Pharmacology of diabetes mellitus

pharmacological notes on drugs used in treatment of type 1 and type 2 diabetes mellitus

1. Pharmacology of Diabetes Mellitus (Insulin & oral anti-diabetic drugs) Dalia K. Zaafar Lecturer of Pharmacology

2. What is Diabetes Mellitus A metabolic disease characterized by Hyperglycemia altered metabolism of lipid, CHO & Proteins. increase risk of complications from vascular diseases

3. Classification of diabetes I) Type 1 DM ( IDDM ) a) Autoimmune (Type 1 A) b) Non auto-immune/ idiopathic (Type 1 B) II) Type 2 DM (NIDDM) III) Type 3 DM (Other specific types of DM) a)Specific defined gene mutation b)Diabetes Secondary to Pancreatic diseases C) Diabetes secondary to Endocrinopathies IV) Type 4 DM Gestational diabetes mellitus (GDM)

4. Symptoms of DM

5. Symptoms of DM ↑PGL→ incomplete reabsorption in prox. Renal tubules→ Glycosuria→↑ osmotic pressure of urine →↓reabsorption of water → polyuria →↑Fluid loss → Dehydration → polydipsia Glucose absorption →changes in shape of lenses → Blurred vision Diabetic ketoacidosis- Kaussmaul breathing, polyuria, nausea, vomiting, altered state of consciousness, coma, death

6. Diagnosis of DM Test Normal GT Impaired GT Diabetic Fasting PG (mg/dl) <100 100-125 ≥ 126 2h after glucose load (mg/dl) <140 > 140-199 ≥ 200 Glycated Hb 4-5.6% 5.7-6.4% >6.5%

7. Comparison between type I & II DM Type I DM Type II DM Age of onset Childhood/ puberty Over 35 years old Primary defect Immune or viral destruction of β cells Inadequate insulin production or insulin resistance Prevalence 10-20% 80-90% Genetic predisposition Moderate Very strong Ketoacidosis common rare Anti-islet cell antibody >80% <5% Insulin TTT Always necessary May be required

8. Honeymoon period It is a phase that some people with type 1 diabetes experience shortly after being diagnosed. During this time, a person with diabetes seems to get better and may only need minimal amounts of insulin . This happens because your pancreas is still making some insulin to help control your blood sugar.

9. Management of T1DM Education Diet and meal planning Insulin therapy Monitoring Educate child & care givers about: Diabetes Insulin Life-saving skills Recognition of Hypo & DKA Meal plan

10. Management of T1DM Diet and meal planning Regular meal plans with calorie exchange options are encouraged. 50-60% of required energy to be obtained from complex carbohydrates. Distribute carbohydrate load evenly during the day preferably3 meals & 2 snacks with avoidance of simple sugars. Encouraged low salt, low saturated fats and high fiber diet.

11. Insulin Mechanism of action

12. Insulin Role of insulin ↑glucose uptake ↑glycogen synthesis ↑lipogenesis ↑protein synthesis ↑triglyceride formation So it is an anabolic hormone

13. Classification of insulin

14. Classification of insulin

15. Classification of insulin

16. Classification of insulin

17. Indications of Insulin 1) DIABETES MELLITUS 2) DIABETIC KETOACIDOSIS

18. Indications of Insulin 3) Hyperosmolar Nonketotic (Hyperglycemia) Coma 4) pregnant diabetic patients

19. Adverse reactions of Insulin 1) hypoglycemia 2) Lipoatrophy & Lipohypertrophy Atrophy→ immune response to insulin Lipohypertrophy→ lipogenic action of high local conc. 3) Insulin allergy & resistance 4) Insulin edema

20. Drug interactions

21. Type 2 DM Management A- Oral Hypoglycemic agents 1- Sulfonylureas First Generation: Tolbutamide, Chlorpropamide Second Generation: Glibenclamide (glyburide), Glipizide, Gliclazide, Glimepiride

