The inhibition of human neutrophil phagocytosis and oxidative burst by tricyclic antidepressants.
BACKGROUND
Tricyclic antidepressants are being investigated as long-acting analgesics for topical application in wounds or IV for postoperative pain relief. However, it remains unclear if tricyclic antidepressants affect the host defense and if reported toxic effects on neutrophils are of relevance in this setting. We therefore investigated the effects of amitriptyline, nortriptyline, and fluoxetine on human neutrophil phagocytosis, oxidative burst, and neutrophil toxicity in a human whole blood model.


METHODS
Heparinized blood samples from healthy volunteers were incubated with amitriptyline, nortriptyline, or fluoxetine (10(-6) to 10(-3) M) for 0, 1, or 3 h. Staphylococcus aureus in a bacteria:neutrophil ratio of 5:1 and dihydroethidium (for the determination of oxidative burst) were added. Phagocytosis was stopped after 5, 10, 20, and 40 min. After lysis of red blood cells, samples were analyzed by flow cytometry.


RESULTS
In concentrations up to 10(-4) M, none of the compounds affected neutrophil phagocytosis and oxidative burst. At 10(-3) M, all three compounds were highly toxic for neutrophils. Amitriptyline preserved morphological integrity, but completely suppressed neutrophil function. Nortriptyline and fluoxetine caused a marked disruption of neutrophils. The effects of the investigated antidepressants were not time-dependent.


CONCLUSIONS
Phagocytosis and intracellular host defense are largely unaffected by antidepressants in concentrations of 10(-4) M and below. Our results confirm that antidepressants are highly toxic to neutrophils in millimolar concentrations. The neurotoxic effects and clinical side effects, but not effects on neutrophil functions, therefore, are likely to be the limiting factors in using antidepressants as analgesics.
Ploppa
Annette
A
Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72 076 Tuebingen, Germany. annette.ploppa@uni-tuebingen.de
Ayers
Donald M
DM
Johannes
Tanja
T
Unertl
Klaus E
KE
Durieux
Marcel E
ME
D000639:Amitriptyline / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009661:Nortriptyline / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects*; D016897:Respiratory Burst / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013211:Staphylococcus aureus
D000639:Amitriptyline; D000779:Anesthetics, Local; D000929:Antidepressive Agents, Tricyclic; D005473:Fluoxetine; D009661:Nortriptyline; D017367:Selective Serotonin Reuptake Inhibitors