oral hypoglycemic agents

1. oral hypoglycemic agents

2. Oral hypoglycemic agents • Biguanides • Sulfonylureas • α- glucosidase inhibitors • Thiazolidinediones • Prandial glucose regulator

3. Biguanides • Biguanides are derivatives of the antimalarial agent Chloroguanide. Which is found to have hypoglycemic action. • The most commonly used member of biguanides is Metformin.

4. Biguanides • Indication: • Type 2 diabetes failed on diet • Metformin can be given alone or in combination with sulfonylureas or Insulin

5. Biguanides • Mode of action Biguanides [Metformin] is an Antihyperglycemic and not Hypoglycemic agent. • It does not stimulate pancreas to secrete insulin and does not cause hypoglycemia (as a side effect) even in large doses. • Also it has no effect on secretion of Glucagon or Somatostatin.

6. Biguanides • Mode of action: • Decreases the intestinal absorption of CHO • Increases glucose uptake (GLUT 4) • Increases glucose utilization (glycogensynthase) • Increases glycolysis via anaerobic pathway (lactic acidosis)

7. Biguanides Pharmacokinetics: • Metformin is well absorbed from small intestine, stable, does not bind to plasma proteins, excreted unchanged in urine. • Half life of Metformin is 1.5 - 4.5 hours, taken in three doses with meals

8. Biguanides Side effects: • occur in 20-25 % of patients. • include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B12.

9. Biguanides Contraindications • Patients with renal or hepatic impairment. • Past history of lactic acidosis. • Heart failure, Chronic lung disease. .. These conditions predispose to increased lactate production which causes lactic acidosis which is fatal.

10. SULFONYLUREAS • SUs., have been discovered during the 2nd. World war (sulfonamide). • SUs are drugs that used orally to control blood glucose levels of type 2 diabetes.

11. SULFONYLUREAS • Types: • First generation, • Chlorpropamide • Tolbutamide • Second generation, • Gliclazide • Glibenclamide • Glipizide • Third generation, • Glimepiride

12. SULFONYLUREAS • Mechanism of action: • Pancreatic effect • Extra-pancreatic effect

13. SULFONYLUREAS Pancreatic effect: • Increase insulin release from pancreas • Suppress secretions of Glucagon

14. SULFONYLUREAS • Extra pancreatic effect: • Increases the number of insulin receptors • Increases post-receptor insulin sensitivity • Increases glucolysis • Increases glycogen storage in muscle and liver • Decreases the hepatic output of glucose

15. SULFONYLUREAS • Pharmacokinetics: • They are effectively absorbed from gastrointestinal tract. • Food can reduce the absorption of sulfonylurea. • Sulfonylureas are more effective when given 30 minutes before eating. • Plasma protein binding is high 90 – 99 % .. mainly bind to albumen.

16. SULFONYLUREAS • Pharmacokinetics: • 1st generation members have short half lives. • 2nd generation is administered once, twice or several times daily. • 3rd generation is administered once daily.

17. SULFONYLUREAS • Pharmacokinetics: • All sulfonylurea are metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged. • Sulfonylurea should be administered with caution to patients with either renal or hepatic insufficiency.

18. SULFONYLUREAS Adverse Reactions : • Very few adverse reactions [4 %] in the first generation and rare in the 2nd and 3rd generation. • SUs may induce hypoglycemia especially in elderly patients with impaired hepatic or renal functions-These cases of hypoglycemia are treated by I/V glucose infusion.

19. SULFONYLUREAS Adverse Reactions : • First generation may induce other side effects as …nausea and vomiting & dermatological reactions …These side effects are fewer in the 2nd generation and rare in the 3rd generation.

20. SULFONYLUREAS Drug interactions: • Some drugs may enhance or suppress the actions of sulfonylureas Either by affecting: • Their metabolism and excretion • The concentration of free sulfonylureas in plasma through competing them on plasma proteins.

21. NSAIDs Salicylates Sulfonamide ß-blockers Chloramphenicol Diazepam MAOI Barbiturates Thiazide and loop diuretics Sympathomimetics Corticosteroids Oestrogen / Progesterone combinations Drug – Drug interaction

22. SULFONYLUREAS • Contraindications : • Type 1 DM • Pregnancy and Lactation. • Significant hepatic or renal failure.

23. α Glucosidase Inhibititor Acarbose • Indicated for type 2 diabetes • In addition with diet • In addition with other anti-diabetic therapies

24. Acarbose (Glucobay) • Mode of action: • Poorly absorbed 1% (act locally in G.I.T.) • Inhibits α glucosidase, so inhibits CHO degradation • Dose: • 50mg to 100mg 3 times daily before meals

25. Acarbose (Glucobay) • Side effects: • Flatulence (77%) • Diarrhea • Abdominal pain (21%) • Decreased iron absorption

26. Thiazolidenedione Rosiglitazone Pioglitazone

27. Thiazolidenedione • Mode of action: • Insulin sensitizer (increase insulin sensitivity in muscle, adipose tissue & liver) • They are not insulin secretagogues (Not insulin releasers)

28. Thiazolidenedione • Drawbacks: • They are not effective alone in case of severe insulin deficiency and should be combined with sulfonylurea or metformin or both • Side effects: • Hepatotoxicity • weight gain • Dyslipidaemia (increases LDL)

29. Prandial glucose regulators (Meglitinide) • Example: • Repaglinide • Rational: • Fast acting, short duration non-sulfonylurea • Designed to minimize mealtime blood glucose peaks

30. Repaglinide • Mechanism of action: • Stimulation of pancreatic insulin release by closing ß-cells KATP channels • Very rapid onset of action and short duration (TMAX = 1 hour, metabolized by liver T1/2 = 70 minutes) • No hypoglycemic metabolites

31. Repaglinide • Clinical efficacy: • Improves postprandial glycemia • Less effective in decreasing fasting blood glucose levels and HbA1C • drawbacks: • Fails to provides a stable 24 hours blood glucose control • Complicated dosage style (3-8 tablets/daily) • How to adapt the dosage to the meal volume?