Lithium

Lithium is well absorbed from the gastrointestinal tract with peak plasma concentrations occurring between 1 and 3 hours after administration. Peak plasma concentrations following administration of extended-release preparations are reached in 4 to 12 hours. Steady-state concentrations are reached in 4 days with the onset of antimanic effect usually occurring within 5 to 7 days. Full therapeutic effect may require 10 to 21 days following initiation of therapy. When lithium is used as augmentation therapy in refractory depression, some patients may respond within 48 hours, but most respond in 1 to 2 weeks.

Lithium is widely distributed into most body tissues and crosses the blood-brain barrier. CSF lithium concentrations are approximately half of plasma concentrations. Lithium does not bind to plasma proteins. Elimination half-life is 24 hours and is increased to 36 hours in geriatric patients and 40 to 50 hours in patients with impaired renal function.

Lithium is excreted primarily in the urine with less than 1% eliminated in the feces. Small amounts are also excreted in sweat. Lithium is filtered by the glomeruli with 80% reabsorbed in the tubules. In patients with normal renal function, 50 to 80% of a single dose is excreted in the urine within 24 hours. Renal lithium excretion varies among individuals and dosage must be individualized. Renal clearance is decreased in geriatric patients and increased in younger patients and during pregnancy. Sodium loading or depletion affects renal clearance of the drug. A low salt intake resulting in low tubular concentration of sodium increases lithium reabsorption and may result in toxicity. Polyuria does not increase renal clearance of the drug. Lithium is removed by hemodialysis. The half-life of lithium is shorter in children.

Routine serum drug concentration monitoring is necessary (see Warnings, Precautions and Dosage).

ACE Inhibitors: Concomitant administration of lithium and ACE inhibitors may increase the risk of lithium toxicity. Frequently monitor lithium levels during concurrent therapy.

Angiotensin II Receptor Blockers: Cases of lithium intoxication have been reported when angiotensin II receptor blockers were added to the therapeutic regimen. Close monitoring for signs of increased lithium serum concentration is recommended if these drugs are used concurrently.

Anticonvulsants: Concurrent use of lithium and carbamazepine or phenytoin might result in an increased risk of CNS toxicity.

Antipsychotics: Both pharmacokinetic interactions and clinical toxicity (e.g., neurotoxicity) have been described with the combined use of these agents. Monitor for altered response to either drug when lithium and an antipsychotic are used in combination, and when either drug is withdrawn.

Calcium Channel Blockers: Concomitant administration of lithium and calcium channel blockers may increase the risk of neurotoxicity.

Cyclooxygenase-2 (COX-2) Inhibitors: In one study in healthy subjects receiving celecoxib and lithium, mean steady-state levels of lithium were increased by 17% compared to subjects receiving lithium alone. Based on this study, some clinicians suggest monitoring patients maintained on lithium for evidence of an interaction if a COX-2 inhibitor is initiated or withdrawn.

Diuretics: Patients stabilized on lithium therapy who receive a thiazide diuretic may require a reduction of lithium dosage to avoid accumulation and toxicity, since there is often a 20 to 40% reduction of renal lithium clearance. Furosemide may increase the risk of lithium toxicity in patients >65 years, especially during the first month of therapy.

Haloperidol: A type of encephalopathy resembling neuroleptic malignant syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated BUN and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with both lithium and haloperidol. Patients receiving combined therapy should be monitored closely for early evidence of neurologic toxicity, such as rigidity and/or hyperpyrexia; discontinue treatment if these signs appear.

Iodides: Concomitant administration of lithium and iodides may increase the hypothyroid effects of either of these medications.

Monoamine Oxidase Inhibitors (MAOIs): Two patients died after developing rigidity, hyperthermia and hepatic failure while taking phenelzine, lithium and L-tryptophan. Though L-tryptophan may have contributed to these reactions, some clinicians recommend avoiding the combination of lithium and nonselective MAOIs.

Methyldopa: Concomitant administration of lithium and methyldopa may increase the risk of lithium toxicity.

