Lithium retention

Most of the lithium is eliminated in the urine, the first phase of the elimination being 6-8 hours after administration, followed by a slower phase which may last for 2 weeks. Sodium-depleting diuretics such as frusemide, ethacrynic acid and the thiazides increase lithium retention and therefore toxicity, while osmotic diuretics as exemplified by mannitol and urea enhance lithium excretion. The principal side effects of lithium are summarized in Table 8.1. 

Renal lithium excretion sensitive to changes in sodium balance. (Sodium depletion tends to cause lithium retention.) Susceptible to drugs enhancing central nervous system lithium toxicity. 

Because lithium is not bound to any plasma or tissue proteins, it is widely distributed throughout the body. Lithium ions are eliminated mainly by the kidneys. There is a direct relationship between the amount of sodium chloride ingested and the fraction of filtered lithium resorbed, in that, the lower the sodium intake, the greater is the lithium retention. The contraindications are significant cardiovascular or renal diseases that would compromise its excretion. 

This interaction may be due to an amiloride-like diuretic effect of trimethoprim, causing lithium retention. 

Dietary restriction of sodium causes lithium retention and an increased risk of toxicity. The same would be true of a diet that markedly restricted fluid intake. In brief, dietary extremes should be avoided. 

Cyclopropyl halides, however, and alkyllithiums react to give good yields of cyclopropyl-lithiums. Retention of configuration is found in cyclopropyl halide-alkyl-Li reactions e.g. ... 

The dewetting problem of the lithium electrode is now under intensive investigation. General Motors has found that high-temperature hydrogen treatment of the nickel Feltmetal substrate improves lithium retention (9). In this process, metal-oxide films are removed from the substrate metal and the lithium and substrate are in more intimate contact. 

Most of the renal tubular reabsorption ofU occurs in the proximal tubule. Nevertheless, Id retention can be increased by any diuretic that leads to depletion of Na, particularly the thiazides (see Chapter 28). Renal excretion can be increased by administration of osmotic diuretics, aceta-zolamide or aminophylline, and triamterene. Spironolactone does not increase the excretion of LiL Some nonsteroidal anti-inflammatory agents can facilitate renal proximal tubular resorption of Id and thereby increase concentrations in plasma to toxic levels. This interaction appears to be particularly prominent with indomethacin, but also may occur with ibuprofen, naproxen, and COX-2 inhibitors, and possibly less so with sulindac and aspirin. A potential drug interaction can occur with angiotensin-converting enzyme inhibitors, causing lithium retention (see Chapter 29). 

B. Chronic intoxication may occur in patients on stable therapeutic doses. Lithium is excreted by the kidney, where it is handled like sodium any state that causes dehydration, sodium depletion, or excessive sodium reabsorption may lead to increased lithium reabsorption, accumulation, and possibly intoxication. Common states causing lithium retention include acute gastroenteritis, diuretic use, use of nonsteroidal anti-inflammatory drugs or angiotensinconverting enzyme (ACE) inhibitors, and lithium-induced nephrogenic diabetes insipidus. 

Not fully understood. It eould be that, as with the ACE inhibitors, angiotensin n reeeptor antagonists inhibit aldosterone secretion, resulting in increased sodium loss by the kidney tubules. This causes lithium retention and thus an increase in lithium levels. However, angiotensin II receptor antagonists have less effect on aldosterone than the ACE inhibitors, making a clinically significant interaction less likely. Animal studies show that ramipril, but not losartan, decreases the excretion of lithium by the kidney, which would support this idea. 

A case report describes lithium toxicity in a man given indometacin 50 mg every 6 hours. Three days after he started the indometacin his serum creatinine was raised, and 9 days later he had symptoms of lithium toxicity and was found to have a lithium levels of 3.5 mmol/L. It was suggested that the indometacin caused renal impairment, which led to lithium retention and toxicity. ... 

Platinan SR, Fieve RR, Lithium retention and excretion The effect of sodium and fluid intake. Arch Gen Psychiatry (1969) 20, 285-9. 

Hamzaoui, H. A., M nif, A., and Rokbani, R. (2000). Lithium Retention by Sodium Chloride Crystals in Tunisia. Eighdi World Salt Symposium 1, 517-521. 

Zinc acetylides, prepared in situ by the treatment of lithium acetylides with ZnCF, are widely used. The zinc acetylide 311, prepared in situ, reacts with (Z)-3-iodo-2-buten-l-ol (312) with nearly complete retention of stereochemistry to afford an important intermediate 313 for carotenoid synthesis[227]. 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

Replacement of an unactivated lone chlonne with hydrogen is also accom-phshed in good yield with lithium aluminum hydride. Chlorofluoronorcaranes are selectively dechlormated to give hydro derivatives, largely with retention of configuration The related monodeutcronorcaranes are prepared with lithium aluminum deutende [27] (equations 20a and 20b). 

Modification of the ketonic side chain is also consistent with retention of analgesic activity. Thus, reduction of methadone with lithium aluminum hydride affords the alcohol, 128 (apparently as a single diastereomer). Acetylation gives acetyl-methadol (129). ... 

It was demonstrated that when a better leaving group than lithium oxide (Li20) is present at the a-position (e. g., epoxide 125 Scheme 5.27), alkene formation occurs with retention of the alcohol moiety [44]. 

By contrast, lithium extraction from the tetrahedral sites in Li[Mn2]04, i.e., for 0cubic symmetry of the spinel structure [105, 114, 120]. It is difficult to extract all the lithium electrochemi-cally from Li[Mn2]04, at least at practical voltages, without causing decomposi-... 

Tin/lithium exchange on the a-alkoxy stannanes and subsequent addition of carbon dioxide led to optically active (7-protected a-hydroxy acids 18 with retention of configuration and without any loss of stereochemical information11. 

Allylstannanes can be prepared by treatment of allyl halides with trialkyl- or triaryltin lithium reagents. Displacement of primary allyl halides tends to be regioselective for formation of the less substituted allylstannane, and takes place with useful retention of double-bond geometry14-16. 

Diisopropylamino(dimethyl)silyl]-2-propenyl]lithium adds to aromatic and x-branched aldehydes in the presence of anhydrous zinc chloride with essentially complete anti stereoselectiv-ity3s. as expected from the chair-like pericyclic transition state formed by the ( -intermediate. The addition products are not isolated, but after O-silylation, oxidative desilylation with retention of configuration forms the rmft-diols. 

Solladie and coworkers545 confirmed the earlier result of Nishihata and Nishio546 that the carbonation of the a-sulphinyl carbanion proceeds under kinetic control with retention of configuration at the metallated carbon atom. However, they also found that the stereochemical outcome of this reaction depends on other factors. They observed that 90% of asymmetric induction may be achieved under kinetic control (reaction time < 0.5 min) by using a base with low content of lithium salts, a result consistent with an electrophilic assistance by the lithium cation (equation 286)545. 

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