Pharm 101: Tricyclic Antidepressants

Examples

Amitriptyline
Clomipramine
Imipramine


Pharmacodynamics
  • Antidepressant activity relates to inhibition of serotonin (SERT) and noradrenaline (NET) reuptake
  • Also potent antagonists of ACh M (acetylcholine muscarinic), histamine (H1) receptors and alpha-1 receptors (peripheral post-synaptic)
  • Increases the amount of serotonin and noradrenaline in certain parts of the brain (cortex and limbus)
  • Also blocks Na and K channels
  • Some blockade of 5-HT2 receptor

Pharmacokinetics
  • Well absorbed
  • Bioavailability 40-50%
  • High plasma protein binding
  • Large volume of distribution (5-30L/kg). Tissue concentrations are high especially in well perfused organs such as the heart and brain.
  • Long half life
  • Extensive hepatic metabolism via demethylation, aromatic hydroxylation, and glucuronide conjugation
    • Substrate of CYP2D6 system, therefore serum levels substantially influenced by concurrent administration of drugs such as fluoxetine
  • Only 5% excreted unchanged in urine

Clinical uses
  • Depression unresponsive to SSRI/SNRI
  • Neuropathic pain
  • Chronic pain
  • Enuresis
  • Insomnia

Adverse effects
  • Anticholinergic effects
  • Postural hypotension due to alpha-blocking effect
  • Weight gain and sedation due to H1 antagonism
  • Arrhythmogenic at higher doses
  • Sexual effects
  • Discontinuation syndrome characterised by cholinergic rebound and flu-like symptoms

Precautions
  • Concurrent administration with:
    • CYP2D6 inhibitors may enhance toxicity
    • Benzotropine or diphenydramine may cause additive anticholinergic or antihistamine effects
    • Antihypertensives may exacerbate postural hypotension induced by TCAs

TCA overdose
  • More than 15-20mg/kg is lethal
  • Anticholinergic findings are common even at moderate doses (tachycardia, dilated pupils, dry mouth)
  • Centrally mediated agitation and seizures may be followed by CNS depression and hypotension
  • Causes Na channel blockade
  • Cardiac:
    • Tachycardia
    • Hypotension (alpha blockade, impaired contractility)
    • ECG – prolonged PR, widened QRS (Na blockade), prolonged QT (K blockade), VT, VF
  • CNS:
    • Drowsiness
    • Delirium (due to anti-cholinergic effects)
    • Seizures
    • Coma
  • Anti-cholinergic:
    • Agitation
    • Delirium
    • Mydriasis
    • Dry, warm, flushed skin
    • Urinary retention
    • Ileus

Further reading

References

Pharm 101 700

Pharmacology 101

Top 200 drugs

MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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