1. 1 Drugs used for Diabetes Mellitus

2. 2 Introduction There are 2 types of diabetes mellitus: There are 2 types of diabetes mellitus: Type 1: Insulin-dependent diabetes mellitus (IDDM) Type 1: Insulin-dependent diabetes mellitus (IDDM) Destruction of pancreatic beta cells Destruction of pancreatic beta cells Is the result of an autoimmune process Is the result of an autoimmune process Type 2: Non-insulin dependent diabetes mellitus (NIDDM) Type 2: Non-insulin dependent diabetes mellitus (NIDDM) Results from a combination of insulin resistance and altered insulin secretion Results from a combination of insulin resistance and altered insulin secretion

3. 3 Characteristics of Type 1 & Type 2 Diabetes Mellitus

4. 4 Oral Antidiabetic Drugs For the treatment of type 2 (non-insulin- dependent) diabetes mellitus For the treatment of type 2 (non-insulin- dependent) diabetes mellitus Use only after diet modification & exercise fail to produce glycemic control Use only after diet modification & exercise fail to produce glycemic control Should be used to augment the effect of diet & exercise, not to replace them Should be used to augment the effect of diet & exercise, not to replace them

5. 5 Evidence-based targets for managing cardiovascular risk factors Fasting blood glucose </= 6mmol/l HbA 1c < 7% Total cholesterol < 5mmol/l LDL cholesterol < 3 mmol/l Blood pressure threshold for intervention -Target for treatment -if significant proteinuria 140/90mmHg </= 140/80mmHg </= 125/75mmHg Recent guidelines recommend statin and low-dose aspirin treatment where the 10- year coronary heart disease ridk is less than 15% -before adding aspirin ensure blood pressure is controlled -combination antihypertnsive treatment is necessary in the majority of patients to achieve blood pressure targets -other recommendations include HDL>1.2mmol/l and fasting triglycerides 1.2mmol/l and fasting triglycerides<1.7mmol/l Summary of treatment targets for cardiovascular risk factor intervention in diabetic patients

6. 6 Sulphonylureas Act mainly by augmenting insulin secretion Act mainly by augmenting insulin secretion May also increase tissue response to insulin May also increase tissue response to insulin Effective only when some residual pancreatic beta-cell activity is present Effective only when some residual pancreatic beta-cell activity is present Considered for patients who are not overweight, or in whom Metformin (Glucophage®) is contraindicated or not tolerated Considered for patients who are not overweight, or in whom Metformin (Glucophage®) is contraindicated or not tolerated

7. 7 Short-acting: Short-acting: Tolbutamide: 0.5-1.5 g daily in divided doses, with or immediately after breakfast; Max: 2 g daily Tolbutamide: 0.5-1.5 g daily in divided doses, with or immediately after breakfast; Max: 2 g daily Gliclazide (Diamicron®): 40-160 mg daily in divided doses, with breakfast; Max: 320 mg daily Gliclazide (Diamicron®): 40-160 mg daily in divided doses, with breakfast; Max: 320 mg daily Intermediate-acting: Intermediate-acting: Glipizide (Minidiab®): 2.5-15 mg daily in divided doses, before breakfast; Max: 20 mg daily Glipizide (Minidiab®): 2.5-15 mg daily in divided doses, before breakfast; Max: 20 mg daily Sulphonylureas (Cont‘d)

8. 8 Long-acting: Long-acting: Chlorpropamide (Diabinese®): 250 mg daily with breakfast; Max: 500 mg Chlorpropamide (Diabinese®): 250 mg daily with breakfast; Max: 500 mg Glibenclamide (Daonil®): 5 mg daily with or immediately after breakfast; Max: 15 mg daily Glibenclamide (Daonil®): 5 mg daily with or immediately after breakfast; Max: 15 mg daily Glimepiride (Amaryl®): 1-4 mg daily shortly before or with first main meal; Max: 4 mg daily Glimepiride (Amaryl®): 1-4 mg daily shortly before or with first main meal; Max: 4 mg daily Sulphonylureas (Cont‘d)

9. 9 Contraindications: Contraindications: Severe hepatic and renal impairment Severe hepatic and renal impairment Breast-feeding and pregnancy Breast-feeding and pregnancy Elderly (Chlorpropamide, glibenclamide) Elderly (Chlorpropamide, glibenclamide) Adverse effects: Adverse effects: Nausea, vomiting, diarrhoea and constipation Nausea, vomiting, diarrhoea and constipation Increased appetite and weight gain Increased appetite and weight gain Hypoglycaemia Hypoglycaemia Hypersensitivity Hypersensitivity Sulphonylureas (Cont‘d)

