Mechanism of action of Sulfonylureas (Glibenclamide) / oral hypoglycemic drug:
I. Pancreatic action:
a. They are effective only in the presence of functioning pancreas at least 30% β- cell should be active.
At pancreatic beta cell membrane there is ATP dependent K+ channel. Sulfonylurea bind to sulfonylurea receptor and blocks the ATP dependent K+ channel. So inhibits the efflux of K+ ion, through the channel resulting depolarization. Depolarization causes opening of voltage gated Ca++ channel leading to influx. This Ca++ then induces insulin secretion. This endogenous release insulin then lowers the blood glucose level. Sulfonylurea acts only in presence of viable pancreatic beta cell that is when at least 30% pancreatic beta cell is viable. It is indirect action of sulfonylurea.
b. Reduction of serum glucagons concentration:
Increase release of both insulin and somatostatin causes inhibition of α cells which leads to reduction of glucagons release
II. Extra pancreatic action:
Sulfonylurea binds to its receptor in K+ channel in extrapncreatic tissue also and may potentiate the action of insulin by –
o Increase number of insulin receptors in tissue
o Increase binding affinity of insulin receptor for insulin
o Increase glucose transport into the cell by glucose transporter
o Decrease release of catecholamines
o Inhibit glycogenolysis by inhibiting phosphorylase enzymes
Three mechanism of Sulfonylureas action have been proposed. Sulfonylureas indirectly decrease blood sugar:
By –
1. Release of insulin from pancreatic beta cell.
2. Reduction of serum Glucagon level.
3. Potentiate the action of insulin on its target tissue & extra pancreatic effect.
1. Hypoglycaemia.
It is not frequently occurs but when occurs tends to be prolong. It is particularly seen with Chlorpropamide, Glibenclamide & elderly patient with impaired hepatic & renal function.
2. GIT upset.
3. Haemotological reaction.
4. Cholestatic jaundice & intolerance to alcohol Chlorpropamide can induce hepatic microsomal enzyme particularly in high doses & due to disulfiram like reaction.
5. Allergic skin reaction – skin rash, exfoliative dermatitis
6. Weight gain – due to increase appetite
7. Muscular weakness, ataxia, dizziness, mental confusion
8. Teratognensis
9. Drug interaction: Sulfonylureas are protein-binding drug so drug interaction occurs with protein binding drugs.
1. Sulfonylureas are used for the treatment of NIDDM who can’t be controlled by diet, exercise & weight reduction. It is usually used in non-obese non-insulin dependent patient.
2. Diabetes with complication e.g. diabetic keto acidosis, diabetic nephropathy etc.
3. Diabetes with surgery.
4. Diabetes with pregnancy & lactation.
5. Hepatic & renal impairment.
N.B:
Combined therapy with Sulfonylureas & insulin:
It is used in cases where daily insulin requirement is very high. Since Sulfonylureas drug not only increase the pancreatic beta cell secretion of insulin but also increase peripheral tissue sensitivity to insulin. So use of Sulfonylureas has been advocated to reduce the total insulin dose.
I. Pancreatic action:
a. They are effective only in the presence of functioning pancreas at least 30% β- cell should be active.
At pancreatic beta cell membrane there is ATP dependent K+ channel. Sulfonylurea bind to sulfonylurea receptor and blocks the ATP dependent K+ channel. So inhibits the efflux of K+ ion, through the channel resulting depolarization. Depolarization causes opening of voltage gated Ca++ channel leading to influx. This Ca++ then induces insulin secretion. This endogenous release insulin then lowers the blood glucose level. Sulfonylurea acts only in presence of viable pancreatic beta cell that is when at least 30% pancreatic beta cell is viable. It is indirect action of sulfonylurea.
b. Reduction of serum glucagons concentration:
Increase release of both insulin and somatostatin causes inhibition of α cells which leads to reduction of glucagons release
II. Extra pancreatic action:
Sulfonylurea binds to its receptor in K+ channel in extrapncreatic tissue also and may potentiate the action of insulin by –
o Increase number of insulin receptors in tissue
o Increase binding affinity of insulin receptor for insulin
o Increase glucose transport into the cell by glucose transporter
o Decrease release of catecholamines
o Inhibit glycogenolysis by inhibiting phosphorylase enzymes
Three mechanism of Sulfonylureas action have been proposed. Sulfonylureas indirectly decrease blood sugar:
By –
1. Release of insulin from pancreatic beta cell.
2. Reduction of serum Glucagon level.
3. Potentiate the action of insulin on its target tissue & extra pancreatic effect.
Adverse effect of Sulfonylureas:
1. Hypoglycaemia.
It is not frequently occurs but when occurs tends to be prolong. It is particularly seen with Chlorpropamide, Glibenclamide & elderly patient with impaired hepatic & renal function.
2. GIT upset.
- Nausea
- Vomiting.
- Diarrhea
3. Haemotological reaction.
- Neutropenia
- Agranulocytosis
- Thrombocytopenia
- Aplastic anemia
4. Cholestatic jaundice & intolerance to alcohol Chlorpropamide can induce hepatic microsomal enzyme particularly in high doses & due to disulfiram like reaction.
5. Allergic skin reaction – skin rash, exfoliative dermatitis
6. Weight gain – due to increase appetite
7. Muscular weakness, ataxia, dizziness, mental confusion
8. Teratognensis
9. Drug interaction: Sulfonylureas are protein-binding drug so drug interaction occurs with protein binding drugs.
- Sulfonamide
- Salicylate
- Phenylbutazone
- Warfarin
Indications of Sulfonylureas:
1. Sulfonylureas are used for the treatment of NIDDM who can’t be controlled by diet, exercise & weight reduction. It is usually used in non-obese non-insulin dependent patient.
Contraindications of Sulfonylureas:
1. In insulin dependent diabetes mellitus (IDDM).2. Diabetes with complication e.g. diabetic keto acidosis, diabetic nephropathy etc.
3. Diabetes with surgery.
4. Diabetes with pregnancy & lactation.
5. Hepatic & renal impairment.
N.B:
Combined therapy with Sulfonylureas & insulin:
It is used in cases where daily insulin requirement is very high. Since Sulfonylureas drug not only increase the pancreatic beta cell secretion of insulin but also increase peripheral tissue sensitivity to insulin. So use of Sulfonylureas has been advocated to reduce the total insulin dose.
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