Metronidazole: Concomitant administration of lithium and metronidazole may cause renal retention of lithium, leading to lithium toxicity. If possible, lithium should be discontinued during therapy with metronidazole.

Neuromuscular Blockers: The action of neuromuscular blockers may be prolonged in patients receiving lithium. A temporary omission of a few doses of lithium can reduce the risks of this interaction.

NSAIDs: Several NSAIDs have been reported to increase steady-state plasma lithium levels substantially. Increased frequency of monitoring plasma lithium levels is recommended during concurrent therapy with NSAIDs.

Serotonergic Drugs: Combined use of lithium and other serotonergic drugs (e.g., SSRIs, sibutramine) may increase the risk of serotonin syndrome.

Sodium Bicarbonate: Concomitant administration of lithium and sodium bicarbonate may enhance lithium excretion. A higher dose of lithium may be required in these patients.

Tetracycline: Concomitant administration of lithium and tetracycline may increase the risk of lithium toxicity.

Theophylline: The administration of aminophylline or theophylline to patients on lithium may require increased lithium doses to maintain the clinical effects of the drug.

Tricyclic Antidepressants: Concurrent use of lithium and tricyclic antidepressants may increase the risk of toxicity (e.g., tremors, ataxia, seizures). Older patients may be particularly susceptible. If the combination is used, some clinicians suggest using the lowest effective dose of each agent and monitoring the patient closely for adverse effects.

Elderly patients appear to be more susceptible to adverse effects and may experience a higher incidence of neurotoxicity at lithium concentrations considered therapeutic for younger adults. Certain groups of elderly patients are particularly vulnerable, including those with neurologic disease, cardiovascular disorders, renal impairment and those over 80 years of age. The recommended therapeutic range for serum lithium concentrations in older patients is ≤ 0.4 to 0.6 mmol/L, not to exceed 1 mmol/L.

Lithium may cause dizziness or decreased mental alertness. Patients should be appropriately cautioned regarding the operation of motor vehicles or hazardous machinery.

Lithium is excreted into breast milk in concentrations ranging from 30 to 100% of maternal serum levels. Lithium should be used with caution in breast-feeding mothers and if possible, avoided until the infant is several months old. If it is used during lactation, the mother should be educated about signs and symptoms of lithium toxicity and the increased risk posed by dehydration in the infant. Some clinicians recommend monitoring lithium serum concentrations and periodic monitoring of renal and thyroid function in infants exposed to lithium through breast-feeding.

Lithium has a shorter half-life in children.

Administration of lithium during pregnancy may result in an increased incidence of cardiac and other anomalies, especially Ebstein's anomaly. Nephrogenic diabetes insipidus, euthyroid goiter and hypoglycemia have also occurred in women treated with lithium during pregnancy. Lithium should not be used during pregnancy or in women of childbearing potential unless it cannot be substituted by other appropriate therapy and if the expected benefits outweigh the possible hazards to the child.

If lithium is used during pregnancy, serum lithium concentrations should be carefully monitored and the dosage adjusted if necessary since renal clearance and distribution of the drug into erythrocytes may be increased during pregnancy. Pregnant women receiving lithium may have subtherapeutic serum lithium concentrations if the dosage is not increased during pregnancy. Immediately postpartum, renal clearance of lithium may decrease to pre-pregnancy levels. To decrease the risk of postpartum lithium intoxication, dosage of the drug should be reduced 1 week prior to parturition or when labor begins.

diabetes insipidus (see Warnings), albuminuria, oliguria, polyuria, glycosuria.

anorexia, nausea, vomiting, diarrhea.

general muscle weakness, ataxia, tremor, muscle hyperirritability, (fasciculation, twitchings, especially of facial muscles and clonic movements of the limbs), choreoathetotic movement, hyperactive deep tendon reflexes.

allergic vasculitis.

anemia, leukopenia, leukocytosis.

euthyroid goiter and/or hypothyroidism (including myxedema) accompanied by lower T₃ and T₄ levels and elevated TSH. Iodine¹³¹ uptake may be elevated. On average, 5 to 15% of patients on long-term lithium therapy manifest clinical signs or have altered serum hormone levels (see Precautions). Paradoxically, rare cases of hyperthyroidism have been reported.

general fatigue, dehydration, weight loss, tendency to sleep, lethargy, transient scotomata, metallic taste, peripheral edema.

