Tricyclic antidepressants distribution

It is structurally and chemically related to tricyclic antidepressant drug imipramine and pharmacologically it is similar to diphenyl hydantoin sodium. It is effective in grandmal and psychomotor epilepsy and also in the treatment of trigeminal neuralgia (a condition characterized by paroxysms of intense pain of stabbing nature within the area of distribution of trigeminal nerve without sensory loss). 

The tricyclic antidepressants are all lipid-soluble, are well absorbed from the gut, and are widely distributed in the body. Peak plasma levels are reached 2-6 hours after a single oral dose and elimination half-life is between 8 hours and 36 hours, generally allowing once-daily dosing. Most have active metabolites, also with relatively long half-lives. They are highly bound to plasma proteins (75-95%) and undergo extensive hepatic metabolism. 

In higher mammals, riboflavin is absorbed readily from the intestines and distributed to all tis.sues. It is the precursor in the biosynthesis of the cocnzyme.s flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). The metabolic functions of this vitamin involve these Iwocoenzymes. which participate in numerous vital oxidation-reduction proces.ses. FMN (riboflavin 5 -phosphate) is produced from the vitamin and ATP by flavokinasc catalysis. This step con be inhibited by phcnothiazincs and the tricyclic antidepressants. FAD originates from an FMN and ATP reaction that involves reversible dinucicotide formation catalyzed by flavin nucleotide pyrophosphorylase. The.se coenzymes function in combination with several enzymes as coenzyme-en-zyme complexes, often characterized as, flavoproteins. 

Tricyclic antidepressants are highly lipid soluble and bind extensively to tissue and plasma proteins. The volume of distribution ranges from 10 to 50lKg . ... 

Therapy for phenothiazines is generally supportive and similar to that for tricyclic antidepressant overdose. Physostigmine can reverse the central and peripheral anticholinergic manifestations of phenothiazines however, because these manifestations are rarely life-threatening and because physostigmine may cause severe bradycardia or asystole it is not recommended for treatment of pheno-thiazine overdose. Because of the large volume of distribution and extensive protein binding, hemodialysis or hemoperfusion is not beneficial for phenothiazine overdose. 

Naloxone is effective in reversing the CNS and respiratory depressant actions of propoxyphene but has little effect on the cardiotoxicity. The latter may be treated with NaHCOs to reverse the Na -channel inhibition (a similar therapeutic rationale applies to the treatment of tricyclic antidepressant cardiotoxicity). Because propox)T)hene has a large volume of distribution (10 to 18L/kg) and is highly protein bound (70% to 80%), hemodialysis-is of little value in instances of serious overdose. Forced diuresis likewise is of httle value because only about 1% is eliminated in urine as unchanged propoxyphene. 

Desipramine is a tricyclic antidepressant, inhibits reuptake of norepinephrine and serotonin in CNS, and is indicated in relief of symptoms of depression. Desipramine (75 to 150 mg p.o./day in divided doses) is indicated in endogenous depression major depression with melancholia or psychotic symptoms depression associated with organic brain disease, alcoholism, schizophrenia, or mental retardation and the depressive phase of manic-depressive disorder. Desipramine is absorbed rapidly from the GI tract, distributed widely in the body, and appears also in breast miUc. It is bound to plasma proteins to the extent of 90%, undergoes extensive first-pass metabolism, and its metabolites are excreted in urine. Desipramine strongly blocks the norepinephrine uptake mechanism and has no effect on the uptake of serotonin. Desipramine has weak alpha -adrenergic and... 

DISTRIBUTION AND SERUM LEVEL MONITORING Once absorbed, tricychc antide pressants are widely distributed. They are relatively lipophilic and strongly bind to plasma proteins and constituents of tissues, leading to apparent volumes of distribution as high as 10-50 L g. The tendency of tricyclic antidepressants and their ring-hydroxy metabolites to accumulate in cardiac tissue adds to their cardiotoxicity. Serum concentrations of antidepressants that correlate meaningfully with clinical effects are only established for a few tricychc antidepressants (particularly amitriptyline. 

Hemodialysis or hemoperfusion usually has limited use in the treatment of intoxication with chemicals. However, under certain circumstances, such procedures can be lifesaving. The utility of dialysis depends on the amount of poison in the blood relative to the total-body burden. Thus, if a poison has a large volume of distribution, as is the case for the tricyclic antidepressants, the plasma will contain too little of the compound for effective removal by dialysis. Extensive binding of the compound to plasma proteins impairs dialysis greatly. The elimination of a toxicant by dialysis also depends on dissociation of the compound from binding sites in tissues for some chemicals, this rate may be slow and limiting. 

D. Enhanced elimination. Owing to extensive tissue and protein binding with a resulting large volume of distribution, dialysis and hemoperfusion are not effective. Although repeat-dose charcoal has been reported to accelerate tricyclic antidepressant elimination, the data are not convincing. 

The Influence of Blood Sampling Technique on the Distribution of Chlor-promazine and Tricyclic Antidepressants Between Plasma and Whole Blood Res. Commun. Psychol. Psychiatry Be-hav. 4(2) 193-203 (1979) CA 91 49173b... 

We have found that the ecto-ATPase is optimally stimulated by Mn at concentrations of 3 x 10" or below, but we have also observed some exceptions (for instance, in mouse neuroblastoma where 10 M Ca was most effective and Mn did not stimulate). Mn concentrations in excess of 3 x 10 M are inhibitory. The ecto-ATPase seems widely distributed in eukaryotic cells. There has been an earlier report that the enzyme was not present on the surface of intact neurons (CUMMINS HYDEN, 1962) but it certainly is present on the surface of intact neuroblastoma cells (TRAMS 6e LAUTER, 1974 STEFANOVIC et ad, 1976b), Conventional sulfhydryl compounds or inhibitors have little effect on the enzyme and ouabain is not inhibitory. We have found that ecto-ATPase of cultured CNS cells was inhibited by certain phenothiazine derivatives. Micromolar concentrations of thiazines and tricyclic antidepressants were inhibitory in rat leukocytes (MEDZIHRADSKY et, 1975). There has been one report that adipocyte membrane Mg ATPase was markedly stimulated by insulin and by Concanavalin A (JARRETT Sc SMITH, 1974). ... 

Tricyclics (TCAs) TricycUc antidepressant drugs (eg, imipramine, amitriptyline) are stmcturally related to the phenothiazine antipsychotics and share certain of their pharmacologic effects. The tricycUcs are weU-absorbed orally but may undergo first-pass metabolism. They have high volumes of distribution and are not readily dialyzable. Exten-... 

Antidepressive activity was noted for some tricyclic compounds having a six-membered central ring. A series of naphthyrldones, C-29 C-42 ( ). and C- 5 (7c). caused inlpramine—like activity in animals. The Influence of on central biogenic amine levels," as well as its absorption, distribution and excretion, was Investigated in mice and rats. Several phenothiazine derivatives had antidepressive activity. In extensive clinical trials fluoracizine (8a). a CPj analog of chloracizine, showed antidepressive efficacy equivalent to imipramine. 

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