10. 10 Biguanides Decreasing gluconeogenesis in the liver Decreasing gluconeogenesis in the liver Increase peripheral utilisation of glucose by muscle Increase peripheral utilisation of glucose by muscle Acts only in the presence of endogenous insulin Acts only in the presence of endogenous insulin Metformin (Glucophage®) is the only available biguanide Metformin (Glucophage®) is the only available biguanide Is antihyperglycemic, not hypoglycemic Is antihyperglycemic, not hypoglycemic Recommended for obese or insulin resistant diabetic patients Recommended for obese or insulin resistant diabetic patients

11. 11 Metformin: Metformin: 500 mg bd-tid; Max: 3 g, usually limit to 2 g daily 500 mg bd-tid; Max: 3 g, usually limit to 2 g daily Contraindications: Contraindications: Hepatic or renal impairment (must withdraw) Hepatic or renal impairment (must withdraw) Ketoacidosis Ketoacidosis Predisposition to lactic acidosis: severe dehydration, which is most likely to occur in patients with renal impairment Predisposition to lactic acidosis: severe dehydration, which is most likely to occur in patients with renal impairment Biguanides (Cont’d)

12. 12 Contraindications (Cont’d): Contraindications (Cont’d): Infection, shock, trauma, heart failure, respiratory failure, recent myocardial infarction, severe peripheral vascular disease Infection, shock, trauma, heart failure, respiratory failure, recent myocardial infarction, severe peripheral vascular disease Hepatic impairment, alcohol dependency Hepatic impairment, alcohol dependency Use of iodine-containing x-ray contrast media (do not restart melformin until renal function returns to normal) Use of iodine-containing x-ray contrast media (do not restart melformin until renal function returns to normal) Pregnancy and breast-feeding Pregnancy and breast-feeding Biguanides (Cont’d)

13. 13 Biguanides (Cont’d) Adverse effects: Adverse effects: Decreased appetite Decreased appetite Nausea, vomiting and diarrhoea Nausea, vomiting and diarrhoea Lactic acidosis (rarely) Lactic acidosis (rarely) Decreased absorption of vitamin B 12 and folic acid Decreased absorption of vitamin B 12 and folic acid Allergic skin reactions Allergic skin reactions

14. 14 Biguanides (Cont’d) Nursing alerts: Nursing alerts: Take metformin with meals and increase dosage slowly to minimise GI adverse effects Take metformin with meals and increase dosage slowly to minimise GI adverse effects Lactic acidosis, characterised by drowsiness, malaise, bradycardia and hypotension is a rare but serious adverse effect. Since this is a medical emergency, report to the physician immediately if suspected Lactic acidosis, characterised by drowsiness, malaise, bradycardia and hypotension is a rare but serious adverse effect. Since this is a medical emergency, report to the physician immediately if suspected

15. 15 Alpha glucosidase inhibitor Delay the digestion & absorption of starch & sucrose by inhibition of intestinal alpha glucosidase in the intestine Delay the digestion & absorption of starch & sucrose by inhibition of intestinal alpha glucosidase in the intestine Acarbose (Glucobay®) Acarbose (Glucobay®) 50-100 mg tid; Max: 200 mg tid 50-100 mg tid; Max: 200 mg tid

16. 16 Contraindications: Contraindications: Pregnancy and breast-feeding Pregnancy and breast-feeding Inflammatory or malabsorptive intestinal disorders Inflammatory or malabsorptive intestinal disorders Hepatic impairment Hepatic impairment Severe renal impairment Severe renal impairment Alpha glucosidase inhibitor (Cont’d)

17. 17 Alpha glucosidase inhibitor (Cont’d) Adverse effects: Adverse effects: Flatulence, soft stools, diarrhoea, abdominal distention and pain Flatulence, soft stools, diarrhoea, abdominal distention and pain Liver dysfunction Liver dysfunction

18. 18 Nursing alerts Nursing alerts Tablets should be taken with first mouthful of food Tablets should be taken with first mouthful of food Absorption of sugar (sucrose) is blocked by acarbose. When hypogylcaemia occurs, only glucose should be given Absorption of sugar (sucrose) is blocked by acarbose. When hypogylcaemia occurs, only glucose should be given Alpha glucosidase inhibitor (Cont’d)

