TRICYCLIC ANTI-DEPRESSANTS

  • Need to know the mechanism of toxicity of TCAs and the treatment.
Structure/Class
  1. Examples of TCAs are amitriptyline and imipramine
Pharmacodynamics
  1. The main anti-depressant activity is from SERT and NET blockade and therefore increased serotonin and increased noradrenaline concentration at the neuronal synapse. However, these drugs are dirty drugs and have muscarinic blockade, alpha-blockade, histaminergic blockade and sodium channel blockade properties. Note that TCAs do not have dopaminergic blockade and therefore do not cause Parkinsonian symptoms.
Receptor Effect
Anti-muscarinic Dry mouth, constipation, etc. (Remember blind as a bat, mad as a hatter, red as a beet, hot as a bare, dry as a bone, the bladder and bowel lost its tone and the heart runs alone)
Alpha-blockade Profound hypotension
Na+ channel blockade Widened QRS (and correspondingly, long QT). Other conduction defects may be seen.
H1-receptor blockade Sedation
Absorption/administration
  1. PO
Distribution
  1. Well absorbed from GIT
  2. Highly protein bound, and large Vd (5-30L/kg) à non-dialysable toxin
Metabolism
  1. Hepatic, by CYP systems
    • CYP inhibitors (e.g. fluoxetine, amiodarone and cimetidine) may prolong its effects.
Excretion
  1. Mainly in urine
Indications
  1. Depressive disorders
  2.  Pain – especially neuropathic
  3. Trigeminal neuralgia
Contraindications
  1. Absolute CI with MAO-I
    • Causes a life threatening serotonin syndrome, characterized by:
      1. Cognitive impairment: delirium, coma
      2. Autonomic instability: hypertension, tachycardia, sweating
      3. Somatic symptoms: myoclonus, hyper-reflexia, tremor

[Note that serotonin syndrome is thought to be due to overstimulation of the serotonin receptors in the medulla/central gray nuclei]
Special precautions
Interactions
  1. Additive sedative effects, especially with other anti-histaminergic/anti-psychotic drugs.
  2. Enzyme inhibitors (e.g. cimetidine and fluoxetine) will increase levels, while
  3. Enzyme inducers (e.g. phenobarbital, smoking) will decrease levels.
  4. Note that usage of concurrent sympathomimetic drugs will cause hypertension (Due to decreased uptake of noradrenaline from NET blockade)
Adverse events
  1. As stated above – important ones are CNS and CVS toxicity
Dosing/administration
Toxicology
  1. Use sodium bicarbonate as the antidote
    • The main effect of this drug is competition at the sodium channel and also to alkalinize the patient.
    • Aim for pH ~7.5, QRS <0.20 and Na 155-160
Withdrawal syndrome
Special notes