CHAPTER 2-93: LITHIUM

INTRODUCTION

Lithium is used for the treatment of bipolar depression and other psychiatric disorders and occasionally to raise the white blood cell count in patients with leukopenia. Serious toxicity is caused most commonly by chronic overmedication in patients with renal impairment. Acute overdose, in contrast, is generally less severe.

MECHANISM OF TOXICITY

1. Lithium is a naturally occurring alkali metal and a monovalent cation that enters cells and substitutes for sodium or potassium. The mechanisms by which lithium produces its therapeutic and toxic effects are not completely understood. Lithium has a similar size to magnesium and competes with magnesium as a cofactor for several key enzymes. Specific enzymes involved in intracellular signaling pathways are inhibited. Newer research suggests that the serotonergic system is strongly involved and the dopaminergic system may be as well. Lithium is also thought to stabilize cell membranes. With excessive levels, it depresses neural excitation and synaptic transmission.

2. Pharmacokinetics. Lithium is completely absorbed within 6–8 hours of ingestion. The initial volume of distribution (Vd) is about 0.5 L/kg, with slow entry into tissues and a final Vd of 0.7–1.4 L/kg. Entry into the brain is slow; this explains the delay between peak blood levels and CNS effects after an acute overdose. Elimination is virtually entirely by the kidney, with a half-life of 14–30 hours. Thyroxine enhances tubular reabsorption, which may increase lithium levels in patients with hyperthyroidism.

TOXIC DOSE

The usual daily dose of lithium ranges from 300 to 2,400 mg (8- 64 mEq/d), and the therapeutic serum lithium level is 0.6–1.2 mEq/L. The toxicity of lithium depends on whether the overdose is acute, acute-on-chronic, or chronic.

1. Acute ingestion of 1 mEq/kg (40 mg/kg) will produce a blood level after tissue equilibration of approximately 1.2 mEq/L. Acute ingestion of more than 20–30 tablets by an adult potentially can cause serious toxicity.

2. Acute-on-chronic ingestions occur when patients regularly taking lithium ingest an acute overdose. Because the patient's tissues are already saturated with lithium, toxicity is potentially more serious than an acute overdose in a patient not regularly using lithium.

3. Chronic intoxication may occur in patients on therapeutic doses. Lithium is excreted by the kidneys, where it is handled like sodium; any state that causes dehydration, sodium depletion, or excessive sodium reabsorption may lead to increased lithium reabsorption, accumulation, and possibly intoxication. Common states causing lithium retention include acute gastroenteritis, diuretic use (particularly thiazides), use of nonsteroidal anti-inflammatory drugs or angiotensin-converting enzyme (ACE) inhibitors, and lithium-induced nephrogenic diabetes insipidus.

CLINICAL PRESENTATION

Severity of toxicity is proportional to the duration of lithium exposure and the amount ingested. Mild-to-moderate intoxication results in lethargy, muscular weakness, slurred speech, ataxia, tremor, and myoclonic jerks. Rigidity and extrapyramidal effects may be seen. Severe intoxication may result in agitated delirium, coma, convulsions, and hyperthermia. Recovery is often very slow, and patients ...