Insulin and Oral Hypoglycemics

Oral hypoglycemic drugs are used only in the treatment of type 2 diabetes which is a disorder involving resistance to secreted insulin. Type 1 diabetes involves a lack of insulin and requires insulin for treatment. There are now four classes of hypoglycemic drugs:

1. INSULIN & ORAL ANTI-DIABETIC AGENTS Prof. Amol B Deore MVP’s Institute of Pharmaceutical Sciences, Nashik (INDIA)

2. Diabetes Diabetes mellitus: it is a metabolic disorder characterized by deficiency of insulin or insulin resistance which leads to hyperglycemia. Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected. Diabetes mellitus type 2 is a disease of insulin resistance by cells. Type 2 diabetes mellitus is the most common type in worldwide.

3. Management Treatments include: (1) Agents that increase the amount of insulin secreted by the pancreas, (2) Agents that increase the sensitivity of target organs to insulin, and (3) Agents that decrease the rate at which glucose is absorbed from the GIT tract.

4. INSULIN Parenteral Insulin preparations Conventional insulin: bovine insulin, porcine insulin

5. HUMAN INSULIN PREPARATIONS Type Preparation Duration of action Time of injection Fast acting Regular Insulin injection Prompt Insulin Zinc suspension (SEMILENTE) Insulin Lispro Insulin aspart 5-7 hrs Before breakfast Intermediate acting Isophane Insulin suspension (NPH insulin) Insulin Zinc suspension (LENTE) Globin Zinc Insulin injection 18-24 hrs Before breakfast Long acting Protamine Zinc Insulin suspension (PZI) Extended Zinc Insulin suspension (ULTRLENTE) 24-36 hrs At breakfast

6. Mechanism of action

7. Pharmacological action

8. EFFECT ON LIVER : Increase protein synthesis Inhibits glycogenolysis Inhibits conversion of fatty acids and amino acids to keto acids Inhibits conversion of amino acids to glucose Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase ) Increases triglyceride synthesis and very low density lipoprotein formation

9. EFFECT ON SKELETAL MUSCLE : Increased protein synthesis Increases amino acid transport (uptake) Increases ribosomal protein synthesis Increased glycogen synthesis Increases glucose transport (uptake) Induces glycogen synthase and inhibits phosphorylase

10. EFFECT ON ADIPOSE TISSUE : Increased triglyceride storage Increased lipogenesis Decreased lipolysis Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins

11. ROUTE OF ADMINISTRATION Insulin is usually taken as subcutaneous injections by single-use syringes with needles, an insulin pump, or by repeated-use insulin pens with needles.

12. Insulin in not given orally. Why ? Insulin is a high molecular weight polypeptide hormone secreted from pancreatic Beta cells of Islets of Langerhans . If Insulin is administered orally in diabetes, then it is inactivated by the gastric enzyme Pepsin in stomach and corboxypeptidase enzyme in small intestine. Hence very little fraction of Insulin enter in to systemic blood circulation for producing hypoglycemic action with low bioavailability. Therefore Insulin should not be given orally. It must be given subcutaneously.

13. ADVERSE DRUG REACTION Hypoglycemia: may be due to insulin over dosage, failure to eat Insulin Allergy: Insulin allergy, immediate type hypersensitivity, is a rare condition characterized by local or systemic urticaria , Lymphadenopathy . In severe cases, anaphylaxis shock. Redness at injection site, atrophy of adipose tissue ( lipodystrophy ) Insulin Resistance: Insulin antibodies will lead to insulin resistance Lipodystrophy at Injection Sites: Injection of older insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection. Insulin presbyopia: difficulty or loss of accommodation, patient can see near objects but failed to see far away objects. Insulin neuropathy Obesity : due to insulin therapy without dietary restriction

14. ORAL HYPOGLYCEMIC AGENTS These are the drugs used in the management of diabetes mellitus type 2 . All are administered orally and are thus also called oral hypoglycemic agents.

