What is the half-life of nortriptyline (tricyclic antidepressant) in adults?

Half-Life of Nortriptyline

Pharmacokinetic Parameters

The elimination half-life of nortriptyline in adults ranges from 14 to 51 hours under normal therapeutic conditions, with most patients experiencing a half-life of approximately 30-36 hours. 1

Key Clinical Considerations

Standard Therapeutic Dosing

• Under normal therapeutic conditions with doses of 10-25 mg daily, nortriptyline demonstrates a half-life of approximately 30-36 hours in most patients 2
• This relatively long half-life allows for once-daily or twice-daily dosing regimens 1
• Steady-state plasma concentrations are typically achieved within approximately 5-7 days (approximately 5 half-lives) 1

Factors Affecting Half-Life

Age and renal function significantly impact nortriptyline elimination, as metabolite clearance is ultimately dependent on renal elimination 3. Elderly patients may experience:

• Accumulation of hydroxy-metabolites due to reduced renal function 3
• Increased risk of cardiovascular and other toxicities from metabolite accumulation 3

Toxic Ingestions and Overdose

In massive overdose situations, nortriptyline pharmacokinetics become highly unpredictable and the half-life can be dramatically prolonged. 4

• A documented case demonstrated an elimination half-life of 184 hours (approximately 7.7 days) following a massive overdose of 2500 mg 4
• This represents more than a 3-fold increase compared to therapeutic dosing 4
• The prolonged half-life in overdose is attributed to:
  • Delayed absorption 4
  • Enterohepatic recirculation 4
  • Large volume of distribution 4
  • Saturable (capacity-limited) metabolism 4, 2

Capacity-Limited Metabolism

Nortriptyline exhibits dose-dependent (nonlinear) pharmacokinetics in some patients, even at therapeutic doses. 2

• One case report documented half-lives increasing from 30.4 hours at 10 mg every other day to 64 hours at 25 mg daily 2
• This capacity-limited metabolism means that small dose increases can result in disproportionately large increases in plasma concentrations 2

Drug Interactions

Drug interactions can dramatically prolong nortriptyline half-life through cytochrome P450 inhibition. 5

• Fluoxetine and its long-acting metabolite norfluoxetine can cause severe, slowly reversible inhibition of nortriptyline metabolism 5
• One case documented an amitriptyline (parent compound of nortriptyline) half-life of approximately 120 hours when combined with fluoxetine, even in a patient with normal CYP2D6 function 5

Clinical Implications for Discontinuation

When discontinuing nortriptyline, a gradual taper over 10-14 days is recommended to minimize withdrawal symptoms, similar to other antidepressants with moderate half-lives 6

Important Caveats

• Do not rely on standard pharmacokinetic parameters to guide clinical decisions in overdose situations 4
• In toxic ingestions, urine tricyclic antidepressant screens and QRS duration provide more reliable guidance than calculated half-lives 4
• Therapeutic drug monitoring should occur at steady state (approximately 1 week after stable dosing) with samples collected 12-16 hours after the last dose 7
• The therapeutic window for nortriptyline is narrow (50-150 ng/mL), making monitoring particularly important 1