Describe the sulphonylureas with their mechanism and adverse effects. Add a note on the management of sulphonylurea hypoglycaemia.

Mechanism and Classification

The drug binds the SUR1 subunit of the ATP-sensitive potassium (KATP) channel on the beta cell → The channel closes → Potassium efflux stops and the cell depolarises → Voltage-gated calcium channels open → Intracellular calcium rises → exocytosis of insulin granules → This is the same final pathway that glucose itself uses — but it operates regardless of the glucose level, which is exactly why hypoglycaemia occurs

Adverse Effects

• Hypoglycaemia — the principal hazard, and unlike insulin-induced hypoglycaemia it is often prolonged and recurrent, lasting many hours or days
• Risk factors — old age, renal or hepatic impairment, missed meals, alcohol, long-acting agents (glibenclamide), and interacting drugs
• Weight gain of 2 to 5 kg, from the anabolic effect of higher insulin levels
• Others — nausea, rash, cholestatic jaundice, and rarely blood dyscrasias; haemolysis in G6PD deficiency
• Secondary failure — efficacy declines over years as beta cell function is lost, which is the natural history of the disease rather than tolerance to the drug
• Interactions — potentiated by sulphonamides, co-trimoxazole, fluconazole, warfarin, salicylates and alcohol (displacement and enzyme inhibition); antagonised by corticosteroids, thiazides and sympathomimetics

Management of Sulphonylurea Hypoglycaemia

• Admit the patient — this is not a matter of a sweet drink and discharge; the drug outlasts the treatment and hypoglycaemia recurs
• Intravenous dextrose as a bolus and then a continuous infusion, with frequent glucose monitoring for at least 24 hours
• Octreotide is used in refractory cases — it suppresses insulin release directly and is more effective than repeated glucose boluses, which themselves stimulate further insulin secretion
• Deliberate overdose and inadvertent dosing errors both require prolonged observation

Applied Aspects

• Prefer gliclazide or glimepiride to glibenclamide, particularly in the elderly and in renal impairment, where glibenclamide causes severe and protracted hypoglycaemia
• Warn the patient and family about hypoglycaemia, teach recognition and treatment, and advise carrying glucose and identification
• Reduce or omit the dose during fasting — illness, Ramadan, religious fasts, or a missed meal; this is a frequent and predictable cause of admission in India and should be discussed in advance
• Review the drug list for interacting agents before adding an antibiotic or antifungal
• Sulphonylureas remain the commonest second-line agent in India because of cost, and used carefully they are effective; the newer classes are better tolerated but are unaffordable for many patients
• Avoid in patients who drive professionally or work at heights wherever an alternative exists