Lithium excretion

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. 

Lithium is a drug with a narrow therapeutic index and therefore plasma concentrations are regularly monitored. Lithium is used in the prophylaxis and treatment of mania. Concurrent administration of lithium and diuretics, particularly the thiazides, is contraindicated as lithium excretion is reduced, resulting in increased plasma-lithium concentration and hence toxicity. 

Lithium excretion is exclusively via the urine, but it is complicated and does not obey first-order kinetics. Nevertheless, for practical purposes, lithium can be considered to have a plasma half-life of between 24 and 48 hours, which is decreased by salt feeding and increased by salt deprivation or kidney damage (T5). 

Lithium is completely absorbed after oral administration reaching peak concentrations after 1-3 hours. Lithium is not metabolized and almost completely excreted unchanged in the urine with a half-life of on average 24 hours, but increasing to 40 hours or longer in the elderly and in patients with compromised renal function. After excretion 70-80% is reabsorbed by proximal renal tubule where it competes with sodium for reabsorption. Therefore low sodium levels decrease lithium excretion with consequent risks for lithium toxicity. 

Many interactions with lithium have been described. Thiazide and loop diuretics decrease lithium excretion predisposing to serious lithium toxicity. Also non-steroidal anti-inflammatory agents, especially indomethacin can increase the risks for lithium toxicity due to decreased renal excretion. 

Other drugs, such as verapamil, caffeine, theophylline, osmotic diuretics, carbonic anhydrase inhibitors, or aminophylline, can increase lithium excretion, possibly dropping plasma levels below the therapeutic threshold ( 329). Further, if doses are increased to compensate for this effect, care must be taken to readjust the lithium downward when these concomitant agents are reduced or discontinued. 

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. 

Nonsteroidal anti-inflammatory drugs (SSRIs given) [NE] Reduced renal lithium excretion (except sulindac and salicylates). 

Prostaglandin inhibition may result in reduced renal sodium excretion, impaired resistance to hypertensive stimuli, and reduced renal lithium excretion. Most NSAIDs inhibit platelet function may increase likelihood of bleeding due to other drugs that impair hemostasis. Most NSAIDs are highly bound to plasma proteins. 

An increased lithium dosage requirement in a hyperglycemic 40-year-old woman was attributed to the osmotic diuretic effect of glycosuria, increasing lithium excretion (682). 

The point of this case is that lithium toxicity can occur in a patient who has been taking a stable lithium dose during an episode that can be associated with nausea, vomiting, and diarrhea, which could reduce lithium excretion. 

Of 56 patients with lithium toxicity, 42 had initially overdosed and they were compared with those who had toxicity that was described as inadvertent and associated with volume depletion (545). The initial lithium concentration was lower in the cases of intentional overdose than in the cases of inadvertent intoxication (2.4 mmol/l versus 3.4 mmol/l). Hemodialysis for lithium toxicity was required in 9% of those who had taken an intentional overdose compared with 50% of those who had inadvertent intoxication. These findings were in contrast to the amount of lithium taken during the 24 hours before hospitalization, which was much higher in those who had taken an intentional overdose, because of the large inhibitory effect of dehydration on lithium excretion. 

There have been scattered reports of lithium toxicity associated with the use of ACE inhibitors and attributed to reduced lithium excretion (573,575). This is not a predictable interaction. 

In a 42-year-old woman, the serum lithium concentration rose from 0.5 to 1.4 mmol/1 after she increased her topiramate dose from 500 to 800 mg/day (606). The authors speculated that topiramate had interfered with lithium excretion. On the other hand, in a crossover study in healthy volunteers, 6 days of treatment with topiramate did not significantly alter serum lithium concentrations however, the maximum topiramate dose was only 200 mg/ day and one subject did have about a 70% fall in lithium Cmax and AUC (607). 

The authors suggested that topiramate reduced renal lithium excretion through several mechanisms, possibly as a carbonic anhydrase inhibitor coupled with sodium depletion. They suggested that patients taking lithium and topiramate be carefully monitored for lithium concentrations and hydration. 

