Oral hypoglycaemic Agents:
Five distinct oral drug classes (?)
derivative of sulphonamide antibiotic first introduced in 1950’s, but have no antibiotic activity; potent oral hypoglycaemic agents; adjunct to diet and exercise, not a substitute; most widely used oral agent
stimulates insulin release from the beta cell – some restore the sensitivity of the beta cell to glucose (will not be effective if pancreas can not synthesise insulin not indicated in type 1); mechanism is via binding to receptors on beta cell membrane that lead to inhibition of ATP sensitive potassium channels depolarisation release of insulin. May have secondary effect of decreasing liver glucose production and improve insulin sensitivity.
used primarily for non-obese type 2 patients who do not respond to diet modification alone (not used often in obese due to weight gain associated with use increase in insulin resistance); diet and increased physical activity should be used prior to initiation of sulphonylurea therapy
rapidly absorbed from GI tract; circulate bound to albumin; excreted through either liver or renal tract
two groups – first and second generation – second generation produce effects at lower dose
eg First generation: Tolbutamide (Rastinon™); Tolazamide; Chlorpropamide (Diabinese™); Second generation: Glibebclamide (Daonil™, Euglucon™, Glimel™); Gliclazide (Diamicron™); Glipizide (Minidiab™); Gliquidone.
adverse effects – hypoglycaemia (can be severe, but mild form can occur in up to 20%; especially if have renal disease), weight gain (common), GI disturbances, rashes, abnormal liver function tests (uncommon and not severe). Not for use during pregnancy.
interactions – aspirin, sulphonamides, trimethoprim may displace sulfonylureas from being bound to plasma proteins in circulation may precipitate hypoglycaemia
appear to decrease liver gluconeogenesis and increases peripheral insulin sensitivity – may also inhibit glucose absorption by GI tract due to observed weight loss that can occur; does not increase insulin secretion (biguanides are only effective in presence of insulin); also can improve lipid profile, reduce blood pressure and improve fibrinolysis (all part of insulin resistance syndrome)
eg Metformin (Diabex™, Diaformin™, Glucaphage™)
metformin was preceded by phenformin which was withdrawn due to severe and fatal lactic acidosis concern by some physicians about metformin, but risk no greater than that with sulphonylureas.
does not cause hypoglycaemia or contribute to weight gain ( use in obese patients)
may be used with a sulfonylurea (effects are synergistic)
adverse side effects – 50% develop GI problems – nausea, diarrhoea, discomfort, anorexia; lactic acidosis (rare). Up to 10% can not tolerate Metformin
contraindications - renal impairment (leads to accumulation of drug), cardiac disease, peripheral vascular disease (due to an increase in tissue lactate production), liver impairment, alcoholism
interactions – cimetidine (reduced renal clearance)
Thiazolidinediones (TZD’s) (troglitazone, rosiglitazone (Avandia™), pioglitazone (Actos™) – enhance endogenous insulin action in liver (decreases glucose production) and peripheral tissues (improves insulin sensitivity in those that are insulin resistant)
increases insulin sensitivity by through activation of the hormone receptor peroxisome proliferators-activated receptor-gamma in adipocytes; – also decrease triglyceride levels, increase HDL levels and lowers blood pressure;
can be used with sulfonylureas (rosiglitazone and pioglitazone) and insulin (pioglitazone)
side effects – oedema, hepatotoxicity (trogilitazone), weight gain, as adipocytes are stimulated to increase fat deposits (rosiglitazone and pioglitazone), mild dilutional anaemia.
Troglitazone has been withdrawn due to severe risk of hepatotoxicity. Maximum effect seen after 6-14 weeks. Liver function tests need to be done regularly.
Meglitinides – (repaglinide, nateglinide) – produce rapid transient increase in insulin secretion (most helpful in reducing post-prandial hyperglycaemia); stimulates release of insulin from pancreas in a similar way to sulphonylureas, but does not cause exocytosis of insulin;
taken with meals gives some flexibility with dosing; appears to be as effective as metformin and can be used in combination with it for better metabolic control; can be used with moderate renal impairment; adverse effects – hypoglycaemia, weight gain;
(Acarbose) – delays dietary carbohydrate absorption in the GI tract, by inhibiting digestive enzymes (alpha-glucosidase) lowers postprandial blood glucose modest improvement in glycaemic control; indicated for those who have a high postprandial blood glucose; as increases insulin sensitivity; can be used in obese patients as does not cause weight gain.
indicated if glucose levels remain high despite dietary changes;
taken immediately prior to meal; can be used with a sulfonylurea, especially if glucose levels are very high;
side effects – flatulence, diarrhoea, bloated abdomen(due to increased glucose being fermented in large intestine), hepatic dysfunction