Amitriptyline / nortriptyline

26 de January de 2021


Therapeutic action

The drugs are a part of detricyclic antidepressants group.This group of drugs has a low therapeutic index and many side effects, even at therapeutic levels, therefore its dosage should be maximum individualized. The drugs are secondary or tertiary amines. Tertiary amines are metabolized by several CYP450 whereas secondary ones are metabolized by CYP2D6 .

More information

FDA warns on the drug label for nortriptyline of the difference in the blood concentrations of the drug depending on the metabolizing phenotype concerning CYP2D6, which is highlighted in the following except:“The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hidroxylase) is reduced in a subset of the Caucasian population (about 7% – 10% of Caucasians are so called “poor metabolizers” … “Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of the drug metabolized by P450 2D6, the increase in plasma concentration can be small, or quite large (8 fold increase in the AUC of the TCA).”


Metabolismo de la amitriptilina
Metabolismo de la amitriptilina

Both of them, in practice, have CYP2D6 as the main metabolizing enzyme. Indeed, amitriptyline (terciary amine) is metabolized primarily through CYP2D6, and to a lesser extent through other CYP enzymes (2C9, 2C19, 3A4) which transforms it into nortriptyline, which is later metabolized mainly through CYP2D6. Nortriptyline (a secondary amine) is metabolized directly through CYP2D6 as the main pathway. The hydroxilated derivates generated by CYP2D6 have some pharmacologic action, although somewhat lower than the parent drug and are eliminated in urine a glucuronides, by means of the UGT (Uridin-Glucuoronyl-Transferase) enzymes in the phase II metabolism.

Both compounds act as moderate CYP2D6 competitive inhibitors. There are big differences in the plasma concentrations obtained by the different phenotypes.

Other factors to be considered

In case of patients who have a PM phenotype for CYP2D6, there have been reports of adverse effects consisting of dizziness and sedation. However, adverse effects can also be found in patients with an EM phenotype who take drugs that are competitive (or other kind) CYP2D6 inhibitors, which can be frequent because this CYP enzyme has low capacity (only 2% of all the CYP content) and there are lots of drugs whose phase I metabolism depends on CYP2D6: 26% of them. Also notice that in patients with the UM phenotype, the standard dose may not produce any therapeutic effect. The solution may be increasing the dose or using an antidepressant drug which is not metabolized through CYP2D6.


When amitriptyline is prescribed,it is convenientknow the phenotype of CYP2D6 and CYP2C19to titrate the dose correctly because it is the enzyme defining the rate of metabolism. It would be even simpler to administer nortriptyline to people who are PM for CYP2C19 as 80% of its metabolism is through CYP2D6. In people who are poor or ultrarrapid metabolizers for CYP2D6 and/or CYP2C19 consider alternative drugs that do not use this metabolic pathway, such as bupropion, citalopram or escitalopram or adjust the dose according to the genotype.In PMs for CYP2D6 or CYP2C19 the doses should be reduced by 30-50%. In IMs for CYP2D6 the conventional dose might be safe, but it would be prudent to reduce it by 20-25%, while in the case of CYP2C19 the intermediate metabolizer phenotype does not appear to be relevant and there is not necessary to take any action.In the case of an UM phenotype for any of the enzymes it is highly encouraged to use another drug. Increasing the dose might allow reaching the desired levels of amitriptyline and nortriptyline, but the accumulation of inactive metabolites might be cardiotoxic despite the lack of therapeutic action.In the case of variant genotypes for both genes, the scientific literature has scarce data due to the low frequency of these combinations. Below there is a transcription of the reccomendations of the Clinical Pharmacogenetics Implementation Consortium. (Hicks JK et al; 2013).


  • Hicks J.K. et al. (2013). Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 93(5):402-8.
  • Thieme D. et al. Correlation of inter-individual variations of amitriptyline metabolism examined in hairs with CYP2C19 and CYP2D6 polymorphisms. Int. J. Legal. Med. 122(2):149-55. Epub 2007 Nov 9.
  • De Leon J et al (2006). Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics; 47(1):75-85.
  • Gardiner SJ, Begg EJ. (2006). Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 58(3):521-90.
  • Steimer W et al (2005). Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem. 51(2):376-85.
  • Kirchheiner J. et al. (2004). Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry; 9(5):442-73.
  • Matthew V. Rudorfer and William Z. Potter. (1999). Metabolism of Tricyclic Antidepressants. Cellular and Molecular Neurobiology; 19 (3), 373-409.

Juan Sabater-TobellaDoctor of PharmacyEuropean Specialist in Clinical ChemistryAnd Laboratory Medicine (EC4)

Last modified: Sep 6, 2017 @ 09:59 am

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