Lithium toxic effects

Lithium toxicity can generate side effects even at therapeutic doses. Lithium... 

Groleau G (1994) Lithium toxicity. Emerg Med Clin North Am 12 (2) 511-531 Han L, McCusker J, Cole M et al. (2001) Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 161 (8) 1099-1105... 

Lithium is somewhat effective for the treatment of agitation however, elderly patients do not tolerate it well. In particular, demented patients are at risk for lithium toxicity, and this toxicity may not be easily detected in these patients. Despite its effectiveness, lithium has been abandoned in the treatment of agitation due to the availability of several effective and better-tolerated treatments, including the atypical antipsychotics described earlier. 

Side effects usually associated with the toxic effects of lithium. 

The long-term toxic effects of lithium, such as nephrogenic diabetes insipidus, which has been calculated to occur in up to 5% of patients, and the rare possibility of lithium combined with neuroleptics being neurotoxic, has stimulated the research for other drug treatments. However, apart from the neuroleptics, these drugs have not been studied as extensively in the treatment of acute mania, but are worthy of consideration because of their reduced side effects. 

Concurrent administration of lithium and selective serotonin re-uptake inhibitors, such as paroxetine, results in an increased risk of central nervous system effects and lithium toxicity has been reported. 

Lithium intoxication can be precipitated by the use of diuretics, particularly thiazides and metola-zone, and ACE inhibitors. NSAIDs can also precipitate lithium toxicity, mainly due to NSAID inhibition of prostaglandin-dependent renal excretion mechanisms. NSAIDs also impair renal function and cause sodium and water retention, effects which can predispose to interactions. Many case reports describe the antagonistic effects of NSAIDs on diuretics and antihypertensive drugs. The combination of triamterene and indomethacin appears particularly hazardous as it may result in acute renal failure. NSAIDs may also interfere with the beneficial effects of diuretics and ACE inhibitors in heart failure. It is not unusual to see patients whose heart failure has deteriorated in spite of increased doses of frusemide who are also concurrently taking an NSAID. 

Geriatric Considerations - Summary Volume of distribution (Vd), clearance, and half-life are significantly altered in older adults. Lithium toxicity may occur within the usual adult therapeutic range. Older adults are likely to exhibit toxic effects at lower serum concentrations. Significantly lower doses are often efficacious for affective disorders than are used in younger adults. Monitor serum concentrations closely, increased riskof lithium toxicity when a diuretic, NSAID, or ACE Inhibitor is started in a patient already taking lithium. 

For some psychotropic drugs (e.g., lithium and some antidepressants) a good correlation exists between plasma levels and therapeutic or toxic effects. Optimum steady-state levels can now be predicted from single-dose blood level data of some drugs (lithium, nortriptyline, desipramine). Altered PK behavior in children has to be taken into consideration in using psychotropic drugs. With development of suitable drug... 

Polyuria, polydipsia, tremor, ataxia, nausea, diarrhea, weight gain, drowsiness, acne, hair loss Possible effects on thyroid and renal functioning with longterm administration Children prone to dehydration are at higher risk for acute lithium toxicity... 

The use of drug plasma levels to effect optimal clinical response and to minimize adverse or toxic effects is standard practice in general medicine (e.g., phenytoin, digoxin), as well as in psychiatry (e.g., lithium, tricyclic antidepressants, valproate see Chapter 3). The theoretical basis for plasma level monitoring rests on several factors, including ... 

While theoretically it is possible that botanicals with diuretic effects can increase drug excretion, most botanical diuretics are not as potent as furo-semide and are unlikely to result in significant interactions. Most botanicals also do not affect urinary pH significantly, and hence are unlikely to affect renal tubular reabsorption of drugs. Nevertheless, lithium toxicity was thought to be related to the use of a botanical diuretic mixture in a patient. If the toxicity indeed is related to the use of the botanical diuretic, the mechanism of action or the responsible constituent(s) is not known (48). 

Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. 

Lithium exists in the body as the Li+ ion. Its toxic effects are likely due to its similarity to physiologically essential Na+ and K+ ions. Some effects may be due to the competion of Li+ ion for receptor sites normally occupied by Na+ or K+ ions. Lithium toxicity may be involved in G protein expression and in modulating receptor-G protein coupling.1... 

Volunteer studies Volunteers taking lithium show signs of mild lithium toxicity. Patient studies also note these effects, such as mental slowing and dysphoria, which are designated as side effects. The data is consistent with the interpretation that it is lithium s neurotoxic effects that result in reductions in manic symptoms. 

Chen et al. (2000) gave lithium to rats in their chow, achieving blood levels comparable with human treatment, and found a proliferation of brain cells in the hippocampus. They made the leap to claim that this neurotrophic effect may make lithium of use in long-term treatment of other neuropsychiatric disorders. In other words, stimulating the brain to make abnormal brain cells is likely to be good for a variety of psychiatric disorders. This kind of giant leap, utterly ignoring the obvious toxic effects of lithium, has become common in the literature. 

Because of the serious risks involved in long-term lithium treatment, patients plasma levels are reassessed regularly, usually every three months. If plasma lithium concentration becomes too high, administration of the drug is suspended and large amounts of sodium salts and fluids are given. Since lithium toxicity is enhanced by sodium depletion, the increased plasma sodium and fluids can reduce its toxic effects. 

During 2004 a number of clinical trials were reported involving acute and maintenance studies of lithium, mostly either comparing new atypical antipsychotic drugs with lithium in bipolar disorder or in combined treatment studies. Of the relatively few studies of the adverse effects of lithium, most clustered in the areas of cardiovascular effects and issues regarding lithium toxicity. 

The adverse effects and interactions of lithium have been reviewed (5,103-105,106). One review focused on lithium toxicity in elderly people (107). The adverse effects of lithium range widely in intensity and can be a major cause of nonadherence to therapy. However, with proper attention to the prevention and management of adverse effects, most patients can be treated effectively and safely. Withdrawal of lithium is almost always followed by resolution of adverse effects, although certain problems can sometimes persist (for example renal). 

Cases of lithium toxicity, its cardiac effects, and issues of cardiac dysfunction in children have been reviewed in the light of a cardiac dysrhythmia in a child. 

A 64-year-old woman had a 2-week history of daily bilateral holocranial headache as the presenting complaint of lithium toxicity (serum concentration 2.5 mmol/1) dosage reduction resolved the headache and the extrapyramidal and cerebellar effects (199). 

To determine the safety of using lithium chloride dilution to measure cardiac output, the pharmacokinetic and toxic effects of intravenous lithium chloride have been studied in six conscious healthy Standardbred horses (527). The mean peak serum concentration was 0.56 mmol/1. There were neither toxic effects nor significant changes in laboratory studies, electrocardiograms, or gastrointestinal motility. Three horses had increased urine output. 

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. 

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