Interactions. Several types of drug interfere with lithium excretion by the renal tubules, causing the plasma concentration to rise. These include diuretics (thiazides more than loop type), ACE inhibitors and angiotensin-11 antagonists, and nonsteroidal anti-inflammatory analgesics. Theophylline and sodium-containing antacids reduce plasma lithium concentration. The effects can be important because lithium has such a low therapeutic ratio. Diltiazem, verapamil, carbamazepine and pheny-toin may cause neurotoxicity without affecting the plasma lithium. Concomitant use of thioridazine should be avoided as ventricular arrhythmias may result. 

Loop diuretics (especially as i.v. boluses) potentiate ototoxicity of aminoglycosides and nephrotoxicity of some cephalosporins. NSAIDs tend to cause sodium retention which counteracts the effect of diuretics the mechanism may involve inhibition of renal prostaglandin formation. Diuretic treatment of a patient taking lithium can precipitate toxicity from this drug (the increased sodium loss is accompanied by reduced lithium excretion). Reference is made above to drug treatments which, when combined with diuretics, may lead to hyper-kalaemia, hypokalaemia, hyponatraemia, or glucose intolerance. 

We utihzed the above principle to treat hthium-induced polyuria [26]. This reduction in urine output could not be ascribed to increased proximal fluid reabsorption and decreased dehvery of fluid to the distal nephron as a result of the volume contraction caused by amiloride. Fractional lithium excretion, a marker of proximal sodium reabsorption, did not fall during amiloride treatment, arguing against volume contraction induced by amiloride as possible mechanism [26]. In lithium treated patients, urinary osmolality increased when treated with amiloride. Amiloride attenuates the inhibitory effect of lithium on vasopressin-mediated water reabsorption [26] (Figure 3). 

As can be expected, many drugs that interfere with renal function also influence lithium excretion. This and other drug interactions are listed in Table 1. 

Acetazolamide, and probably other diuretics which inhibit carbonic anhydrase, cause a strong inhibition of proximal NaHCOg reabsorption and lithium reabsorption. However, unlike loop diuretics, acetazolamide does not interfere with tubuloglomerular feedback and causes a 20% decrease in glomerular filtration rate. The increase in absolute lithium excretion is somewhat lower than that caused by loop diuretics [22]. Colussi et al. [25] reported the effect of furosemide and acefazola-mide to be additive, indicating a dual site of action (i.e., inhibition of lithium reabsorption in both the proximal tubule and the loop of Henle). 

Additionally, lithium excretion is directly related, in an inverse way, to sodium excretion. Conditions leading to excess sodium elimination will cause a corresponding increase in the amount of lithium retained in the body. Excessive sodium loss occurs from diarrhea, vomiting, fever, dehydration, profuse sweating, diuretic medications, and severely salt-restricted diets. 

The benign effects of lithium on the kidney will be experienced by the majority of patients as increased thirst (polydipsia) and increased urination (polyuria). To ensure adequate lithium excretion, patients must be advised to maintain fluid intake, even in the presence of polyuria. 

Lithium excretion parallels that of sodium. It readily passes the glomerular membrane and is reabsorbed in the proximal convoluted tubules. In situations in which patients are vulnerable to dehydration (fever, watery stools, vomiting, loss of appetite, and hot weather), the potential for lithium intoxication is increased. In dehydration, the proximal tubular response to reabsorption of sodium (and lithium) is reduction of clearance. Increased reabsorption of lithium leads to increased blood concentration of lithium. Severe intoxication, characterized by muscle rigidity, hyperactive deep tendon reflexes, and epileptic seizures, is usually associated with lithium concentrations in excess of 2.5mmoi/L. 

Antacid preparations containing sodium bicarbonate should be avoided by patients on lithium therapy. Sodium ions are preferentially reabsorbed in the kidney, increasing lithium excretion and reducing plasma lithium concentrations. 

Lithium transport along the nephron Effects of drugs on lithium excretion Other situations... 

Abnormal values of fractional lithium excretion have been reported in a variety of conditions. In hyperthyroidism and Bartter s syndrome fractional hthium clearance is increased. After unilateral nephrectomy, hthium clearance by the remaining kidney increases. After two weeks, fractional lithium clearance returns to normal. Rombola et al. [8] reported markedly increased fractional hthium clearance values in patients with Fanconi syndrome, renal glycosuria, and hypercalciuria. 

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