Lithium is one of the most effective medications for the continuous treatment of bipolar disorder. It is particularly useful for the treatment of acute manic episodes and reduces rates of suicide associated with affective disorders.1–3 Off-label uses for lithium include augmentation of the action of other antidepressant drugs and treatment of aggression, posttraumatic stress disorder, and pediatric conduct disorders. Lithium for the treatment of Alzheimer’s disease is under investigation.4 Lithium toxicity most often results from accidental or intentional overdose, increased dose, or reduction in renal clearance of lithium.
The specific pharmacologic effect responsible for the therapeutic benefit in bipolar disorder and mania is unknown.5 Lithium competes with other similar cations, including sodium, potassium, magnesium, and calcium, and displaces them from intracellular and extracellular sites. Interference with sodium ions at the sodium channel and the sodium-potassium pump on the cell membrane is responsible for lithium’s adverse effect on myocardial electrical activity. Lithium inhibits arginine vasopressin, an effect that is responsible for polyuria and nephrogenic diabetes insipidus seen during lithium therapy. Some toxic effects of lithium may be due to inhibition of 3-glycogen synthase kinase, which is present in high quantities in the brain.5 Other pharmacologic effects include inhibition of inositol monophosphatase and reduction of the concentration of inositol in the cytoplasm, inhibition of adenylate cyclase and reduction of intracellular cyclic adenosine monophosphate and possibly cyclic guanosine monophosphate, and interference with the release and reuptake of norepinephrine at the nerve terminal site. Lithium may enhance serotonin release, particularly from the hippocampus, and has been implicated in serotonin syndrome when combined with other medications that alter serotonin metabolism.
Lithium is excreted by the kidneys, so medications that reduce glomerular function have the potential to contribute to lithium toxicity, particularly thiazide diuretics.6 Neuromuscular blocking agents such as succinylcholine, vecuronium, and pancuronium may result in a prolonged neuromuscular blockade when given to patients receiving long-term lithium therapy.
After oral ingestion of therapeutic doses, lithium is rapidly and almost completely absorbed, although delayed absorption may occur with sustained-release products and after ingestion of a large number of tablets.7 Lithium is not bound to plasma proteins and has an initial volume of distribution of 0.6 L/kg, which is similar to that of body water, but over time this can increase to 0.9 L/kg as the ion distributes throughout the body. Ingestion of a single tablet of lithium carbonate 300 milligrams containing 8.12 mEq of lithium ion will acutely raise serum lithium levels by about 0.2 mEq/L (0.2 mmol/L) in a 70-kg adult.
Lithium distribution into and out of the brain is slower, resulting in neurologic effects that do not correlate with serum levels. The lithium concentrations in the brain and in the serum may differ by twofold to threefold.8 Continuation of toxic effects, even after hemodialysis, can be due to the drug’s slow movement out of ...