Pharmacology for Anaesthesia and Intensive Care

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9780521704632c24 CUFX213A/Peck 9780521618168 December 29, 2007 15:7

24 Drugs used in Diabetes

Uses

Sulphonylureas are used to control type II or non-insulin dependent diabetes

(NIDDM), but should not replace dietary control.

Mechanism of action

Ingeneral these drugs work at the pancreas by displacing insulin fromβ-cells in

the islets of Langerhans. For this reason they are ineffective in insulin-dependent

diabetics who have no functioningβ-cells. They may also induceβ-cell hyperplasia,

while reducing both glucagon secretion and hepatic insulinase activity. During long-

term administration they also reduce peripheral resistance to insulin.

Kinetics

Sulphonylureas are all well absorbed from the gut and have oral bioavailabilities

greater than 80%. Albumin binds these drugs extensively in the plasma. Chlor-

propamide undergoes hepatic metabolism but to a much lesser extent than the

others. A significant fraction is excreted unchanged in the urine and in the presence

of renal failure its half-life is prolonged. The other drugs in this class are extensively

metabolized in the liver to inactive metabolites (with the exception of glibenclamide

whose active metabolites are probably of little clinical significance), which are sub-

sequently excreted in the urine. Cimetidine inhibits their metabolism and, therefore,

potentiates their actions. Drugs that tend to increase blood sugar (thiazides, corti-

costeroids, phenothiazines) antagonize the effects of the sulphonylureas and make

diabetic control harder.

The second-generation sulphonylureas bind to albumin by non-ionic forces in

contrast with tolbutamide and chlorpropamide that bind by ionic forces. Thus,

anionic drugs such as phenylbutazone, warfarin and salicylate do not displace

second-generation drugs to such an extent and may be safer during concurrent

drug therapy.

Other effects

Side effects are generally mild but sometimes include gastrointestinal disturbances

and rashes.


Chlorpropamide – its long half-life and partial reliance on renal elimination results

in a greater chance of hypoglycaemia, especially in the elderly. It may also cause

facial flushing and vomiting following alcohol and rarely may enhance antidiuretic

hormone secretion resulting in hyponatraemia. Photosensitivity may also occur.


Tolbutamide – this drug has been associated with cholestatic jaundice, deranged

liver function and blood dyscrasias.