Lithium Pharmacokinetics and Drug Interactions Study Notes

Lithium Pharmacokinetics and Drug Interactions

Introduction

  • Lithium (marketed as Eskalith®) is considered the gold standard treatment for Bipolar Disorder and effectively reduces suicide risk.

  • In the U.S., prescribing rates of lithium have decreased to around 15% due to the approval of SGAs (Second Generation Antipsychotics) for treating Bipolar Disorder (both manic and depressive episodes).

  • Therapeutic Drug Monitoring (TDM) is crucial for lithium due to its narrow therapeutic window, making it less commonly prescribed in primary care settings.

  • Patients may discontinue SGAs due to metabolic-related adverse drug reactions (ADRs).

Objectives

  1. Identify at least four clinically significant situations (such as drug interactions or disease states) that impact lithium pharmacokinetics and pharmacodynamics.

  2. Detail strategies to avoid treatment failure or toxicity in identified clinical situations, focusing on dosage, frequency, and therapeutic ranges.

  3. Explain the necessity of waiting 12 hours before determining serum lithium concentrations and how changes in dosage schedules may affect blood levels.

  4. Define an acceptable targeted therapeutic range for lithium serum concentrations.

  5. Discuss practical applications of therapeutic drug monitoring in patient care management.

Lithium Kinetics (ADME)

Absorption

  • Peak Plasma Concentration (Cmax):
      - Tablets/capsules: 1-3 hours
      - Solution: 15-45 minutes
      - Sustained-release products: 4-5 hours

  • Food Effects: Food intake decreases the rate of absorption.

  • Bioavailability: Sustained-release formulations exhibit a slight decrease in bioavailability compared to immediate-release forms.

Distribution

  • Pharmacokinetic Model: Lithium follows a two-compartment open pharmacokinetic model; it is not protein-bound and has uneven distribution across various body compartments such as:
      - Brain
      - Spinal fluid
      - Saliva
      - Thyroid gland
      - Bone
      - Kidney
      - Erythrocytes

  • Distribution Phases:
      - Plasma distribution phase lasts 6-10 hours.
      - Intracellular distribution phase takes 25-30 hours, with steady state reached in 3-10 days.

  • Neurotoxic Effects: These effects are attributed to intracellular concentrations of lithium, which crosses the placenta and can concentrate in breast milk at levels up to half of maternal plasma levels.

Factors Affecting Distribution

  • Antipsychotics can influence intracellular lithium storage and transport into cells, potentially leading to toxicity.

  • Geriatric Considerations: Older adults often have a decreased volume of distribution affecting lithium pharmacokinetics.

Clearance

  • Lithium is eliminated unchanged by the kidneys, with approximately 80% passively reabsorbed in the proximal tubules and not reabsorbed in the distal tubules.

  • Glomerular Filtration Rate (GFR): Typically averages 20-30% (approximately 10-40 mL/min).

Factors Affecting Clearance

  1. Sodium Balance:
       - Negative sodium balance decreases lithium clearance due to reduced sodium intake and extra-renal sodium loss (e.g., heavy sweating, vomiting, diarrhea).

  2. Renal Impairment: Impairs lithium clearance.

  3. Geriatric Factors: Lithium clearance decreases with age.

Drug Interactions Affecting Lithium Clearance

  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
      - NSAIDs, particularly those inhibiting prostaglandin synthesis (like Cox2 inhibitors), may reduce lithium clearance by decreasing renal blood flow.
      - Note: Sulindac may have lesser interactions due to kidney metabolism; aspirin has minimal effects.

  • Thiazide Diuretics: Such as Hydrochlorothiazide decrease lithium clearance.

  • ACE/ARB Inhibitors: Medications like Lisinopril and Losartan affect lithium clearance.

  • Calcium Channel Antagonists: Such as Amlodipine impact lithium serum concentrations.

  • Other Interactions:
      - Theophylline, Acetazolamide, Spironolactone, and sodium bicarbonate also impact lithium clearance.

Condition-Related Clearance Factors

  • Pregnancy: Increases lithium clearance due to physiological changes.

  • Pediatrics: Varied clearance rates compared to adults.

  • Dialysis: Affects lithium levels significantly:
      - Hemodialysis: 50 mL/min clearance
      - Peritoneal dialysis: 13-15 mL/min clearance.

Diabetes Insipidus and Lithium

  • Lithium inhibits antidiuretic hormone (ADH), resulting in decreased lithium clearance and altered concentrating ability. This can lead to elevated serum lithium levels and toxicity due to toxic effects on distal tubules, where lithium concentration is high.

  • Renal Diurnal Variation: There is a decrease in lithium clearance at night, with renal function highest in the afternoon to early evening.

Therapeutic Drug Monitoring (TDM)

Monitoring Protocols

  • Serum Lithium Concentration Monitoring:
      - Samples are taken 12 hours after dosing: before the morning dose and 10-12 hours after the last evening dose.

  • Frequency of Monitoring:
      - First week of treatment: every 3-5 days.
      - After dosage changes: again in 3-5 days.
      - For clinically stable patients on the same dose—retesting occurs every 4 weeks.
      - If the patient remains stable at the same dose, retesting frequency can shift to every 1-3 months during the first year, then annually for stable patients.

Other Monitoring Considerations

  • Increased monitoring is necessary with dietary changes, medication additions (especially diuretics, NSAIDs), and during pregnancy, with bi-weekly checks until a new steady state is established. Adjustments to the lithium dose are made accordingly.

Lithium Pharmacodynamics and Treatment Responses

  • Initial Response to lithium typically occurs within 1-3 weeks.

  • Treatment Response takes about 6-8 weeks.

  • Target Therapeutic Range for serum lithium concentrations:
      - Acute symptoms: 0.8 - 1.4 mEq/L
      - Maintenance: 0.6 - 1.2 mEq/L

Adverse Drug Reactions (ADRs) and Toxicity

  • Common Adverse Effects:
      - Gastrointestinal issues (nausea, vomiting, diarrhea), alopecia, acne, weight gain, hypothyroidism, and polyuria.

  • Lithium Toxicity Symptoms:
      - < 2 mEq/L: Nausea, vomiting, diarrhea, tremor, drowsiness.
      - 2 - 3 mEq/L: Ataxia, blurred vision, vertigo, slurred speech, hypertonia, dysarthria, confusion.
      - > 3 mEq/L: Seizures, arrhythmias, hypotension, and coma.

Lithium Dosing Methods

Methods Overview

  • Fixed Dose (Titration) Method:
      - Initial dose is 300 mg orally three times daily for 3-7 days, then increased to 600-900 mg orally three times daily.
      - Required monitoring includes BUN, Serum Creatinine, and calculating Estimated Creatinine Clearance (CrCl).
      - It is estimated that each 8 mEq (or 300 mg) of lithium increases the serum concentration by 0.2 - 0.4 mEq/L.

Advantages and Disadvantages

  • Advantages: Simple to initiate and commonly utilized.

  • Disadvantages: Variability among patients and potential delays in achieving therapeutic concentrations.

A-Priori Dosing Methods

  • These methods calculate doses based on population averages, taking factors such as weight, age, and renal function into account.

Specific Calculating Methods

  • Citations for specific kinetic model methods like those by Pepin, Zetin, and Winter are available upon request for more detailed insights.

Predictive Dosing Methods

  • Predictive (Single-point) methods utilize a standardized loading dose alongside serum levels and specific patient kinetics to tailor dosing.

Specificity of Predictive Methods

  • Citations for methods developed by Cooper and Perry are also available upon request to understand their importance in clinical settings.