# 20 - A. Tricyclic antidepressants

# A. Tricyclic antidepressants:

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4. Clinically relevant kinetics and interactions: 
A. Tricyclic antidepressants: 
 The tricyclics are orally well absorbed but have variable time to achieve peak plasma 
concentration (1 to 12 h). 
 Many of them have active metabolites – see table below. 
 Nearly 7-9% Caucasians are slow metabolizers (measured by debrisoquin hydroxylation) of 
tricyclics due to CYP2D6 polymorphism (Up to a 40 times difference in plasma TCA 
concentrations can occur as a result). 
 Children clear more tricyclics from their body whereas the elderly clear less. 
 Most tricyclics have a long half-life (close to 24 h) that allows once-daily dosing. They readily 
cross lipid barriers such as blood-brain barrier and placenta. 
 They are extensively bound to plasma proteins e.g. Imipramine 80-95%. 
 For TCAs plasma (not serum) levels are measured to assess therapeutic dosing. The levels are 
determined after 5-7 days when steady state is reached, and 8-12hrs after last dose to avoid 
false peaks earlier when absorption is occurring. A sigmoidal curve where proportional doseresponse plateaus at a particular dose is noted for imipramine and desipramine. For 
nortriptyline a clear therapeutic window is seen between 50 to 150ng/ml. This inverted U is 
not due to decreased responsivity secondary to side-effects. 
 
 
 
 
 
 
 Amitriptyline and clomipramine decrease the metabolism of morphine and may 
contribute to opioid toxicity through UDP glucuronyl transferase interaction. (Chadwick 
2005) 
 
 
 
 
 
Antidepressant 
Active metabolite 
Imipramine 
desipramine 
Amitriptyline 
nortriptyline 
Trazodone, nefazodone 
mCPP 
Fluoxetine 
norfluoxetine 
Sertraline 
desmethylsertraline

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Drugs 
Mechanism 
Effect 
Quinidine, cimetidine, 
fluoxetine, paroxetine, 
phenothiazines, disulfiram, 
methylphenidate 
Inhibit TCA metabolism 
Increase plasma TCA levels 
Smoking, phenytoin, 
carbamazepine, OC pills and 
barbiturates 
Induce metabolism 
Reduce TCA levels 
Phenothiazines 
Mutual inhibition of metabolism 
Both antipsychotic and TCA levels 
increase 
Anticoagulants 
TCAs increase warfarin levels 
High risk of bleeding 
Clonidine 
TCAs reduce clonidine levels 
Hypertensive crisis 
MAOIs 
Synergistic serotonergic 
enhancement esp. clomipramine 
TCAs reduce tyramine entry via 
monoamine reuptake channels 
Higher risk of serotonin syndrome 
Lower risk of cheese reaction 
l-dopa 
TCAs reduce absorption of l-dopa 
Lowers l-dopa efficacy in Parkinsonism 
Morphine 
Amitriptyline and clomipramine 
decrease the metabolism through 
UDP glucuronyl transferase 
interaction 
Increased opioid toxicity