lithium (Rx)

>10%

Leukocytosis (most patients)

Polyuria/polydypsia (30-50%)

Dry mouth (20-50%)

Hand tremor (45% initially, 10% after 1 year of treatment)

Confusion (40%)

Decreased memory (40%)

Headache (40%)

Muscle weakness (30% initially, 1% after 1 year of treatment)

Electrocardiographic (ECG) changes (20-30%)

Nausea, vomiting, diarrhea (10-30% initially, 1-10% after 1-2 years of treatment)

Hyperreflexia (15%)

Muscle twitch (15%)

Vertigo (15%)

1-10%

Extrapyramidal symptoms, goiter (5%)

Hypothyroidism (1-4%)

Acne (1%)

Hair thinning (1%)

Frequency Not Defined

Coma

Lethargy

Seizures

Renal toxicity

Acute lithium toxicity

Lithium-induced polyuria

Ataxia/gait disturbance

Postmarketing Reports

Dermatologic: Drying and thinning of hair, alopecia, anesthesia of skin, chronic folliculitis, xerosis cutis, psoriasis onset or exacerbation, generalized pruritus with or without rash, cutaneous ulcers, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS)

Contraindications

Documented hypersensitivity

Severe cardiovascular disease

Pregnancy in 1st trimester

Unstable renal function, sodium depletion, severe dehydration

Severe debilitation

Cautions

Cardiovascular disease; reports of possible association between lithium treatment and unmasking of Brugada syndrome (abnormal ECG and risk of sudden death)

Use with caution in patients with thyroid disease

Narrow therapeutic index

Risk of nephrogenic diabetes insipidus; such patients should be carefully managed to avoid dehydration with resulting lithium retention and toxicity; condition is usually reversible when lithium is discontinued

Lithium-sensitive patients may experience toxicity symptoms with serum lithium concentrations of 1-1.5 mEq/L

Lithium toxicity is closely related to serum levels and can occur at therapeutic dosages; if manifestations of toxicity occur, discontinue for 24-48 hours, then resume at lower dosage

Mainitain geriatric patients on dosages that produce serum lithium concentrations at lower end of desired range

May cause central nervous system (CNS) depression and impair ability to operate heavy machinery

Hypercalcemia reported with or without hyperparathyroidism; women and older patients are possibly at greater risk; onset does not appear to be associated with duration of therapy

Monitor changes in renal function; chronic therapy may diminish renal concentrating ability; usually reversible when lithium therapy discontinued

Use caution in debilitated patients; may increase risk of lithium toxicity

Use with caution in patients at risk for suicide

Cases consistent with nephrotic syndrome reported with use of lithium; discontinuation of lithium in patients with nephrotic syndrome has resulted in remission of nephrotic syndrome

Routine urinalysis and other tests may be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine ,creatinine clearance, or proteinuria); during lithium therapy, progressive or sudden changes in renal function, even within normal range, indicate the need for re-evaluation of treatment

An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) has reported in a few patients treated with lithium plus a neuroleptic, most notably haloperidol; in some instances, the syndrome was followed by irreversible brain damage; because of possible causal relationship patients receiving such combined therapy or patients with organic brain syndrome or other CNS impairment should be monitored closely for early evidence of neurologic toxicity and treatment discontinued promptly if such signs appear; encephalopathic syndrome may be similar to or the same as Neuroleptic Malignant Syndrome (NMS)

Lithium may prolong effects of neuromuscular blocking agents; neuromuscular blocking agents should be given with caution to patients receiving lithium

Lithium toxicity

• The risk of lithium toxicity is increased in patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, and for patients receiving prescribed medications that may affect kidney function, such as angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), diuretics (loops and thiazides) and NSAIDs; for these patients, consider starting with lower doses and titrating slowly while frequently monitoring serum lithium concentrations and signs of lithium toxicity
• Neurological signs of lithium toxicity range from mild neurological adverse reactions such as fine tremor, lightheadedness, lack of coordination, and weakness; to moderate manifestations like giddiness, apathy, drowsiness, hyperreflexia, muscle twitching, ataxia, blurred vision, tinnitus, and slurred speech; severe manifestations such as clonus, confusion, seizure, coma, and death may occur; in rare cases, neurological sequelae may persist despite discontinuing lithium treatment and may be associated with cerebellar atrophy
• Cardiac manifestations involve electrocardiographic changes, such as prolonged QT interval, ST and T-wave changes and myocarditis; renal manifestations include urine concentrating defect, nephrogenic diabetes insipidus, and renal failure; respiratory manifestations include dyspnea, aspiration pneumonia, and respiratory failure; gastrointestinal manifestations include nausea, vomiting, diarrhea, and bloating; no specific antidote for lithium poisoning known
• Monitor for signs and symptoms of toxicity; if symptoms occur, decrease dosage or discontinue lithium treatment

Serotonin syndrome

• Lithium can precipitate serotonin syndrome, a potentially life-threatening condition; risk is increased with concomitant use of other serotonergic drugs (including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin, eg, MAOIs
• Monitor all patients taking lithium for emergence of serotonin syndrome; discontinue treatment with lithium and any concomitant serotonergic agents immediately if above symptoms occur and initiate supportive symptomatic treatment; if concomitant use of lithium with other serotonergic drugs is clinically warranted, inform patients of increased risk for serotonin syndrome and monitor for symptoms

Pregnancy category: D

Lactation: Drug is excreted in breast milk; use not recommended

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits postsynaptic D2 receptor supersensitivity

Alters cation transport in nerve and muscle cells and influences reuptake of serotonin or norepinephrine

Inhibits phosphatidylinositol cycle second messenger systems

Absorption

Bioavailability: Immediate release, 95-100%; extended release, 60-90%

Onset: Initial antimanic effect, 5-7 days; full effect, 10-21 days

Peak serum time: Immediate release, 0.5-2 hr; extended release, 4-12 hr

Peak plasma concentration: 0.4-0.9 mEq/L

Steady-state therapeutic plasma concentration: 0.5-1.3 mEq/L

Distribution

Vd: Approximates total body water (0.7-1 L/kg)

Metabolism

Not metabolized

Elimination

Half-life: 18-24 hr; up to 36 hr with advanced age or renal impairment

Dialyzable: Yes (hemodialysis, 50-90 mL/min; peritoneal dialysis, 13-15 mL/min)

Renal clearance: 20-40 mL/min

Excretion: Urine (95-99%)