19. 19 Metglitinides Stimulate insulin release Stimulate insulin release Rapid onset of action & short duration Rapid onset of action & short duration Taken shortly before meals Taken shortly before meals

20. 20 Repaglinide (NovoNorm®): Repaglinide (NovoNorm®): 500 mcg – 4 mg daily within 30 min before main meals; Max: 16 mg daily 500 mcg – 4 mg daily within 30 min before main meals; Max: 16 mg daily Nateglinide: Nateglinide: 60 mg tid within 30 min before main meals; Max: 180 mg tid 60 mg tid within 30 min before main meals; Max: 180 mg tid Metglitinides (Cont’d)

21. 21 Contraindications: Contraindications: Ketoacidosis Ketoacidosis Pregnancy and breast-feeding Pregnancy and breast-feeding Severe hepatic impairment (for repaglinide) Severe hepatic impairment (for repaglinide) Metglitinides (Cont’d)

22. 22 Metglitinides (Cont’d) Adverse effects: Adverse effects: Hypoglycaemia Hypoglycaemia Hypersensitivity reactions including pruritus, rashes and urticaria Hypersensitivity reactions including pruritus, rashes and urticaria Abdominal pain, diarrhoea, constipation, nausea and vomiting (repaglinide) Abdominal pain, diarrhoea, constipation, nausea and vomiting (repaglinide) Nursing alert: Nursing alert: Administration must always be associated with meals Administration must always be associated with meals

23. 23 Thiazolidinediones Also known as Glitazones Also known as Glitazones Reduce peripheral insulin resistance by enhancing uptake of glucose by skeletal muscle cells Reduce peripheral insulin resistance by enhancing uptake of glucose by skeletal muscle cells Rosiglitazone (Avandia®): Rosiglitazone (Avandia®): 4 mg daily in combination with metformin or a sulphonylurea; Max: 8 mg daily when with metformin 4 mg daily in combination with metformin or a sulphonylurea; Max: 8 mg daily when with metformin Pioglitazone (Actos®): Pioglitazone (Actos®): 15-30 mg daily 15-30 mg daily

24. 24 Contraindications: Contraindications: Hepatic impairment Hepatic impairment History of heart failure, combination of insulin History of heart failure, combination of insulin Pregnancy and breast-feeding Pregnancy and breast-feeding Thiazolidinediones (Cont’d)

25. 25 Adverse effects: Adverse effects: GI disturbances, headache, anaemia GI disturbances, headache, anaemia Weight gain Weight gain Oedema Oedema Hypoglycaemia (less common for Pioglitazone) Hypoglycaemia (less common for Pioglitazone) Liver dysfunctions (rare) Liver dysfunctions (rare) Thiazolidinediones (Cont’d)

26. 26 Nursing Alerts: Nursing Alerts: Monitor liver function before treatment, then every 2 months for 1 year and periodically thereafter Monitor liver function before treatment, then every 2 months for 1 year and periodically thereafter Seek immediate medical attention if symptoms such as nausea, vomiting, abdominal pain, fatigue & dark urine develop Seek immediate medical attention if symptoms such as nausea, vomiting, abdominal pain, fatigue & dark urine develop Discontinue if jaundice occurs Discontinue if jaundice occurs Monitor closely for oedema & other signs of congestive heart failure Monitor closely for oedema & other signs of congestive heart failure Thiazolidinediones (Cont’d)

27. 27 Non-oral antidiabetic drugs Insulin: Insulin: Supplement the insulin secreted by pancreas Supplement the insulin secreted by pancreas Promote uptake of glucose in muscle Promote uptake of glucose in muscle Facilitate conversion of glucose to glycogen in liver, inhibit gluconeogenesis & glycogenolysis in liver Facilitate conversion of glucose to glycogen in liver, inhibit gluconeogenesis & glycogenolysis in liver

28. 28 Actions of Insulin Glucose transport into muscle & fat cells. Glucose transport into muscle & fat cells. Increased glycogen synthesis. Increased glycogen synthesis. Inhibition of gluconeogenesis. Inhibition of gluconeogenesis. Inhibition of lipolysis & increased formation of triglycerides. Inhibition of lipolysis & increased formation of triglycerides. Stimulation of membrane-bound energy- dependent ion transporters (e.g. Na/K ATPase). Stimulation of membrane-bound energy- dependent ion transporters (e.g. Na/K ATPase). Stimulation of cell growth Stimulation of cell growth

