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
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.
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.
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
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.
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: -
(Consult British National Formulary for available drugs in each class)
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
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.
Ciprofloxacin and erythromycin can lead to increased clozapine plasma levels1, 2, 8.
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).
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.
Concerns Regarding Absorption
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.
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.