TRICYCLIC ANTIDEPRESSANTS
TRICYCLIC ANTIDEPRESSANTS
- Drugs with low safety/therapeutic index (TCA poisoning can occur).
MOA:
- Acts by inhibiting serotonin & noradrenaline reuptake.
Steps:
- 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.
Metabolism:
- 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
- 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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