Catechol-O-methyltranseferase (COMT) Inhibitors


Entacapone, Opicapone, Tolcapone 


  Issues for Surgery


Risk of exacerbation of Parkinson’s Disease (PD) and akinesia if omitted1.

Reduced effectiveness of levodopa preparations if omitted.

Risk of parkinsonism-hyperpyrexia syndrome (PHS) if omitted, especially with combination products containing levodopa (see Further Information).

Increased sensitivity to inotropes and vasopressors if continued (see Interaction(s) with Common Anaesthetic Agents).


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue (including combination products)2, 3 – for tolcapone, consider checking LFTs (see Further Information).

Combination product: -

  • Stalevo® – contains entacapone, levodopa and carbidopa (see also Levodopa with Dopa-Decarboxylase Inhibitor Monograph).

To minimise disruption to the patient’s usual medication regime Parkinson’s medication can be given with a sip of water up until anaesthetic induction2.

If a long nil by mouth (NBM) period is anticipated post-operatively the patient’s specialist should be contacted pre-operatively for advice on alternative routes / medications4.

Post-operative Advice

Resume post-operatively at patient’s usual dose3.

If a long nil by mouth (NBM) period is anticipated or if there are concerns regarding enteral absorption alternative routes / medications should be considered2, 4 (see Further Information).


  Interaction(s) with Common Anaesthetic Agents


For general information regarding the use of anaesthetic agents in PD– see Parkinson’s Disease – A General Overview’.

Inotropes and Vasopressors

COMT inhibitors inhibit the enzyme which is involved in the metabolism of inotropes and vasopressors therefore it is predicted that their action may be potentiated2, 3, 5, 6, 7, 8, 9, 10, 11. Entacapone potentiated the increase in heart rate and arrhythmogenic effects of epinephrine / adrenaline and isoproterenol / isoprenaline in a study confirming this theory; similar effects are anticipated with other inotropes and vasopressors and other COMT inhibitors are predicted to interact similarly9.

The manufacturers advise caution when drugs known to be metabolised by COMT are given to patients taking COMT inhibitors – they specifically name epinephrine / adrenaline, dobutamine, dopamine, isoproterenol / isoprenaline and norepinephrine / noradrenaline5, 6, 7, 8, 9. Dose reduction and careful monitoring for increased inotrope or vasopressor adverse effects is advised9.


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


For general information regarding the use of antiemetics in PD – see Parkinson’s Disease – A General Overview’.

Iron

Entacapone formed chelates with iron in vitro. The clinical relevance of this is not known but it is recommended that entacapone and iron compounds should be administered at least 2 to 3 hours apart3, 5, 8, 9, 10. For combination products containing levodopa see also Levodopa with Dopa-Decarboxylase Inhibitor (DDI) monograph.


  Further Information


Tolcapone and Hepatotoxicity

Tolcapone has been associated with hepatotoxicity and acute liver failure. Liver function tests (LFTs) should be monitored every 2 weeks for the first year of treatment with tolcapone, every 4 weeks for the next 6 months and every 8 weeks thereafter. If recent LFTs are not available consider checking pre-operatively7, 8, 11.

Manufacturer advises treatment should be discontinued immediately if alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) exceed the upper limit of normal or if signs and symptoms of hepatic failure (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, right upper quadrant tenderness) develop7. COMT inhibitors prevent peripheral breakdown of levodopa increasing the amount reaching the brain8. If tolcapone is discontinued due to abnormal LFTs consult patient’s specialist as an increase in levodopa dose may be necessary7, 8.

Parkinsonism-Hyperpyrexia Syndrome (PHS)

Risk of PHS with combination products containing levodopa – see Levodopa with Dopa-Decarboxylase Inhibitor (DDI) monograph.

Symptoms associated with PHS were not reported in controlled trials in which entacapone was discontinued abruptly, however, isolated cases have been reported in practice following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic medications. Ideally withdrawal of COMT inhibitors should be slow; if symptoms still develop an increase in levodopa dose may be necessary3, 5, 11.

NBM Period and Alternative Routes

If there is significant post-operative nausea and vomiting, post-operative ileus or concerns about enteral absorption, the oral route is likely to be unreliable and may lead to suboptimal treatment and potentially PHS. Alternative routes / medications should be considered – see Parkinson’s Disease – A General Overview’.

Patients who do not rapidly regain the ability to take their usual PD medication should be seen by a PD Specialist Nurse or Movement Disorder Consultant at the earliest opportunity4.

Prescribing and Administration

Access to the correct medication / formulation at the correct time remains a problem for people with PD whilst they are in hospital4. Delayed doses can have serious implications (see PHS above). PD patients often have complex medication regimes; prescribers should take care to confirm the correct dose, formulation and time of administration with the patient or carer. The time of administration should be documented on the prescription chart and nursing staff should ensure that PD medications are given promptly.


  References


  1. National Institute of Health and Clinical Excellence (2017). NG71 Parkinson’s disease in adults. https://www.nice.org.uk/guidance/ng71 [Accessed on 9th June 2019]
  2. Chambers DJ. Sebastian J. and Ahearn DJ. Parkinson’s disease. BJA Education. 2017; 17:145-149
  3. Summary of Product Characteristics – Stalevo® (entacapone, levodopa and carbidopa) 100/25/200mg. Orion Pharma (UK) Limited. Accessed via www.medicines.org.uk 22/06/2019 [date of revision of the text February 2018]
  4. Brennan KA & Genever RW. Managing Parkinson’s disease during surgery. BMJ. 2010; 341:c5718
  5. Summary of Product Characteristics – Comtess® (entacapone) 200mg film-coated Tablets. Orion Pharma (UK) Limited. Accessed via www.medicines.org.uk 22/06/2019 [date of revision of the text December 2016]
  6. Summary of Product Characteristics – Ongentys® (opicapone) 50mg hard capsules. Bial Pharma Uk Ltd. Accessed via www.medicines.org.uk 22/06/2019 [date of revision of the text June 2016]
  7. Summary of Product Characteristics – Tamsar® (tolcapone) 100mg Tablets. Meda Pharmaceuticals. Accessed via www.medicines.org.uk 22/06/2019 [date of revision of the text September 2014]
  8. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 22nd June 2019]
  9. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 22nd June 2019]
  10. Entacapone. 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 18th June 2019]
  11. Tolcapone. 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 18th June 2019]