO qhs T by 10-25 mg at 1-2-wk int vals (max 50 mg for 6-12 y, 75 mg for >12 y) Rx for 2-3 mo, then tap Caution [D, /-] Contra Use w/ MAOIs, NAG, acute recovery from MI, PRG, CHF, angina, CVD, arrhythmias Disp Tabs, caps SE CV Sxs, dizziness, xerostomia, discolored urine Interactions t Effects W/ amiodarone, anticholinergics, BBs, cimetidine, diltiazem, Li, OCPs, quinidine, phenothiazines, ritonavir, verapamil, EtOH, evening primrose oil t effects OF CNS depressants, hypoglycemics, warfarin T risk of serotonin synd W/MAOIs 4-... 

Similar to the phenothiazine derivatives (e.g., chlorpromazine), tricyclic antidepressants (e.g., imipramine) may ... 

Tricyclic antidepressants, like some of the phenothiazine derivatives, are sedative in nature. Those compounds containing a tertiary amine (imipramine, amitriptyline, and doxepin) are the most sedative. Those compounds containing a secondary amine (nortriptyline and desipramine) are less so, and protriptyline has no sedative effect. 

Tricyclic antidepressants—so called because of the characteristic three-ring nucleus—have been used clinically for four decades (Figure 30-1). They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful as antihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties. 

Amitriptyline hydrochloride and imipramine hydrochloride are similar in structure, with the exception of the nitrogen in the center ring, and belong to the family of phenothiazine compounds. Finally, the two-carbon bridge linking the aromatic rings may be ethyl (-CH2CH2-) or ethylene (-CH=CH-). 

For the set of 17 phenothiazines and related structures, four features were found to be of significance in explaining the observed variation in MDR-reversing activity the ring system type, SI, S2 (phenothiazine, imipramine), the side chain type, NALK, and the cis-isomerism ... 

For the two antidepressants (imipramine and maprotiline), the bioisosterism is geometrical insofar that the dihedral angle a formed by the two benzo rings is comparable a = 65° for the dibenzazepine and a = 55° for the dibenzocyclohepta-diene [12]. This angle is only 25° for the neuroleptic phenothiazines and for the thioxanthenes. In these examples, the part of the molecule modified by isosterism is not involved in the interaction with the receptor. It serves only to position correctly the other elements of the molecule. 

The phenothiazines, such as chlorpromazine, used in the treatment of schizophrenia, the tricyclic antidepressant drugs such as imipramine and amitryp-tUine, antimalarials such as quinacrine, and the anticancer agent adriamycin are structural analogs of riboflavin (see Figure 7.6) and inhibit flavokinase. In experimental animals, administration of these drugs at doses equivalent to those used clinically results in an increase in the EGR activation coefficient (Section 7.5.2) and increased urinary excretion of riboflavin, with reduced tissue concentrations of riboflavin phosphate and FAD, despite feeding diets providing more riboflavin than is needed to meet requirements (Pinto et al., 1981). 

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations Fluvoxamine, a CYP450 1A2 inhibitor, can decrease the conversion of imipramine to desmethylimipramine (desipramine) and increase imipramine plasma concentrations Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms Phenothiazines or haloperidol may raise TCA blood concentrations May alter effects of antihypertensive drugs may inhibit hypotensive effects of clonidine... 

Of the systemic antihistamines, the ethanolamines, including diphenhydramine, have significant antimuscarinic activity. In addition, the antipsychotic agents, particularly the phenothiazines such as thioridazine (Mellaril), have well-dociunented anticholinergic properties. Therapeutic doses of tricyclic antidepressants, like amitriptyline hydrochloride (Elavil) and imipramine (Tofranil), produce significant anticholinergic actions and thus have the potential for ocular side effects. 

At about the same time, the drug imipramine was first produced. It was originally developed as a phenothiazine (antipsychotic), but was found to have antidepressant properties. Soon came amitriptyline, followed later by other "tricyclic" and "heterocyclic" antidepressants. 

CYP1A2 Antidepressants amitriptyline, clomipramine, imipramine, fluvoxamine Neuroleptics haloperidol, phenothiazines, thiothixene, clozapine, olanzapine Others tacrine, caffeine, theophylline, acetaminophen, phenacetin No report of polymorphism until 1999 significance of following findings remains unclear 1C reduced activity 23% in Japanese 1F higher inducibility 32% in Caucasians... 

Clinically important, potentially hazardous interactions with amiodarone, amisulpride, amitriptyline, amoxapine, arsenic, bepridil, bretylium, calcium, chlorpromazine, clomipramine, desipramine, disopyramide, doxepin, erythromycin, fluphenazine, imipramine, iron salts, magnesium, mesoridazine, nortriptyline, pentamidine, perphenazine, phenothiazines, pimozide, procainamide, prochlorperazine, promazine, promethazine, protriptyline, quinidine, sotalol, sucralfate, thioridazine, tricyclic antidepressants, trifluoperazine, trimipramine, zinc salts... 

Imipramine, a substance with a structure similar to the phenothiazines (Figure 5) but varying in that the ring is a dibenzazepine rather than a phenothiazine, was the first active antidepressant of the nonmomoamine oxidase inhibitor series of agents. It, like the monoamine oxidase inhibitors, is effective in less than half the patients treated. Its mode of action is not clearly understood, but there is increasing evidence that it too exerts an effect on catechol amine metabolism (19). Although serious toxic effects have been uncommon, excitement, jaundice, and blood dyscrasias have occurred (17). 

Phenothiazines Buterophenones Rauwolfia alkaloids Benzodiazepines MAO inhibitors Imipramine Amitriptyline Lithium salts... 

The TCAs arrived on the scene in the same period as the MAOIs. Imipramine (Table 12-17), which is a dibenzazepine, was synthesized as a logical isosteric extension of the phenothiazines. The antidepressant properties were subsequently discovered and the drug was clinically introduced in 1957. Furthermore, isosterically replacing the N with an sp3... 

Imipramine is structurally analogous to chlorpromazine but the replacement of sulphur by a —CHj - CH2— linkage causes a considerable change in steric and electronic geometry and in pharmacological activity. Like the phenothiazine compounds, imipramine shows some activity against acetylcholine, noradrenaline and histamine , and extrapyramidal side effects... 

It seems, therefore, that central nervous depressants may have one of two characteristic actions they either deplete the brain of its monoamines or they uncouple oxidative phosphorylation. Some depressants have neither of these actions, none has both, though as has been seen, reserpine and the phenothiazine derivatives slightly reduce the ATP content of brain. Not only depressant drugs uncouple oxidative phosphorylation the antidepressant imipramine for instance, is much more active in this respect than chlorpromazine . It is possible, however, as Decs has pointed out, that the anatomical site of maximal uncoupling is important in determining the pharmacological consequences of the biochemical lesion. 

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