Lecture on Anti Diabetic Drugs Submitted by WWW.ASSIGNMENTPOINT.COM www.assignmentpoint.com

Diabetes mellitus A disease caused by elevated glucose levels Major causes: Body does not produce enough insulin Cells do not respond to the insulin that is produced www.assignmentpoint.com

Anti Diabetic Drugs Sulfonylureas: Stimulate beta cells to release more insulin. Meglitinides: Nonsulfonylurea insulinotropic agent. Biguanides: No effects on beta cells. 3 sites for work: peripheral tissue, liver, intestine. Thiazolidinediones: Decrease insulin resistance in peripheral target tissue. α-glucosidase inhibitor: Delay carbohydrate absorption from GI tract. www.assignmentpoint.com

Sulfonylureas These agents promote the release of insulin from β-cells e.g. tolbutamide, glyburide, glipizide and glimepiride. Mechanism: Require functioning β-cells, stimulate release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca2+ influx which promotes insulin secretion. Reduce glucagon secretion and increase the binding of insulin to target tissues. Increase the number of insulin receptors Pharmacokinetics: Bind to plasma proteins Metabolized in the liver and excreted by the liver or kidney. www.assignmentpoint.com

Mechanism of Action www.assignmentpoint.com

Sulfonylureas Adverse effects Onset and duration Weight gain Hyperinsulinemia Hypopglycemia Onset and duration Short acting: tolbutamide Intermediate acting: tolazamide , glipizide , glyburide Long acting: chloropropamide, glimerpiride www.assignmentpoint.com

Meglitinides Mechanism: Binds to ATP sensitive K+channels like sulfonylureas acting in a similar fashion to promote insulin secretion Onset and duration of action are much shorter. Particularly effective at mimicking the prandial and post-prandial release of insulin. Used in combination with other oral agents they produce better control than any monotherapy. Pharmacokinetics: Reach effective plasma levels when taken 10-30 minutes before meals. Metabolized to inactive products by CYP3A4 and excreted in bile. www.assignmentpoint.com

Meglitinides Adverse Effects: Less hypoglycemia than sulfonylureas Drugs that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin, etc.) prolong their duration of effect. Drugs that promote CYP3A4 (barbiturates, carbamazepine and rifampin) decrease their effectiveness. The combination of gemfibrozil and repaglinide has been reported to cause severe hypoglycemia. www.assignmentpoint.com

Biguanides Mechanism: Metformin is classified as an insulin sensitizer, it increases glucose uptake and utilization by target tissues. It requires the presence of insulin to be effective. The risk of hypoglycemia is greatly reduced. Mechanism: Inhibit hepatic gluconeogenesis Slows the intestinal absorption of sugars Reduces hyperlipidemia (↓LDL and VLDL cholesterol and ↑ HDL) Metformin also decreases appetite. It is the only oral hypoglycemic shown to reduce cardiovascular mortality. It can be used in combination with other oral agents and insulin. www.assignmentpoint.com

Biguanides www.assignmentpoint.com

Biguanides Adverse effects: Hypoglycemia occurs only when combined with other agents. Rarely severe lactic acidosis is associated with metformin use particularly in diabetics with CHF. Drug interactions with cimetidine, furosemide, nifedipine and others have been identified. www.assignmentpoint.com

Thiazolidinediones Mechanism : These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. E.g. Pioglitazone and rosigglitazone. Mechanism : Activate peroxisome proliferator-activated receptor-γ (PPAR-γ) Ligands for PPAR-γ regulate adipocyte production, secretion of fatty acids and glucose metabolism. Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all improved. HDL levels are also elevated. www.assignmentpoint.com

Thiazolidinediones www.assignmentpoint.com

Thiazolidinediones Pharmacokinetics: Adverse Effects: In the liver: ↓glucose output In muscle: ↑glucose uptake In adipose: ↑glucose uptake , ↓FA release Pharmacokinetics: Extensively bound to albumin and undergo extensive P450 metabolism; metabolites are excreted in the urine the primary compound is excrete unchanged in the bile. Adverse Effects: Fatal hepatotoxicityhepatic Oral contraceptives levels are decreased with concomitant administration, this has resulted in some pregnancies. www.assignmentpoint.com

α-Glucosidase Inhibitors Mechanism of action: These agents are oligosaccharide derivatives taken at the beginning of a meal delay carbohydrate digestion by competitively inhibiting α-glucosidase, a membrane bound enzyme of the intestinal brush border. Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal lumen. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen. www.assignmentpoint.com

α-Glucosidase Inhibitors www.assignmentpoint.com

α-Glucosidase Inhibitors Adverse Effects Flatulence, diarrhea, cramping Metformin bioavailability is severely decreased when used concomitantly. These agents should not be used in diabetics with intestinal pathology. www.assignmentpoint.com

Thank You All 31st May 2013 www.assignmentpoint.com