Tricyclic Antidepressants (TCAs)


Amitriptyline, Clomipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine 


  Issues for Surgery


For depression - risk of withdrawal symptoms if omitted (see Further Information).

Lower doses (used for neuropathic pain, abdominal pain, migraine prophylaxis) - risk of loss of symptom control if omitted.

Risk of hypotension and cardiac arrhythmias if continued (see Interaction(s) with Common Anaesthetic Agents).

Potentiated effects of vasopressors if continued (see Interaction(s) with Common Anaesthetic Agents).


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue1.

Due to increased risk of arrhythmias and interactions with vasopressor drugs inform anaesthetist on the day of surgery if patient is taking a TCA 1, 2, 3, 4, 5, 6, 7, 8 (see Interaction(s) with Common Anaesthetic Agents).

Post-operative Advice

Patients Prescribed High Dose TCAs for Depression 

If a long Nil by Mouth (NBM) period is anticipated, or if there are concerns with enteral absorption, advice on alternative preparations / routes should be sought from a Psychiatrist.


  Interaction(s) with Common Anaesthetic Agents


General Anaesthetics

TCAs may increase risk of cardiac arrhythmias and hypotension during general anaesthesia1, 2, 3, 4, 5, 6, 7, 8, 9. There have been case reports of prolonged cardiac arrhythmias with concomitant use of nortriptyline with halothane and imipramine with halothane and pancuronium; however, it is thought to be a class effect9.

TCAs are expected to prolong the duration of barbiturate anaesthesia; however, as the dose should be titrated to response this should be managed by standard anaesthetic practice9.

Sympathomimetics

Vasopressors
Cardiovascular effects of adrenaline / epinephrine, isoprenaline, noradrenaline / norepinephrine and phenylephrine are potentiated in patients taking TCAs1, 2, 3, 4, 5, 6, 7, 8, 9, 10. TCAs inhibit the uptake of noradrenaline into adrenergic neurones, increasing the concentration outside the neurone. If direct-acting inotropes or vasopressors are given to a patient taking TCAs a grossly exaggerated response including hypertension and cardiac arrhythmias is observed. Conversely, the effects of indirectly-acting sympathomimetics are expected to be reduced by TCAs, but only a few reports of reduced efficacy with ephedrine have been noted9.

Whilst the manufacturers of some TCAs recommend concomitant administration of sympathomimetic agents is avoided4, 6, 7, 8, this is not thought to be necessary provided much reduced doses are used and titrated carefully against clinical response9.

Local anaesthetics
Reports of interactions with local anaesthetics containing adrenaline / epinephrine or noradrenaline / norepinephrine date from the 1960s and 1970s when the concentrations were higher than currently available preparations. The scarcity of recent reports indicates this reaction is rarely clinically important; however, as a reaction may rarely occur patients taking TCAs should be monitored for adverse cardiovascular effects if given local anaesthetics containing sympathomimetics9.

Central Nervous System (CNS) depression

Concomitant use of TCAs with anaesthetic agents, benzodiazepines or opioids may have an additive effect on CNS depression3, 5, 6.

CNS Excitation (Serotonin Syndrome)

Clomipramine and imipramine are predicted to have serotonergic effects9; amitriptyline has also been associated with serotonin syndrome11, 12. Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with other serotonergic medication. Symptoms of serotonin syndrome may occur if TCAs with serotonergic activity are given concomitantly with1, 9, 12: -

  • fentanyl
  • methadone
  • pentazocine
  • pethidine
  • tapentadol
  • tramadol

Patients should be monitored closely and the possibility of serotonin toxicity considered if patients experience altered mental state, autonomic dysfunction or neuromuscular adverse effects with concomitant treatment1.


  Interaction(s) with other Common Medicines used in the Perioperative Period


Analgesia

CNS Depression (see Interaction(s) with Common Anaesthetic Agents above)

Tramadol
TCAs can lower the seizure threshold; concurrent use with tramadol, which also lowers the seizure threshold, may have an additive effect on the risk of seizure9. In addition tramadol may increase the risk of serotonin syndrome1, 9 (see Interaction(s) with Common Anaesthetic Agents). Concomitant administration of tramadol with amitriptyline may result in opioid toxicity due to CYP2D6 inhibition2.

Nefopam
Concomitant administration of nefopam with TCAs may have an additive effect on the risk of seizures9 and is also expected to result in increased antimuscarinic side effects1, 3, 5, 6, 9.

QT-Interval Prolongation

TCAs may cause QT-interval prolongation1, 2, 3, 5, 6, 8. This is most notable with clomipramine; the risk with other TCAs is largely in overdose9. Co-administration with other medicines known to prolong the QT-interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase.