22. Sulfonylureas Mech. Of action 1- Stimulates Insulin release from β- cells 2- blocks ATP sensitive K+ channels → depolarization→ Ca entry →insulin release 3- Glucagon levels are suppressed Pharmacokinetics well absorbed and metabolized in liver or kidney and excreted in urine

23. Sulfonylureas Adverse effects 1- Hypoglycemia 2- Weight gain 3- Cross placental barrier – fetal hypoglycemia Contra indications 1- Ketocanazole , chloramphenicol and anticoagulants- inhibit their metabolism 2- Sulfonamides, salicylates etc - protein binding displacement 3- Propranolol masks the symptoms of sulfonylureas

24. Meglitinides 2- Meglitinide Analogues: Repaglinide, Nateglinide Mech. Of action 1- Stimulate insulin release, same as sulfonylurea 2- Administered before meal to control PP blood glucose

25. Meglitinides Advantages of Nateglinide /Repaglinide 1- No significant increase in bodyweight 2- Can be utilized in mild to moderate renal failure 3- Nateglinide : approved in hepatic failure

26. Management B- Oral antihyperglycemic agents 1- Biguanides : Metformin and Phenformin Metformin is the drug of choice for newly diagnosed type 2 DM patients according to ADA. Phenformin is an obsolete drug because of its high lactic acidosis risk Metformin is excreted unchanged in urine

27. Biguanides Mech. Of action 1- Increased uptake and utilization of glucose by muscles →reduce insulin resistance 2- Inhibition of hepatic gluconeogenesis → reduce hepatic glucose output 3- Slowing of glucose absorption from GIT 4- Promotion of insulin binding to its receptor

28. Biguanides Contraindications of metformin 1- renal impairment with elevated serum creatine levels (eGFR < 30 mL/min/1.73 m 2 ). 2- congestive heart failure 3- advanced age (more than 80 years of age). 4- radiologic studies with contrast. As these patients have higher risk for lactic acidosis.

29. Management 2- Thiazolidinediones ( Glitazones ) Rosiglitazone: withdrawn from the market in 2010 b/o risk of Heart failure and MI. Pioglitazone: M.O.A: Stimulates (PPAR-Ƴ) receptor → promotes transcription of insulin responsive genes which control glucose & lipid metabolism → ↑ insulin sensitivity & ↓ insulin resistance Promotes uptake and utilization of glucose by increasing the GLUT-4 Inhibit gluconeogenesis

30. α- Glycosidase Inhibitors C- α- Glycosidase Inhibitors Ex. Acarbose, Miglitol M.O.A:1- Reduce digestion and absorption of carbohydrates by inhibiting α glucosidase enzyme Do not directly affect insulin secretion No hypoglycemia

31. GLP-1 agonists Glucagon like peptide- 1 released after meals from the upper & lower bowel → augment glucose dependent insulin secretion, during the phase of nutrition absorption from GIT t ½ GLP-1 – 1 to 2 min Metabolized quickly by DPP-IV enzyme Exenatide

32. GLP-1 agonists Exenatide: GLP-1 agonist Resistant to DPP-IV degradation Potent agonist of GLP-1 receptor, Orally inactive Given SC (5-10μg) twice daily, 30-60 min before meals It reduces only post meal glucose rise M.O.A: Stimulates insulin secretion from β- cells and decreases glucagon release

33. DPP IV inhibitors Dipeptidyl piptedase inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Septagliptin, Allogliptin Orally active Selective inhibitors of DPP-IV enzyme that deactivates GLP-1. M.O.A 1- Increase insulin secretion 2- Decrease glucagon release 3- Delay gastric emptying 4- Suppress appetite

34. DPP IV inhibitors

35. SGLT-2 inhibitors Newer antidiabetic drugs: Dapaglifozin , Serglifozin , Remoglifozin Kidney continuously filters glucose through glomerulous which is reabsorbed back by Na2+ glucose co-transporter -2 (SGLT-2) Inhibition of SGLT – 2 decreases glucose re-absorption Advantages: Weight loss, No hypoglycemia Disadvantages: Increased risk of urinary infection in presence of glycosuria

36. SGLT-2 inhibitors

37. Thank You!