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

• Long N. TCA Toxicity. LITFL

References

• Katzung BG. Basic and Clinical Pharmacology. 14e. 2018: 537-550