What is the half-life of amitriptyline?

Half-Life of Amitriptyline

The half-life of amitriptyline ranges from 12-36 hours, with an average of approximately 17 hours for the parent compound, while its active metabolite nortriptyline has a similar half-life of around 38 hours. 1, 2

Pharmacokinetic Profile

Amitriptyline demonstrates several important pharmacokinetic characteristics:

• Absorption and Distribution:

  • Good oral absorption
  • Extensive tissue distribution with high volume of distribution
  • Rapid distribution to the central nervous system
  • High plasma protein binding (90-99%)
  • Brain concentrations 10-40 times higher than blood levels 1

• Metabolism:

  • Undergoes extensive hepatic metabolism (first-pass effect)
  • Primarily metabolized by CYP2D6 and CYP2C19 enzymes
  • Converted to nortriptyline (active metabolite) mainly by CYP2C19
  • Additional metabolites include hydroxylated forms 1

• Elimination:

  • Terminal elimination half-life of parent compound: 12-36 hours
  • Nortriptyline half-life: approximately 38 hours 3
  • Requires metabolism for excretion

Clinical Implications of Amitriptyline's Half-Life

The relatively long half-life of amitriptyline has several important clinical implications:

1. Dosing Frequency:

   • Can be administered once daily, typically at bedtime
   • Steady state concentrations reached after approximately 5-7 days of consistent dosing

2. Pharmacodynamic Effects:

   • Pharmacodynamic half-life (135 hours) is significantly longer than the plasma half-life
   • Clinical effects may persist for 9-12 days (228-300 hours) after discontinuation 3
   • This extended pharmacodynamic effect should be considered when:
     • Switching medications
     • Evaluating for drug interactions
     • Managing overdose situations

3. Drug Interactions:

   • Inhibitors of CYP2D6/CYP2C19 can dramatically increase amitriptyline levels and extend half-life
   • Case reports show interactions with drugs like fluoxetine and terbinafine can extend the half-life to 120 hours or more 4, 5
   • Some drug interactions may persist for months after discontinuation of the interacting medication 5

4. Genetic Variations:

   • CYP2D6 and CYP2C19 polymorphisms significantly affect amitriptyline metabolism
   • Poor metabolizers (5-8% of Caucasians) may experience much longer half-lives
   • Ultra-rapid metabolizers (1-7%) may have shortened half-lives 1

Monitoring Considerations

• Therapeutic range for amitriptyline is 80-200 ng/ml
• Therapeutic drug monitoring is recommended in cases of:
  • Suspected non-compliance
  • Inadequate response
  • Suspected drug interactions
  • Presence of adverse effects
  • Patients with known genetic variations affecting metabolism 1

Practical Considerations

• When discontinuing amitriptyline, the prolonged pharmacodynamic effects should be considered
• Allow for adequate washout periods (at least 2 weeks) when switching to medications with potential interactions
• In cases of overdose, monitoring should continue well beyond the expected 5-6 half-lives due to the extended pharmacodynamic effects
• Elderly patients and those with hepatic impairment may experience longer half-lives and require dose adjustments

The significant difference between pharmacokinetic half-life and pharmacodynamic effects is a critical consideration when managing patients on amitriptyline therapy.