What are the pharmacokinetics of lithium in patients with bipolar affective disorder (BPAD), considering factors such as age, weight, renal function, and comorbidities?

Pharmacokinetics of Lithium in Bipolar Affective Disorder

Distribution and Elimination

Lithium distributes throughout total body water with a volume of distribution approximating total body water, and is primarily eliminated renally with a half-life of approximately 24 hours. 1

• Lithium is excreted proportionally to its plasma concentration, with renal excretion being the primary route and insignificant fecal elimination 1
• The drug decreases sodium reabsorption by renal tubules, which can lead to sodium depletion and requires patients to maintain normal salt intake and adequate fluid intake of 2500-3000 mL daily, particularly during initial stabilization 1

Factors Affecting Lithium Pharmacokinetics

Renal Function

• Renal clearance of lithium is directly proportional to glomerular filtration rate, making kidney function the most critical determinant of lithium elimination 1
• Declining kidney function toward end-stage renal disease necessitates lithium cessation due to accumulation risk and potential toxicity 2
• Diuretics and ACE inhibitors reduce renal clearance of lithium by causing sodium loss, increasing serum lithium levels and toxicity risk, requiring dose reduction and more frequent monitoring when used concomitantly 1

Age-Related Considerations

• Elderly patients require lower target plasma levels (0.5-0.8 mmol/L) in the first instance due to increased sensitivity to adverse effects, particularly neurotoxicity, and often respond to reduced dosages. 1, 3
• Younger adults can achieve desirable plasma lithium levels of 0.6-0.8 mmol/L with comparatively lower doses than middle-aged adults 3
• The elderly exhibit signs of toxicity at serum levels ordinarily tolerated by other patients 1

Disease State Effects

• Tolerance to lithium is greater during acute manic phases and decreases when manic symptoms subside, requiring dose adjustments as clinical state changes. 1
• Patients abnormally sensitive to lithium may exhibit toxic signs at serum levels of 1.0-1.5 mEq/L that are typically therapeutic in others 1

Therapeutic Drug Monitoring

Target Serum Concentrations

• For acute mania, target serum lithium levels of 1.0-1.5 mEq/L (or 0.8-1.2 mEq/L per some guidelines) are recommended, typically achieved with 600 mg three times daily. 1, 4
• For long-term maintenance therapy, desirable serum levels are 0.6-1.2 mEq/L, usually maintained with 300 mg three to four times daily. 1, 3
• The consensus across clinical practice guidelines establishes 0.6-0.8 mmol/L as the ideal lithium plasma concentration for maintenance monitoring 3

Sampling Timing

• Blood samples for serum lithium determination must be drawn 8-12 hours after the previous dose (trough levels) when lithium concentrations are relatively stable, immediately prior to the next dose. 1
• During acute phase treatment, serum levels should be determined twice per week until both serum level and clinical condition stabilize 1
• During maintenance therapy in uncomplicated cases, serum lithium levels should be monitored at least every two months 1

Dosing Formulation Considerations

Prolonged-Release vs Immediate-Release

• Prolonged-release (PR) formulations provide consistent serum lithium concentrations with fewer adverse events and improved adherence compared to immediate-release (IR) formulations. 5
• Single daily dosing with PR formulations may reduce the risk of long-term renal damage and increase compliance compared to multiple daily doses, without significant differences in plasma concentrations, adverse effects, or symptom recurrence 6, 5
• Multiple daily schedules maintain more constant plasma lithium concentrations than single daily regimens, which are associated with significant fluctuations throughout the day, though clinical outcomes remain equivalent 6

Drug Interactions Affecting Pharmacokinetics

• NSAIDs (particularly indomethacin and piroxicam) significantly increase steady-state plasma lithium concentrations, requiring close monitoring when patients initiate or discontinue NSAID use 1
• Neuromuscular blocking agents have prolonged effects when combined with lithium, requiring cautious administration 1
• Haloperidol combined with lithium has been associated with an encephalopathic syndrome in some patients, requiring close monitoring for early neurological toxicity 1

Conditions Requiring Dose Adjustment

• Protracted sweating or diarrhea decreases tolerance to lithium and requires supplemental fluid and salt administration 1
• Concomitant infection with elevated temperatures may necessitate temporary dose reduction or cessation 1
• Thyroid disorders do not contraindicate lithium use, but hypothyroidism occurring during treatment may require supplemental thyroid therapy while continuing lithium with careful monitoring 1

Critical Monitoring Parameters

• Baseline assessment before initiating lithium must include complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, and pregnancy test in females 4
• Ongoing monitoring every 3-6 months should include lithium levels, renal function (BUN, creatinine), thyroid function, and urinalysis 4, 3