Hypercalcemia, associated with lithium-induced hyper-parathyroidism, has also been reported.

blurred vision, dry mouth.

anesthesia of the skin, slurred speech, blurred vision, blackout spells, headache, seizures, cranial nerve involvement, psychomotor retardation, somnolence, toxic confusional states, restlessness, stupor, coma, acute dystonia, EEG changes.

dryness and thinning of the hair, leg ulcers, skin rash, pruritus and exacerbation of psoriasis.

transient hyperglycemia, slight elevation of plasma magnesium, goiter.

arrhythmia, hypotension, ECG changes consisting of flattening or inversion of T-waves, peripheral circulatory failure, cardiac collapse.

Lithium toxicity is closely related to the concentration of lithium in the blood and is usually associated with serum concentrations in excess of 2 mmol/L. Patients chronically on lithium have more severe symptoms for a given serum level than those with no previous lithium load who have ingested a single large dose. Early signs of toxicity which may occur at lower serum concentrations (see Adverse Effects) usually respond to a reduction in dosage. Chronic lithium intoxication has been preceded by the appearance or aggravation of the following symptoms: sluggishness, drowsiness, lethargy, coarse hand tremor or muscle twitches, loss of appetite, vomiting and diarrhea. Occurrence of these symptoms requires immediate cessation of medication and careful clinical reassessment and management.

Symptoms of overdose vary depending on whether the intoxication is acute or chronic. Patients with acute overdose usually have early gastrointestinal symptoms such as nausea, vomiting and diarrhea. These are often absent in patients experiencing chronic toxicity. In all patients with lithium intoxication, the primary problem is neurologic toxicity that may progress from fine tremor to hyperreflexia, fasciculations, muscular irritability, choreoathesis, clonus, agitation, altered mental status, lethargy, seizures and coma. The serum concentration may not correlate with neurologic symptoms due to the delay in lithium distribution from blood to the central nervous system (i.e., serum concentrations may be elevated before neurologic symptoms appear). Cardiac complications such as arrhythmias or significant hypotension are rare. If hypotension does occur it is generally secondary to volume depletion.

Early symptoms of chronic lithium toxicity can usually be treated by reduction or cessation of dosage of the drug and resumption of treatment at a lower dose after 24 to 48 hours. Whole bowel irrigation with a balanced polyethylene glycol-electrolyte solution (e.g., PegLyte) may help minimize lithium absorption. Activated charcoal does not adsorb lithium but may be of value if multiple drug ingestion is suspected. Measure serum lithium levels every 4 to 6 hours until the serum lithium level is below 2 mmol/L.

Maintain fluid and electrolyte balance. Maintain urine output and sodium excretion by administering iv sodium chloride. Administration of large amounts of sodium in the absence of sodium depletion has not been shown to be successful in speeding lithium excretion. Sodium bicarbonate, mannitol, loop and thiazide diuretics, carbonic anhydrase inhibitors or phosphodiesterase inhibitors are not recommended.

The definitive therapy for lithium intoxication is hemodialysis. Indications for hemodialysis include: potentially toxic exposures in patients with renal failure; neurologic dysfunction including altered mental status; acute ingestion with serum lithium concentration of ≥4.0 mEq/L; acute-on-chronic or chronic overdose with serum lithium concentration ≥2.5 mEq/L; and moderate to severe neurologic toxicity. Patients who may not be able to tolerate sodium repletion should also be considered for early hemodialysis.

Draw serum lithium levels immediately after hemodialysis and again 6 hours later. If either level is high or the patient continues to exhibit signs of neurotoxicity a second course of hemodialysis may be necessary.

Peritoneal dialysis is not indicated in the management of lithium toxicity in patients with normal renal function. It may be used as a temporizing measure in a patient with a functioning peritoneal dialysis catheter until hemodialysis can be started.