Tricyclic Antidepressants



  • Drugs with low safety/therapeutic index (TCA poisoning can occur).


  • Acts by inhibiting serotonin & noradrenaline reuptake.
  • NA & serotonin initially act on pre-synaptic α2 & 5HT receptors.
  • By inhibiting them, transmitter concentration is increased in synaptic cleft.  
  • Decreased firing of locus ceruleus (NA) & nucleus raphe Magnus (5HT).   

Long-term administration:

  • Results in desensitization of pre-synaptic α2 & 5HT receptors –> Enhanced transmission.
  • Thus, despite immediate inhibition of reuptake process, there is long latency (2-3 weeks) for anti-depressant action of TCA & SSRIs.


  • Metabolized in liver via demethylation.
  • Results in active metabolite formation.
    • Active metabolites of imipramine – Desipramine.
    • Active metabolites of amitriptyline – Nortriptyline.

Important drugs & characteristics:

  • Bupropion, imipramine, amitriptyline, trimipramine, lofepramine, amoxapine, clomipramine, maprotiline, doxepin, dothiepin etc.,
  • Bupropion MOA: 
    • Inhibits dopamine reuptake
  • Amoxapine MOA:
    • Acts by blocking D2-receptors & also inhibits NA uptake.
    • Metabolite of antipsychotic drug “loxapine”.
    • Risk of extrapyramidal symptoms & convulsion.
  • Imipramine – For nocturnal enuresis in children.
  • (Note: DOC for nocturnal enuresis – desmopressin)
  • Lofepramine -TCA with least cardiotoxic nature.

Actions of TCA’s:

  • Most drugs have powerful anti-cholinergic properties
    • Results in dry mouth, bad taste, blurring of vision, epigastric distress, constipation, urinary hesitancy (especially in males with enlarged prostate) & palpitation.
  • Weak α-blocking property.
  • Lowers seizure threshold (particularly bupropion, clomipramine & maprotiline 
  • Have antipsychotic property (amoxapine)

Adverse effects:

  • Weight gain (except bupropion)
  • Tremors & insomnia
    • Due to inhibition of pre-synaptic NT uptake.
    • Mainly amitriptyline.
  • Cause postural hypotension
    • Due to α1 adrenergic blockade
  • Risk of extrapyramidal symptoms & convulsion – 
    • Mainly Amoxapine.
  • Conduction defects, arrhythmias & hypotension – 
    • Due to inhibition of cardiac fast Na+ channels.
    • Mainly with amitriptyline & dosulepin.
  • Hyperthermia, flushing, mydriasis, paralytic ileus, urinary retention, sinus tachycardia – 
    • Due to inhibition of muscarinic ACh receptors
  • Sedation –
    • Due to H1 histamine receptor inhibition

Overdose manifestations:

  • Are mainly anticholinergic
    • Delirium
    • Urinary retention
    • Blurred vision
    • Constipation
    • Cardiac arrhythmia, at toxic levels.

Exam Important


  • Tricyclic antidepressants are drugs with low safety/therapeutic index.
  • TCA acts by inhibiting serotonin & noradrenaline reuptake, particularly on
  • On long-term administration of TCA, desensitization of pre-synaptic α2 & 5HT receptors occurs resulting in enhanced transmission.
  • Despite immediate inhibition of reuptake process, there is long latency (2-3 weeks) for anti-depressant action of TCA & SSRIs, mainly due to desensitization of pre-synaptic α2 & 5-HT receptors on long-term administration.
  • Active metabolite of imipramine is desipramine.
  • Active metabolite of amitriptyline is Nortriptyline.
  • Bupropion acts by inhibits dopamine reuptake.
  • Amoxapine acts by blocking D2-receptors & also, inhibits NA uptake.
  • Amoxapine is a metabolite of antipsychotic drug “loxapine”.
  • Imipramine is useful in nocturnal enuresis in children.
  • Most TCA’s have powerful anti-cholinergic characteristics, resulting in dry mouth, bad taste, blurring of vision, epigastric distress, constipation, urinary hesitancy (especially in males with enlarged prostate) & palpitation.
  • Bupropion, clomipramine & maprotiline lowers seizure threshold.
  • Amoxapine has antipsychotic property.
  • TCA with least cardiotoxic property is Lofepramine.
  • Tremors & insomnia are caused by TCA, due to inhibition of pre-synaptic NT uptake.
  • TCA causes postural hypotension, due to  α1 adrenergic blockade.
  • There is risk of extrapyramidal symptoms & convulsion, mainly because of Amoxapine
  • TCA causes conduction amitriptyline defects, arrhythmias & hypotension, due to inhibition of cardiac fast Na+ channels.
  • Among TCA drugs, amitriptyline causes arrhythmia, on toxic dosage.
  • TCA drugs cause hyperthermia, flushing, mydriasis, paralytic ileus, urinary retention, sinus tachycardia, due to inhibition of muscarinic ACh receptors.
  • TCA drugs are sedative in nature, mainly due to H1 histamine receptor inhibition.
  • TCA overdose manifestations are mainly anticholinergic.


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