10.2 Internal Medicine Drugs: Endocrine, Respiratory, Psychiatric and Antiepileptic Agents and Their Anaesthetic Interactions
Key Takeaways
Sodium-glucose co-transporter 2 (SGLT2) inhibitors can cause euglycaemic diabetic ketoacidosis; UK guidance omits them on the day before and the day of surgery, while US labelling advises stopping 3 days before (4 days for ertugliflozin).
Non-selective monoamine oxidase inhibitors interact dangerously with pethidine, tramadol, dextromethorphan and methadone (serotonin syndrome) and with indirectly acting sympathomimetics such as ephedrine (hypertensive crisis).
Lithium has a narrow therapeutic range (about 0.4-1.0 mmol/L), prolongs neuromuscular blockade, and its levels rise with dehydration, NSAIDs, ACE inhibitors and thiazide diuretics.
Enzyme-inducing antiepileptics such as carbamazepine and phenytoin increase requirements for non-depolarising neuromuscular blockers and opioids and accelerate the metabolism of many drugs.
Antiparkinsonian drugs should be continued perioperatively because omission can precipitate rigidity and a neuroleptic malignant-like syndrome, and dopamine antagonists such as metoclopramide and haloperidol should be avoided.
10.2 Internal Medicine Drugs: Endocrine, Respiratory, Psychiatric and Antiepileptic Agents and Their Anaesthetic Interactions
Why These Drugs Matter
EDAIC Paper A tests the pharmacology of drugs used in internal medicine, and Paper B tests their perioperative management. Most interactions follow a few principles: enzyme induction or inhibition, additive effects on the central nervous system or QT interval, and drugs that alter catecholamine or serotonin handling.
Drugs for Diabetes
| Class | Examples | Mechanism | Perioperative points |
|---|---|---|---|
| Biguanide | Metformin | Reduces hepatic glucose output, improves insulin sensitivity | Low hypoglycaemia risk; omit if contrast or acute kidney injury risk, or on the day of surgery when a meal is missed (local protocols vary) |
| Sulphonylureas | Gliclazide, glibenclamide | Close beta-cell ATP-sensitive potassium channels, releasing insulin | Hypoglycaemia risk; omit on the morning of surgery |
| SGLT2 inhibitors | Dapagliflozin, empagliflozin | Glycosuria by blocking renal glucose reabsorption | Euglycaemic ketoacidosis; omit the day before and the day of surgery; check ketones if unwell |
| DPP-4 inhibitors | Sitagliptin | Prolong incretin action | Low risk; may continue |
| GLP-1 receptor agonists | Semaglutide, liraglutide, tirzepatide (dual) | Increase insulin secretion, slow gastric emptying | Delayed gastric emptying and aspiration risk; follow current society guidance on withholding and consider gastric ultrasound or rapid sequence induction |
| Insulin | Basal and bolus regimens | Replacement | Continue long-acting basal insulin at about 80% of the usual dose; use a variable-rate infusion for long fasting |
Thyroid Drugs
- Levothyroxine: half-life about 7 days, so a missed dose on the day of surgery is harmless.
- Carbimazole and propylthiouracil (PTU) inhibit thyroid peroxidase. PTU also inhibits peripheral conversion of T4 to T3 and is preferred in the first trimester of pregnancy and thyroid storm. Agranulocytosis is a rare serious adverse effect of both.
- Beta-blockers (propranolol) control adrenergic symptoms and reduce peripheral T4-to-T3 conversion.
- Iodine (Lugol's solution) acutely inhibits hormone release (Wolff-Chaikoff effect) and reduces gland vascularity before thyroidectomy.
Corticosteroids
| Steroid | Relative glucocorticoid potency | Relative mineralocorticoid potency | Equivalent dose |
|---|---|---|---|
| Hydrocortisone | 1 | 1 | 20 mg |
| Prednisolone | 4 | 0.8 | 5 mg |
| Methylprednisolone | 5 | Minimal | 4 mg |
| Dexamethasone | 25-30 | Negligible | 0.75 mg |
| Fludrocortisone | 10 | 125-250 | Used for mineralocorticoid replacement |
Patients on long-term steroids need perioperative cover, typically hydrocortisone 100 mg at induction followed by an infusion or regular doses for major surgery.
Respiratory Drugs
- Beta-2 agonists (salbutamol, salmeterol): bronchodilation through cyclic AMP; cause tachycardia, hypokalaemia and lactic acidosis at high doses.
- Antimuscarinics (ipratropium, tiotropium): block M3 receptors on airway smooth muscle.
- Inhaled corticosteroids: reduce airway inflammation; high doses can suppress the adrenal axis.
- Theophylline and aminophylline: non-selective phosphodiesterase inhibition and adenosine antagonism. Narrow therapeutic range (10-20 mg/L); toxicity causes arrhythmias and seizures. Levels rise with enzyme inhibitors (erythromycin, ciprofloxacin) and fall with smoking and inducers.
- Leukotriene receptor antagonists (montelukast): continue perioperatively.
- Magnesium sulphate (2 g IV over 20 minutes) is used in acute severe asthma.
