Besides treatment of bipolar disorder, many other medical and psychiatric uses for lithium have been suggested, including impulsive/aggressive behavior, neutropenia, alcohol dependence, and cluster and migraine headaches. Lithium toxicity may result from accidental or intentional overdose or from an alteration in lithium clearance. The true incidence of lithium toxicity and subsequent medical outcomes are not known, since there is not a mandatory reporting requirement for toxic exposures in the United States.

It has been estimated that up to 75 to 90 percent of patients who are chronically treated with lithium will develop toxicity some time in their therapy. 1 Over the past 5

years, the American Association of Poison Control Centers has reported over 25,000 cases of lithium toxicity. Of these 44 resulted in death. 2 PATHOPHYSIOLOGY

Lithium is thought to cause toxicity through several mechanisms. It has the ability to compete with other similar molecular weight ions, including sodium, potassium, magnesium, and calcium, displacing them from both intracellular and bone sites. Competition with and displacement of other ions can result in lithium retention and subsequent toxicity. Therefore, activities, medical conditions, and medications that affect water and electrolyte balance can contribute to lithium toxicity. Loss of salt, water, or both leads to an increase in proximal reabsorption of lithium and a rise in lithium level. Inhibition of arginine vasopressin and the resultant hydroosmotic effects have also been attributed to lithium.

It is also thought that lithium, through adenylate cyclase inhibition, causes decreases in intracellular cyclic adenosine monophosphate. Decreases in cyclic guanosine monophosphate may also occur. Inositol may play a role in lithium's therapeutic and adverse effects. Inositol, in the form of phosphatidylinositol, is found in the phospholipids of cell membranes and plasma lipoproteins. It may be released from phospholipids in response to a variety of hormones and neurotransmitters. Activated inositol may interact with G proteins to form intracellular messengers that enhance intracellular calcium release and activate protein kinase C. 3 It has been suggested that lithium may increase inositol monophosphate and reduce free inositol through inhibition of inositol monophosphatase. Lithium is also thought to interfere with the release and re-uptake of the neurotransmitter norepinephrine at the nerve terminal site. 4 Lithium may enhance serotonin release from the hippocampus.5 Finally, risk of lithium toxicity exists when it is combined with a variety of medications. The mechanism for toxicity differs based on the drug-drug interactions. A number of these potential drug interactions are listed in T.a,b.l.e 15.6.-1... In addition, the use of succinylcholine and vecuronium in patients taking lithium may result in a prolonged neuromuscular blockade.

The pharmacokinetics of lithium also play a vital role in toxicity. The absorption of lithium is rapid and complete following oral administration. Delayed absorption may occur with sustained-release products and following ingestion of a large number of pills. Toxic effects appear later and last longer. Lithium has a volume of distribution of 0.79 L/kg, which is similar to that of body water. Lithium distribution to and from the central nervous system (CNS) is slower, resulting in CNS symptoms that do not correlate with serum levels. Sustained toxic effects, even after hemodialysis, can be due to the slow distribution in the CNS. Lithium is not bound to plasma proteins. The half-life of lithium is reported to be approximately 29 h. There is no appreciable hepatic metabolism, and it is primarily excreted unchanged in the urine. The presence or development of renal insufficiency is an important factor in the development of lithium toxicity.

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