2. Treatment of diabetes:  Life style modification  Insulin  Oral hypoglycemic agents

3. Life style modification  Diet control  Exercise  Smoking cessation

5. DIET CONTROL  All diabetic patients should be on diet control.  Diet control is a must either the patient is taking insulin or oral therapy.  Over weight should be reduced.

6.  Diet control should be tried at first before the next step [insulin or tablets] especially in obese patients, When diet fails drugs are indicated. DIET CONTROL

7.  The diet for a diabetic patient is not so different from the healthy diets for the whole population.  Simple sugars Carbohydrate [as sucrose], should be limited for the diet of diabetic patients. DIET CONTROL

8.  Carbohydrate content should be in a fiber-rich diet [for example fruits containing fibers as apples]. ….. because the fiber content of diet delays absorption of carbohydrates avoiding the rapid elevation of blood glucose levels. DIET CONTROL

9. Calories : Calories should be tailored to the need of the patient. Diet should contain :  Carbohydrates → 50 - 55%  Fat → 30-35%  Protein → 10 - 15% DIET CONTROL

11. Indication of Insulin  Type 1 diabetes  Unstable diabetes  Type 2 diabetes failed on SUs.  Pregnant diabetic patients  Surgery (all diabetic patients)  Diabetic coma

13. Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

14. 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 [Cidophage].

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

16. 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.

17. 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)

18. 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

19. Biguanides Side effects:  occur in 20-25 % of patients.  include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B 12.

20. 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.

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

22.  Types: First generation,  Chlorpropamide ( Pamidin )  Tolbutamide ( Diamol ) Second generation,  Gliclazide (Diamicron)  Glibenclamide (Daonil)  Glipizide (Minidiab) Third generation,  Glimepiride (Diabride) (Amaryl)

23. SULFONYLUREAS  Mechanism of action: Pancreatic effect Extra-pancreatic effect

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

25.  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

26. 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.

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

28. 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.

29. SULFONYLUREAS Adverse Reactions :  Very few adverse reactions [4 %] in the first generation and rare in the 2 nd and 3 rd 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.

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

31. 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.

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

33. SULFONYLUREAS  Contraindications : Type 1 DM Pregnancy and Lactation. Significant hepatic or renal failure.

34. α Glucosidase Inhibititor Acarbose (Glucobay) Indicated for type 2 diabetes  In addition with diet  In addition with other anti- diabetic therapies

35. 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

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

37. Thiazolidenedione Rosiglitazone (Avandia) Pioglitazone (Actos)

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

39. 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)

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

41. Repaglinide, Novonorm  Mechanism of action: Stimulation of pancreatic insulin release by closing ß-cells K ATP channels Very rapid onset of action and short duration (T MAX = 1 hour, metabolized by liver T 1/2 = 70 minutes) No hypoglycemic metabolites

42. Repaglinide, Novonorm  Clinical efficacy: Improves postprandial glycemia Less effective in decreasing fasting blood glucose levels and HbA 1C  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?