Clozapine


  Issues for Surgery


Potential relapse of treatment resistant schizophrenia if stopped.

Central nervous system (CNS) depression (sedation), respiratory depression and hypotension if continued (see Interaction(s) with Common Anaesthetic Agents).


  Advice in the Perioperative period


Elective surgery

Stop 12 hours before operation to minimise the sedative and hypotensive effects without risking relapse1.

Consider checking clozapine levels (see Further Information).

For patients who may decide to quit smoking during the perioperative period see Further Information.

Emergency surgery

If there is insufficient time to follow the advice for elective surgery inform Anaesthetist about potential for intraoperative hypotension (see Interaction(s) with Common Anaesthetic Agents).

For patients who may decide to quit smoking or reduce their smoking during the perioperative period see Further Information.

Post-operative advice

Restart post-operatively when next dose due providing blood pressure normal.

If more than 48-hour gap in treatment clozapine dose will need re-titrating (see Further Information) 1.

If concerns regarding enteral absorption – consider checking clozapine levels (see Further Information).


  Interaction(s) with Common Anaesthetic Agents


Hypotension

Clozapine can increase the risk of hypotension when used concomitantly with inhalational or intravenous anaesthetics2, 3.

Clozapine has an alpha-adrenoceptor blocking effect, so it may reduce the blood pressure increasing effect of norepinephrine / noradrenaline 1, 3, 4, 5, 6, 7. Epinephrine / adrenaline should NOT be used as patients treated with clozapine may paradoxically experience hypotension when this is administered1, 3, 4, 5, 6, 7. This ‘reverse epinephrine effect’ has been attributed to beta2-mediated vasodilation in the face of profound alpha1-blockade7.

Low-dose vasopressin has been successfully used to treat severe intraoperative hypotension refractive to alpha-adrenergic agents in a patient on clozapine7.

Local Anaesthetics

Clozapine is metabolised through the same cytochrome enzymes as aminoamide local anaesthetics (e.g. lidocaine, bupivacaine, prilocaine, mepivacaine, ropivacaine, etidocaine). Potentially these agents may compete with clozapine for metabolism leading to increased levels of both clozapine and aminoamides1.

No problems are anticipated with amino ester local anaesthetics (e.g. chloroprocaine, amethocaine, tetracaine, cocaine), which are metabolised by plasma cholinesterase1.

CNS Depression (see also Interaction(s) with other Common Medicines used in the Perioperative Period)

Clozapine has CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as2: -

  • benzodiazepines
  • Inhalational anaesthetics and intravenous anaesthetics
  • local anaesthetics
  • opioids

(Consult British National Formulary for available drugs in each class)

Delayed Recovery
An isolated case report of delayed recovery after short duration anaesthesia has been noted in a patient given desflurane and nitrous oxide1, 8. Due its sedative properties clozapine has the potential to enhance the sedative effects of general anaesthetics, which may result in delayed recovery. However, there appear to be no reports of a problem in practice and so it would seem reasonable to conclude that, in most patients, any effect is modest8.

Seizure Threshold

Clozapine can lower the seizure threshold; concurrent use with medications that also lower the seizure threshold (e.g. anaesthetic agents, tramadol) may have an additive effect on the risk of seizure, particularly if clozapine levels are high1, 3.


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


Hypotension

Clozapine can increase the risk of hypotension when used concomitantly with droperidol or prochlorperazine2.

CNS Depression (see Interaction(s) with Common Anaesthetic Agents for information on opioids)

Clozapine has CNS depressant effects which may be additive with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine2.

Antimicrobials

Ciprofloxacin and erythromycin can lead to increased clozapine plasma levels1, 2, 8.

Myelosuppression
Concomitant use of clozapine with the following can increase the risk of myelosuppression2, 8: -

  • co-trimoxazole
  • linezolid
  • trimethoprim

Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring. Consult current product literature.

Seizure Threshold (see Interaction(s) with Common Anaesthetic Agents).


  Further Information


Restarting Post-operatively / Treatment Interruption

Tolerance to the sedative and hypotensive effects of clozapine is rapidly lost. If the break in treatment exceeds 48 hours do not restart at the patient’s usual dose. The patient’s Psychiatrist should be contacted urgently as the dose will need to be re-titrated under expert supervision1, 3.

Monitoring

Pre-operatively
The manufacturers recommend checking plasma clozapine level preoperatively (samples would need to be sent away for testing – follow local arrangements). If clozapine levels are high preoperatively seek advice from patient’s Psychiatrist as to whether the dose should be adjusted and monitor the patient for signs of toxicity (e.g. severe sedation, tachycardia, hypersalivation and hypotension1).

Smoking Cessation
Admission to hospital may result in smoking cessation or a reduction in smoking. This causes increased clozapine plasma levels1, 4, 5, 6 regardless of whether electronic cigarettes or nicotine replacement therapy are used1. Clozapine plasma levels should be monitored, as dose reduction (under the guidance of a Psychiatrist) may be necessary1.

Concerns Regarding Absorption
If there are concerns regarding absorption of oral medications it may be necessary to monitor clozapine levels during the admission - seek advice from Psychiatrist1.

Risk of Ileus / Constipation

Clozapine is associated with constipation, intestinal obstruction, faecal impaction and paralytic ileus so patients may be more likely to develop post-operative ileus.

Monitor closely and discontinue clozapine if ileus suspected1, 2, 4, 5, 6.

Opioids and anticholinergic medications (e.g. cyclizine) may exacerbate constipation. Consider prophylactic laxatives for patients susceptible to constipation or at increased risk of developing constipation (e.g. following abdominal or bowel surgery). Actively treat any constipation that develops1, 2, 4, 5, 6.

Thromboprophylaxis

Clozapine may increase the risk of venous thromboembolism; consider pharmacological thromboprophylaxis post-operatively1, 2, 4, 5, 6.

Patients newly started on clozapine

Where possible the manufacturers advise avoiding surgery during the first 3 months of clozapine treatment (titration period) because hypotension, sedation and tachycardia are most prominent during clozapine titration1.


  References


  1. Van Beelen AJ. & Jollie-Helthuis M for ZTAS. Zaponex® fact sheet – Clozapine during surgery and anaesthesia (2016).
  2. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 1st June 2019]
  3. Clozaril Patient Monitoring Service. Clozapine and general anaesthesia (2018) http://www.hcpinfo.clozaril.co.uk [Accessed on 1st June 2019]
  4. Summary of Product Characteristics – Clozaril® (clozapine). Mylan Products Limited. Accessed via www.medicines.org.uk 01/06/2019 [date of revision of the text December 2018]
  5. Summary of Product Characteristics – Zaponex® (clozapine). Leyden Delta BV. Accessed via www.medicines.org.uk 01/06/2019 [date of revision of the text December 2018] 
  6. Summary of Product Characteristics – Denzapine® (clozapine). Britannia Pharmaceuticals Limited. Accessed via www.medicines.org.uk 01/06/2019 [date of revision of the text March 2018]
  7. John A. Yeh C. Boyd J et al. Treatment of Refractory Hypotension With Low-Dose Vasopressin in a Patient Receiving Clozapine. Journal of Cardiothoracic and Vascular Anesthesia. 2010; 24(3):467-468
  8. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 1st June 2019]