Lithium clearance

Several factors predispose to lithium toxicity, including sodium restriction, dehydration, vomiting, diarrhea, drug interactions that decrease lithium clearance, heavy exercise, sauna baths, hot weather, and fever. Patients should be told to maintain adequate sodium and fluid intake and to avoid excessive coffee, tea, cola, and other caffeine-containing beverages and alcohol. 

Lithium clearance increases by 50% to 100% during pregnancy. Serum levels should be monitored monthly during pregnancy and weekly the week before delivery. At delivery, a dose reduction to prepregnancy doses and adequate hydration are recommended. 

Sedvall, G., Petersson, U., and Fyro, B., Individual differences in serum levels of lithium in human subjects receiving fixed doses of lithium carbonate. Relation to renal lithium clearance and body weight. Pharmacol. Clin. 2, 231-235 (1970). 

During pregnancy, serum lithium levels need to be carefully monitored. The 50% to 100% increase in glomerular filtration rate (GFR) that normally occurs in the third trimester will proportionally lower lithium levels due to its increased clearance. Thus, dosage may need to be increased to maintain a therapeutic range ( 341). Because the GFR and lithium clearance quickly return to normal after delivery, it may be wise to stop the drug shortly before delivery and restart a few days after delivery at a lower dose. In summary ... 

Amiloride Blocks epithelial sodium channels in collecting tubules Reduces Na retention and wasting increases lithium clearance Hypokalemia from other diuretics reduces lithium-induced polyuria Orally active duration 24 h Toxicity Hyperkalemic metabolic acidosis... 

Excretion Virtually entirely in urine. Lithium clearance about 20% of creatinine. Plasma half-life about 20 hours. 

Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium. 

Bachofen M, Bock H, Beglinger C, Fischer JA, Thiel G. Calcitonin, ein proximal tubular wirkendes Diuretikum Lithium-Clearance-Messungen am Menschen. [Calcitonin, a proximal-tubular-acting diuretic lithium clearance measurements in humans.] Schweiz Med Wochenschr 1997 127(18) 747-52. 

Lithium + diuretics — reduced lithium clearance and raised plasma lithium concentration thereby enhancing toxicity. 

A reduction in glomerular filtration rate (GFR) will reduce lithium clearance, as will a negative sodium balance. Lithium is not metabolized and is not bound to plasma proteins. 

Fluid and sodium balance are important to the safe use of lithium. Both dehydration and a negative sodium balance (for example a low salt intake, diuretic-induced sodium loss) will reduce renal lithium clearance and predispose to toxicity (331). Hyponatremia (for example, secondary to polydipsia or SIADH) may also increase the risk of lithium toxicity (332). 

A review of the effects of obesity on drug pharmacokinetics briefly mentioned that the steady-state volume of distribution of lithium correlated with ideal body weight and fat-free mass but not with total body weight (514). Lithium clearance was greater in those with obesity than in lean controls, suggesting that obese patients may require larger maintenance doses to maintain target serum concentrations. 

Thus, the term overdose (109,530,531) can be misleading, because poisoning can develop not only as a result of overdosage but also by a fall in lithium clearance. Of 205 cases of lithium poisoning reported to the Ontario Canada Regional Poison Information Centre in 1996,12 were acute overdoses (someone else s tablets), 19 were chronic poisonings, and 174 were acute-on-chronic poisonings. Over 80% had no or... 

In rats, ramipril reduced renal lithium clearance and increased fractional lithium reabsorption in association with decreased systolic blood pressure and decreased sodium excretion. These effects were attenuated by icati-bant, a specific bradykinin B2 receptor antagonist (577). 

In 34 healthy men, ziprasidone did not alter serum lithium concentrations or renal lithium clearance (640). 

In a placebo-controlled, open-label study in 25 healthy subjects there were no changes in serum lithium concentration or renal lithium clearance when ziprasidone (40-80 mg/day) was added for 7 days (640). 

Osmotic diuretics increase lithium clearance, the change being proportional to the increased rate of urine flow. 

Thiazide diuretics predictably reduce renal lithium clearance and increase the risk of toxicity (652). The same may be true of potassium-sparing diuretics, although this is less well established. 

A review of the psychiatric effects of NSAIDs included a section on renal function and lithium clearance (666). 

In 16 subjects, meloxicam 15 mg increased plasma lithium concentrations by 21% (range —9 to 59%) and reduced total plasma lithium clearance by 18% (685). 

Some data have suggested that cisplatin-containing chemotherapy can alter lithium clearance through impaired renal function, and lithium therapy should be closely monitored during treatment with cisplatin-containing regimens (723). 

Renal lithium clearance is increased and serum lithium concentrations are reduced by theophylline and amino-phylline (496). 

Caffeine increases renal lithium clearance (693), and there have been case reports of caffeine withdrawal leading to increased serum lithium concentrations, assumed to be due to reduced renal lithium clearance (693). 

Thomsen K, Schou M. Avoidance of lithium intoxication advice based on knowledge about the renal lithium clearance under various circumstances. Pharmacopsychiatry 1999 32(3) 83-6. 

Bagate K, Grima M, De Jong W, Imbs JL, Barthelmebs M. Effects of icatibant on the ramipril-induced decreased in renal lithium clearance in the rat. Naunyn Schmiedebergs Arch Pharmacol 2001 363(3) 281-7. 

Bruun NE, Ibsen H, Skott P, Toftdahl D, Giese J, Holstein-Rathlou NH. Lithium clearance and renal tubular sodium handling during acute and long-term nifedipine treatment in essential hypertension. Clin Sci (Lond) 1988 75(6) 609-13. 

Pinkofsky HB, Sabu R, Reeves RR. A nifedipine-induced inhibition of lithium clearance. Psychosomatics 1997 38(4) 400-1. 

Colussi G, Rombola G, Surian M, De Ferrari ME, Airaghi C, Benazzi E, Malberti F, Minetti L. Lithium clearance in humans effects of acute administration of acetazo-lamide and furosemide. Kidney Int Suppl 1990 28 S63-6. 

Beutler JJ, Boer WH, Koomans HA, Dorhout Mees EJ. Comparative study of the effects of furosemide, ethacrynic acid and bumetanide on the lithium clearance and diluting segment reabsorption in humans. J Pharmacol Exp Ther 1992 260(2) 768-72. 

BETA-BLOCKERS LITHIUM Report of episode of t lithium levels in elderly patient after starting low-dose propanolol. However, propanolol is often used to treat lithium-induced tremor without problems Mechanism uncertain at present, but propanolol seems to 1 lithium clearance Monitor lithium levels when starting propanolol therapy in elderly people... 

Only the kidneys eliminate lithium. Like sodium, it is filtered by the glomerulus and 80% is reabsorbed by the proximal tubule but it is not reabsorbed by the distal tubule. Intake of sodium and water are the principal determinants of its elimination. In sodium deficiency lithium is retained in the body, thus concomitant use of a diuretic can reduce lithium clearance by as much as 50% and precipitate toxicity. Sodium chloride and water are used to treat lithium toxicity. 

Heys SD, Eremin O, Franks CR, Broom J, Whiting PH. Lithium clearance measurements during recombinant interleukin 2 treatment tubular dysfunction in man. Ren Fail 1993 15(2) 195-201. 

Caffeine increases renal lithium clearance, and it is conceivable that drastic curtailment of caffeine intake could result in an increase in serum lithium concentration. 

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