- First generation: tolbutamide, chlorpropamide
- Second generation: glibenclamide, gliclazide, glipizide, glimepiride
- Older, long-acting agents (chlorpropamide, glibenclamide) carry the greatest risk of hypoglycaemia and should no longer be prescribed
- Shorter-acting, hepatically metabolised agents such as gliclazide are considered safer
Sulphonylureas
Sulphonylureas
Resources
- Non-insulin diabetes medicines: a narrative review for anaesthetists and intensivists (BJA, 2025)
- Diabetes medication pharmacology (BJA Education, 2017)
- Peri-operative management of diabetes mellitus: a multidisciplinary consensus statement (Association of Anaesthetists and JBDS-IP, 2026)
- Current practice in the perioperative management of patients with diabetes mellitus: a narrative review (BJA, 2023)
- Sulphonylureas are insulin secretagogues and the oldest class of non-insulin diabetes medicine, in use since the 1950s
- They stimulate insulin release independently of blood glucose concentration
- Their key peri-operative concern is hypoglycaemia in the fasted patient
- Type 2 diabetes mellitus
- Added to initial treatment when further glucose lowering is needed and a DPP-4 inhibitor is unsuitable or ineffective (NICE guidance)
- Also considered for symptomatic hyperglycaemia at any stage
- Cheap and effective, but long-term use is associated with deteriorating glycaemic control, weight gain and possible cardiovascular harm
- Short-term control of steroid-induced hyperglycaemia
- Bind to the sulphonylurea receptor (SUR1) on the pancreatic β-cell membrane
- This closes ATP-dependent K+ (KATP) channels, depolarising the cell
- Voltage-gated Ca2+ channels open and the Ca2+ influx triggers exocytosis of insulin-containing vesicles
- Require functioning β-cells and are therefore ineffective in type 1 diabetes
- Other effects include reduced hepatic insulin clearance and reduced glucagon secretion
Absorption
- Well absorbed from the GI tract; oral bioavailability ~80%
Distribution
- Extensively bound to albumin
- Second generation agents bind by non-ionic forces and so are less readily displaced by anionic drugs (e.g. warfarin, salicylates) than tolbutamide
Metabolism
- Mostly hepatic metabolism to inactive metabolites
- Metabolism is inhibited by cimetidine, potentiating their effect
Excretion
- Metabolites are excreted in the urine; a significant fraction of chlorpropamide is excreted unchanged
- Half-life 8-12hrs, but effects may be prolonged in renal or hepatic impairment and the elderly
Nutritional and metabolic
- Hypoglycaemia, particularly in the starved state; severe hypoglycaemia occurs at a rate of ~0.1 per patient-year
- Weight gain
Gastrointestinal
- GI disturbance
- Deranged liver function and cholestatic jaundice (particularly tolbutamide)
Haematological
- Blood dyscrasias (rare)
Drug interactions
- Effects are antagonised by drugs that raise blood glucose e.g. thiazide diuretics, corticosteroids
Perioperative management
- Because of the risk of hypoglycaemia, sulphonylureas are withheld peri-operatively:
- Morning surgery: omit the morning dose
- Afternoon surgery: omit all doses due on the day of surgery
- Patients on a liver reduction diet or bowel preparation may need a longer cessation period coinciding with reduced food intake
- Schedule patients early on the list to minimise fasting
- Target capillary blood glucose 6-10mmol/L in patients taking sulphonylureas
- Glucose <6mmol/L requires intervention to prevent progression to hypoglycaemia (<4mmol/L)
- Anaesthesia masks the symptoms of hypoglycaemia, so regular CBG measurement is essential
- Restart once the patient is eating and drinking normally and any VRII has been stopped
- Some guidance suggests re-starting at 50% previous dose esp. if oral intake not back to 100% baseline
- Review or stop after bariatric surgery owing to rapid falls in glucose
- Stop in critical illness, where impaired absorption and renal or hepatic impairment increase the risk of hypoglycaemia