Introduction to TCAs Pharmacology

TCAs are used in the treatment of depression, hence their name – tricyclic antidepressants. They are also used in the treatment of neuropathic pain, even though they are not strictly licensed for this indication.

Examples of tricyclic antidepressants include:

  • Amitriptyline
  • Nortriptyline
  • Maprotiline (often classified as tetracyclic)
  • Dosulepin (not available in US)
  • Doxepin
  • Imipramine
  • Trimipramine
  • Clomipramine

Though TCAs are mostly used to treat depression, they have also been used to treat anxiety disorders, as well as panic disorder. For example – clomipramine is used to treat depression, OCD, panic disorder and chronic pain.

TCAs are often considered for depression after other, first-line agents have been used – such as SSRIs.

Mechanism of action

Tricyclic antidepressants work as serotonin and norepinephrine reuptake inhibitors (SNRIs).

By inhibiting their reuptake, more serotonin and norepinephrine lingers within the synaptic cleft, available to bind to postsynaptic receptors and trigger their neuronal effects.

However, TCAs do not evenly inhibit reuptake of these two neurotransmitters. Some drugs preferentially inhibit serotonergic reuptake, whereas other TCAs preferentially inhibit norepinephrine reuptake:

Preferential reuptake of serotonin (by at least 10-fold) [“TIC”]

  • Trimipramine
  • Imipramine
  • Clomipramine

Preferential reuptake of norepinephrine (by at least 10-fold) [“MaN”]

  • Maprotiline
  • Nortriptyline

Relatively equal inhibition [“ADD”]

  • Amitriptyline
  • Doxepin
  • Dosulepin

In addition, TCAs don’t limit their inhibition to serotonin and norepinephrine receptors. Depending on the TCA in question, they can also inhibit:

  • Muscarinic receptors
  • Histamine receptors
  • Adrenergic receptors – mostly alpha-1 and alpha-2
  • Dopamine receptors – mostly D2

As a result, tricyclic antidepressants are associated with a diverse range of potential side effects.

Side effects

Most commonly experienced side effects are related to the antimuscarinic action of TCAs:

  • Dry mouth / nose
  • Blurred vision
  • Reduced GI motility / constipation
  • Urinary retention

Sedation and hypotension are linked to their inhibition of H1 and alpha-1 receptors.

Other side effects include:

  • Convulsions
  • QT prolongation
  • Arrythmias
  • Appetite / weight fluctuations
  • Sexual dysfunction

TCAs in overdose are associated with hypotension, arrhythmias, seizures, respiratory failure and coma.

Sudden withdrawal from TCAs can induce:

  • GI upset
  • Flu-like symptoms
  • Insomnia
  • Anxiety
  • Headache
  • Motor disturbances
  • Delirium / hallucinations

TCAs should be withdrawn gradually, over time, to eliminate these risks.

Clinical Considerations

When we talk about the clinical pharmacology of TCAs, we need to think about the following factors:

  • That TCAs should be used with caution in patient groups more likely to experience side effects. For example – the elderly, patients with cardiovascular disease or who suffer from seizures; or in patients with established constipation, prostatic hypertrophy or elevated intraocular pressure. Antimuscarinic effects can worsen these clinical states.
  • That MAO inhibitors should not be taken with TCAs; a combination which increases the risk of developing serotonin syndrome.
  • Given that TCAs have antimuscarinic, hypotensive and sedative effects – these effects are worsened when taken with other drugs that also have one or more of these properties.
  • TCAs are usually prescribed as second-line agents in treating depression. First-line agents include SSRIs – which are better tolerated and have a lower side effect risk profile.
  • That is takes many weeks for full antidepressant effect to manifest. Patients should not anticipate immediate relief of their symptoms. Patients should also be informed not to suddenly stop treatment as it may precipitate withdrawal symptoms (listed above).
  • That when used to treat neuropathic pain, doses are much lower. For example – starting dose for depression with amitriptyline is 75mg whereas, for neuropathic pain, it is 10mg to be taken at night.
  • Amitriptyline, imipramine and doxepin are more likely to cause weight gain and sleepiness.

Not everyone responds the same way to an antidepressant medicine.

Some patients respond to one drug, other patients respond to another. Similarly, some patients experience more side effects even if they have been prescribed the same drug. There are many variables at play – including genetic factors – that influence these responses.

Doctors take these factors into consideration, alongside symptoms and previous history of antidepressant use, to find the best antidepressant for the patient. Often, much experimentation is required before the patient, and the doctor, find the most optimum solution.

That concludes our review of the pharmacology of TCAs. For even more facts and quiz questions about TCAs pharmacology, register with PharmaFactz today. Check back to our pharmacy blog soon for even more great drug summaries!