Lithium Salts

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The lithium salts used in the United States are the carbonate (tetrahydrate) and the citrate. Lithium chloride is not used because of its hygroscopic nature and because it is more irritating than the carbonate or citrate to the GI tract.

The active species in these salts is the lithium ion. The classic explanation for its antimanic activity is that it resembles the sodium ion (as well as potassium, magnesium, and calcium ions) and can occupy the sodium pump. Unlike the sodium ion, it cannot maintain membrane potentials. Accordingly, it might prevent excessive release of NTs (e.g., DA) that characterize the manic state. Many of the actions of lithium ion have been reviewed.37 Despite considerable investigation, the mode of action of lithium remains unclear. The major possibility is that lithium reduces signal transduction through the phosphatidylinositol signaling pathway by uncompetitive inhibition of inositol phos-phatase. As a result, the pool of inositol available for the

resynthesis of phosphatidylinositol-4,5-bisphosphate (PIP2) is depleted, the cellular levels of PIP2 is decreased, thereby, enzymatic formation of the second messengers is reduced.

The indications for lithium salts are acute mania (often with a potent neuroleptic agent for immediate control, because lithium is slow to take effect) and as a prophylactic to prevent occurrence of the mania of bipolar manic-depressive illness. Lithium salts are also used in severe recurrent unipolar depression. One effect of the drug that might be pertinent is an increase in the synthesis of presynaptic serotonin. Some have speculated that simply evening out transmission, preventing downward mood swing, for example, could be a basis for antidepressant action.

Because of its water solubility, the lithium ion is extensively distributed in body water. It tends to become involved in the many physiological processes involving sodium, potassium, calcium, and magnesium ions, hence, many side effects and potential drug interactions exist. The margin of safety is low; therefore, lithium should be used only when plasma levels can be monitored routinely. In the desired dose range, side effects can be adequately controlled.

Because of the toxicity of lithium, there is substantial interest in design of safer compounds. As more is learned about lithium's specific actions, the likelihood of successful design of compounds designed to act on specific targets is increased. Actually, carbamazepine and valproic acid, which target sodium channels, are proving to be effective.38 These two drugs are discussed in the anticonvulsant section.

Lithium Carbonate, USP, and Lithium Citrate. Lithium carbonate (Eskalith, Lithane) and lithium citrate (Cibalith-S) are the salts commercially available in the United States.

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