29. 29 Insulin (Cont’d) They are divided into short, intermediate & long-acting preparations: They are divided into short, intermediate & long-acting preparations: Short-acting: Short-acting: Neutral/soluble insulin Neutral/soluble insulin E.g. Actrapid®HM, Humulin R® E.g. Actrapid®HM, Humulin R® Insulin Lispro Insulin Lispro E.g. Humalog® E.g. Humalog® Insulin Aspart Insulin Aspart E.g. NovoRapid® E.g. NovoRapid®

30. 30 Intermediate-acting: Intermediate-acting: Isophane insulin Isophane insulin E.g. Protaphane®HM, Humulin N® E.g. Protaphane®HM, Humulin N® Insulin zinc suspension Insulin zinc suspension E.g. Monotard®, Humulin L® E.g. Monotard®, Humulin L® Insulin (Cont’d)

31. 31 Insulin (Cont’d) Long-acting: Long-acting: Crystalline insulin zinc Crystalline insulin zinc E.g. Ultratard®HM E.g. Ultratard®HM Insulin glargine Insulin glargine E.g. Lantus® E.g. Lantus®

32. 32 Mixed Insulins: Mixed Insulins: Biphasic isophane insulin Biphasic isophane insulin 30% soluble insulin/70% isophane insulin 30% soluble insulin/70% isophane insulin E.g. Mixtard ®30, Humulin ®70/30 E.g. Mixtard ®30, Humulin ®70/30 20% soluble insulin/80% isophane insulin 20% soluble insulin/80% isophane insulin E.g. Mixtard ®20 E.g. Mixtard ®20 Insulin (Cont’d)

33. 33 Dose: Dose: Given through subcutaneous injection Given through subcutaneous injection According to the requirements According to the requirements Short-acting: Short-acting: Usually inject 15-30 min before meals Usually inject 15-30 min before meals Intermediate- & long-acting: Intermediate- & long-acting: Once or twice daily Once or twice daily Can be given in conjunction with short-acting insulin Can be given in conjunction with short-acting insulin Insulin (Cont’d)

34. 34 Insulin Formulations

35. 35 Precautions: Precautions: may decrease requirements in renal or hepatic impairment, some endocrine disorders, coeliac disease may decrease requirements in renal or hepatic impairment, some endocrine disorders, coeliac disease Insulin (Cont’d)

36. 36 Nursing Alerts: Nursing Alerts: Teach patients how to prepare & use the subcutaneous (SC) injection, and the usual areas used for SC injection including abdomen, thigh & upper arm Teach patients how to prepare & use the subcutaneous (SC) injection, and the usual areas used for SC injection including abdomen, thigh & upper arm Rotate the injection site within the general area employed. Allow about 1 inch between sites Rotate the injection site within the general area employed. Allow about 1 inch between sites Insulin (Cont’d)

37. 37 Nursing Alerts (Cont’d): Nursing Alerts (Cont’d): Storage Storage Penfill Penfill Cartridges not in use should be stored between 2-8 ℃ Cartridges not in use should be stored between 2-8 ℃ Cartridges used in the pen or carried as spare can be used for up to one month Cartridges used in the pen or carried as spare can be used for up to one month Vial Vial Vials not in use should be stored between 2-8 ℃ Vials not in use should be stored between 2-8 ℃ Vial in use can be kept at room temp for 6 weeks (Novo Nordisk) Vial in use can be kept at room temp for 6 weeks (Novo Nordisk) Vials in use can be kept at room temp for 28 days (Lilly) Vials in use can be kept at room temp for 28 days (Lilly) Insulin (Cont’d)

38. 38 Hypoglycaemia Nursing Alerts: Nursing Alerts: Observe for and teach the patient about signs and symptoms of hypoglycaemia Observe for and teach the patient about signs and symptoms of hypoglycaemia Tachycardia, palpitations Tachycardia, palpitations Sweating Sweating Nervousness, headache, confusion, drowsiness Nervousness, headache, confusion, drowsiness Fatigue Fatigue Rapid treatment is required Rapid treatment is required Patient is conscious: oral glucose should be given Patient is conscious: oral glucose should be given Patient is unconscious: IV glucose should be used Patient is unconscious: IV glucose should be used