15. INSULIN SECRETOGOGUES Sulfonylureas : Glyburide, Glimepiride, Glipizide , Glibenclamide , Tolbutamide , chlorpropamide , acetohexamide Meglitinides : Repaglinide , Nateglinide INSULIN SENSITIZERS Biguanides : Metformin, Phenformin , Buformin Thiazolidinediones : Pioglitazone , Rosiglitazone MISCELANEOUS Alpha glucosidase inhibitors: Acarbose , Miglitol , Voglibose Gliptins : Vildagliptin , Sitagliptin , Septagliptin , Saxagliptin , Alogliptin , Linagliptin

16. SULFONYLUREAS Ex. Glyburide, Glimepiride, Glipizide , Glibenclamide , Tolbutamide , chlorpropamide , acetohexamide

17. Mechanism They increase the sensitivity of Beta-cells towards glucose, enabling them to increase insulin release at every glucose level. These drugs probably act on sulphonylureas receptors on the cell membrane of Beta cells. These receptors are linked to ATP sensitive K + channels on the cell membrane. Sulphonylureas bind to their receptors leads to closing off ATP-sensitive K + channels and promote depolarization (decreased repolarization) of the Beta-cell membrane. This produces Ca ++ influx resulting in insulin release from Beta cells by degranulation. Hence they are insulin secretagogues . They also inhibit hepatic gluconeogenesis and glycogenolysis . They increase insulin sensitivity of insulin receptors in the peripheral tissues such as skeletal muscles and liver.

18. They work best with patients over 40 years old who have had diabetes mellitus for under ten years. They cannot be used with type I DM. They can be safely used with metformin or Thiazolidinediones . Adverse drug reactions Sulfonylureas may cause hypoglycemic reactions , including coma, particularly in elderly patients with impaired hepatic or renal function who are taking longer-acting sulfonylureas. Allergic skin reactions Bone marrow depression : leukopenia, thrombocytopenia, agranulocytosis Teratogenicity, embryopathy jaundice Intolerance to alcohol

19. BIGUANIDES e.g. Metformin, Phenformin , Buformin They act by stimulating peripheral utilization (uptake) of glucose by skeletal muscles, liver cells and adipocytes (fat cells) Increase insulin sensitivity of insulin receptors of skeletal muscles and liver inhibit hepatic gluconeogenesis reduce intestinal absorption of glucose they lower blood glucose level in absence of functioning pancreas (endogenous insulin) hence may use in Type-1 DM (IDDM) They are used in NIDDM who are obese or where sulphonylureas are not effective alone.

20. Adverse drug reactions Metallic taste, anorexia, weight loss, nausea, abdominal discomfort, diarrhea, lethargy, muscular weakness Anaphylaxis reactions rarely Ketoneuria and lactic acidosis

21. THIAZOLIDINEDIONES Ex. pioglitazone, rosiglitazone Thiazolidinediones principally act by increasing insulin sensitivity (lowering insulin resistance) in peripheral tissues—and thus are effective only when insulin is present Decrease hepatic glucose production (gluconeogenesis) Thiazolidinediones increase glucose transport (uptake) into muscle and adipose tissue by enhancing the synthesis and translocation of specific forms of the glucose transporters. The thiazolidinediones also activate genes that regulate fatty acid metabolism in peripheral tissue.

22. Differentiate between sulfonylureas and biguanides SULFONYLUREA BIGUANIDES   Ex. Glyburide, Glimepiride, Glipizide , Glibenclamide , Tolbutamide Ex. Metformin, Phenformin, Buformin   -Stimulating pancreatic Beta cells for insulin release (secretion) by degranulation of Beta cells) -Inhibit hepatic glycogenolysis -inhibit hepatic gluconeogenesis   - decrease insulin resistance -Increase insulin sensitivity of insulin receptors of skeletal muscles and liver -inhibit hepatic gluconeogenesis -reduce intestinal absorption of glucose   No action on peripheral glucose utilization (uptake) Increase peripheral glucose utilization (uptake) by the skeletal muscle and liver   They are insulin secretagogues They are Insulin sensitizers

23.   Sulfonylureas are useful only in Type II diabetes with patients over 40 years Most commonly used agent for type II diabetes in children and teenagers   Never used in type 1 diabetic patient Phenformin may be used in Type 1 diabetes patients in combination with Insulin   Weight gain in patients Weight loss, anorexia in patients   No effect on effect on LDL cholesterol Good effect on LDL cholesterol   Sulfonylureas are contraindicated in breast feeding mother Biguanides are contraindicated in cardiovascular disorders   Increased risk of hypoglycemia low risk of hypoglycemia as compared to alternatives   lower risk of gastrointestinal problems increased risk of gastrointestinal problems