Chlorpropamide

Chlorpropamide is an example of a drug class called sulphonylureas used to treat type 2 diabetes mellitus.

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Mechanism of action

The sulphonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present; during long-term administration they also have an extrapancreatic action. All may cause hypoglycaemia but this is uncommon and usually indicates excessive dosage. Sulphonylurea-induced hypoglycemia may persist for many hours and must always be treated in hospital.

Sulphonylureas are considered for patients who are not overweight, or in whom metformin is contra-indicated or not tolerated. Several sulphonylureas are available and choice is determined by side-effects and the duration of action as well as the patient’s age and renal function. The long-acting sulphonylureas chlorpropamide and glibenclamide are associated with a greater risk of hypoglycaemia; for this reason they should be avoided in the elderly and shorter-acting alternatives, such as gliclazide or tolbutamide, should be used instead. Chlorpropamide also has more side-effects than the other sulphonylureas and therefore it is no longer recommended.

When the combination of strict diet and sulphonylurea treatment fails other options include:

combining with metformin(reports of increased hazard with this combination remain unconfirmed);

combining with acarbose, which may have a small beneficial effect, but flatulence can be a problem;

combining with pioglitazone or rosiglitazone

combining with bedtime isophane insulin but weight gain and hypoglycaemia can occur.

Insulin therapy should be instituted temporarily during intercurrent illness (such as myocardial infarction, coma, infection, and trauma). Sulphonylureas should be omitted on the morning of surgery; insulin is required because of the ensuing hyperglycaemia in these circumstances.

Cautions Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite adequate attempts at dieting; metformin is considered the drug of choice in obese patients. Caution is needed in the elderly and in those with mild to moderate hepatic and renal impairment because of the hazard of hypoglycaemia. The short-acting tolbutamide may be used in renal impairment, as may gliquidone and gliclazide which are principally metabolised in the liver, but careful monitoring of blood-glucose concentration is essential; care is required to choose the smallest possible dose that produces adequate control of blood glucose.

Contra-indications Sulphonylureas should be avoided where possible in severe hepatic and renal impairment and in porphyria. They should not be used while breast-feeding and insulin therapy should be substituted during pregnancy. Sulphonylureas are contra-indicated in the presence of ketoacidosis.

Side-effects Side-effects of sulphonylureas are generally mild and infrequent and include gastro-intestinal disturbances such as nausea, vomiting, diarrhoea and constipation.

Chlorpropamide has appreciably more side-effects, mainly because of its very prolonged duration of action and the consequent hazard of hypoglycemia and it should no longer be used. It may also cause facial flushing after drinking alcohol; this effect does not normally occur with other sulphonylureas. Chlorpropamide may also enhance antidiuretic hormone secretion and very rarely cause hyponatraemia (hyponatraemia is also reported with glimepiride and glipizide).

Sulphonylureas can occasionally cause a disturbance in liver function, which may rarely lead to cholestatic jaundice, hepatitis and hepatic failure. Hypersensitivity reactions can occur, usually in the first 6–8 weeks of therapy, they consist mainly of allergic skin reactions which progress rarely to erythema multiforme and exfoliative dermatitis, fever and jaundice; photosensitivity has rarely been reported with chlorpropamide and glipizide. Blood disorders are also rare but may include leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia, and aplastic anaemia.

Indications type 2 diabetes mellitus

Cautions see notes above. Also causes disulfiram-like reaction with alcohol

Contra-indications see notes above

Side-effects see notes above. Dose

Initially 250 mg daily with breakfast (elderly 100–125 mg but avoid—see notes above), adjusted according to response; max. 750 mg daily