Medicines that may be used in the perioperative period that are known to prolong the QT-interval include9: -

  • ciprofloxacin*
  • clarithromycin*
  • domperidone - avoid
  • droperidol – avoid for clomipramine, other TCAs*
  • erythromycin (especially intravenous)*
  • granisetron – avoid for clomipramine if risk factors present, other TCAs*
  • haloperidol – avoid for clomipramine, other TCAs caution if risk factors present
  • loperamide (increased risk with high doses)*
  • ondansetron – avoid for clomipramine, other TCAs*
  • prochlorperazine*

*monitor ECG with concurrent use if risk factors for QT-interval prolongation also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia)

Increased Risk of Hyponatraemia (see also Further Information)

Concomitant use of SSRIs with NSAIDS may increase the risk of hyponatraemia1.

CNS Excitation (Serotonin Syndrome)

Opioids
For a discussion of opioids see under Interaction(s) with Common Anaesthetic Agents above.

Methylthioninium chloride (methylene blue)
There have been case reports of serotonin syndrome in patients taking clomipramine who were also given methylthioninium chloride9. The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission, they specifically name clomipramine9 but imipramine is also predicted to have serotonergic activity1, 9. If concurrent use is necessary the lowest possible dose of methylthioninium chloride should be given and the patients should be closely monitored for signs of CNS toxicity for 4 hours after administration9, 13. However, this advice is contested in one report which suggests even doses as low as 1mg/kg may be sufficient to inhibit monoamine oxidase-A, thus causing a reaction9.

Other medications
There is also an increased risk of developing serotonin syndrome when clomipramine or imipramine are used concurrently with the following1: -

  • granisetron
  • ondansetron
  • linezolid

Monitor patients for symptoms of serotonin syndrome such as fever, tremors, diarrhoea, and agitation. Concurrent treatment should be stopped if serotonin syndrome occurs1.

Increased Risk of Bleeding (see also Further Information)

Concomitant use of clomipramine with other medications that can increase the risk of bleeding e.g. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) may have an additive effect3.


  Further Information


Withdrawal

Abruptly stopping or interrupting treatment with TCAs is not recommended. The risk of withdrawal is increased if TCAs are stopped suddenly after regular administration for more than 8 weeks1. Withdrawal effects may occur within 5 days of stopping treatment, they are usually mild and self-limiting, but in some cases may be severe1. Withdrawal symptoms include malaise, chills, headache, increased perspiration, anxiety, agitation, sleep disturbance, hypomania, mania and cardiac arrhythmias10.

Hyponatraemia

Hyponatraemia, possibly because of inappropriate secretion of antidiuretic hormone has been associated with antidepressants. Whilst this is not common with TCAs caution is required in patients at increased risk of hyponatraemia, such as elderly, or volume depleted / dehydrated patients or patients treated with diuretics6, 12.

Bleeding 

Clomipramine has significant serotonergic activity and therefore may increase the risk of bleeding3 (see Selective Serotonin Reuptake Inhibitors monograph).

 

  References


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 21st July 2019]
  2. Summary of Product Characteristics – Amitriptyline 10mg Film-coated Tablets. Accord Healthcare Limited. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text October 2018]
  3. Summary of Product Characteristics – Clomipramine 10mg Capsules, Hard. Generics UK T/A Mylan. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text April 2016]
  4. Summary of Product Characteristics – Doxepin 25mg Capsules. Marlborough Pharmaceuticals Ltd. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text January 2014]
  5. Summary of Product Characteristics – Imipramine Tablets 10mg. Accord-UK Ltd. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text September 2018]
  6. Summary of Product Characteristics – Lofepramine 70mg Tablets. Accord-UK Ltd. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text December 2017]
  7. Summary of Product Characteristics – Nortriptyline 25mg Film-coated Tablets. ADVANZ Pharma. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text April 2019]
  8. Summary of Product Characteristics – Trimipramine 10mg Tablets. ADVANZ Pharma. Accessed via www.medicines.org.uk 21/07/2019 [date of revision of the text April 2019]
  9. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 21st July 2019]
  10. Amitriptyline. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. Electronic version. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com. [Accessed 21st July 2019]
  11. Bazire S. Psychotropic Drug Directory 2016. The Professionals’ Pocket Handbook and Aide Memoire. Dorsington: Lloyd-Reinhold Publications Limited. 2016.
  12. Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry. 13th ed. Chichester: Wiley- Blackwell; 2018.
  13. Summary of Product Characteristics – ProveBlue® (methylthioninium chloride) 5mg/ml solution for injection. Martindale Pharma. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text February 2018]