Antidepressants and Psychiatric Drugs
Selective Serotonin Reuptake Inhibitors (SSRIs)
Usually continued. They increase the risk of serotonin syndrome with tramadol, pethidine, fentanyl (rarely), ondansetron combinations, methylene blue and linezolid. They impair platelet serotonin uptake, slightly increasing bleeding, and can cause hyponatraemia (SIADH).
Tricyclic Antidepressants (TCAs)
Block noradrenaline and serotonin reuptake and have antimuscarinic, antihistaminic and alpha-1 blocking effects. They prolong the QT interval and increase sensitivity to directly acting catecholamines; give vasopressors in reduced doses. Overdose causes sodium channel blockade with a wide QRS (treated with sodium bicarbonate).
Monoamine Oxidase Inhibitors (MAOIs)
| Interaction | Mechanism | Result |
|---|---|---|
| Pethidine, tramadol, dextromethorphan, methadone | Serotonin reuptake inhibition | Serotonin syndrome (hyperthermia, clonus, agitation, autonomic instability) |
| Indirect sympathomimetics (ephedrine, metaraminol) | Release of accumulated noradrenaline | Severe hypertensive crisis |
| Tyramine-rich foods | Unmetabolised tyramine releases noradrenaline | Hypertensive crisis |
Directly acting vasopressors (phenylephrine, noradrenaline) in small titrated doses are safer. Irreversible MAOIs used to be stopped 2 weeks before surgery, but current practice is usually to continue them and avoid interacting drugs, after discussion with the psychiatrist. Moclobemide is reversible and short-acting.
Lithium
- Narrow therapeutic range (about 0.4-1.0 mmol/L); toxicity above about 1.5 mmol/L causes tremor, confusion, seizures and arrhythmias.
- Renally excreted like sodium: dehydration, NSAIDs, ACE inhibitors and thiazides raise levels.
- Prolongs neuromuscular blockade and may reduce anaesthetic requirements; causes nephrogenic diabetes insipidus and hypothyroidism.
- Usually continued for minor surgery with levels checked; often withheld 24 hours before major surgery and restarted when renal function and fluid balance are stable.
Antipsychotics
Dopamine D2 antagonists (haloperidol, olanzapine, quetiapine) cause sedation, hypotension (alpha-1 block), QT prolongation, extrapyramidal effects and, rarely, neuroleptic malignant syndrome (hyperthermia, rigidity, raised creatine kinase, autonomic instability), treated with cooling, dantrolene and bromocriptine.
Antiepileptic Drugs
| Drug | Mechanism | Anaesthetic interaction |
|---|---|---|
| Phenytoin | Sodium channel blockade | Enzyme inducer; chronic use causes resistance to non-depolarising NMBDs; zero-order kinetics at therapeutic levels |
| Carbamazepine | Sodium channel blockade | Strong enzyme inducer; resistance to NMBDs and opioids; hyponatraemia |
| Sodium valproate | Several mechanisms | Enzyme inhibitor; thrombocytopenia and platelet dysfunction; hepatotoxicity |
| Levetiracetam | Binds synaptic vesicle protein SV2A | Few interactions; available intravenously |
| Lamotrigine | Sodium channel blockade | Few anaesthetic interactions |
All antiepileptics should be continued perioperatively, using intravenous forms when the enteral route is unavailable. Missed doses risk breakthrough seizures.
Drugs for Parkinson's Disease
Levodopa (with a decarboxylase inhibitor) has a short half-life; missing even a few hours of doses can cause severe rigidity, dysphagia and respiratory compromise. Give the usual doses up to and immediately after surgery, use a nasogastric tube if needed, or switch to a rotigotine skin patch. Avoid metoclopramide, prochlorperazine and haloperidol; use domperidone or ondansetron for nausea. Selegiline and rasagiline are MAO-B inhibitors and interact with pethidine.
Enzyme Induction and Inhibition
| Inducers (reduce effect of other drugs) | Inhibitors (increase effect of other drugs) |
|---|---|
| Rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort, chronic alcohol, smoking (CYP1A2) | Amiodarone, macrolides (clarithromycin, erythromycin), azole antifungals, ciprofloxacin, grapefruit juice, ritonavir, cimetidine, acute alcohol |
CYP3A4 inhibitors such as clarithromycin, diltiazem or ritonavir can markedly prolong the effects of midazolam, fentanyl and alfentanil.
A patient taking an irreversible non-selective monoamine oxidase inhibitor becomes hypotensive after induction. Which vasopressor approach is safest?
Ephedrine 6 mg boluses, because it acts mainly on beta receptors
Metaraminol 1 mg boluses, because it releases stored noradrenaline gradually
Small titrated doses of a directly acting agent such as phenylephrine
Pethidine to reduce the sympathetic response
Which factor is most likely to cause lithium toxicity in the perioperative period?
Concurrent carbamazepine therapy
Dehydration with regular ibuprofen
Increased dietary intake of sodium chloride
Use of a short-acting volatile anaesthetic
A patient with Parkinson's disease develops postoperative nausea. Which antiemetic should be avoided?
Ondansetron
Domperidone
Cyclizine, an antihistamine
Metoclopramide
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