DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

1. DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

2. DIABETES MELLITUS One of the leading cause of death by diseases (cardiovascular problems, stroke) One of the leading cause of blindness One of the leading cause of renal failure One of the leading cause of impotence (males) Risk of foot amputation

3. N.B. IDDM: insulin dependent diabetes mellitus. NIDMM: non-insulin dependent diabetes mellitus.

5. Effects of insulin

6. Insulin deficiency ↓K+ uptake by cells

7. Some notes: Glucose is reabsorbed in the kidney tubules in the form of glucose 6 phosphate. In diabetic patients glucose filtration floods the renal tubules exceeding 180 g/dl, threshold for glucose’s reabsorption, leading to the appearance of glucose in the urine (glucosuria). This results in osmotic dragging of water into the tubules resulting in polyuria with subsequent polydypsia.

8. Insulin Degradation • Hydrolysis of the disulfide linkage between α & β chains. • Metabolism of insulin: Endogenous: 60% in liver & 40% in kidney (because it goes directly to the liver by the portal circulation). Exogenous: 60% kidney & 40% liver • Half-Life 5-7min (endogenous insulin) Delayed-release form( injected one) • Pregnant women with type II or gestational DM should take insulin by injection and avoid taking oral hypoglycemics.

9. cont’d • Category B (not teratogenic) • The site of injection should be changed every once in a while, (Injection in same place  hypertrophy to subcutaneous tissue  ↓ absorption) • Should be stored in refrigerator & warm up to room temp before use. • Must be used within 30 days.

10. Fast action of insulin in the abdomen

11. TYPES OF INSULIN PREPARATIONS • A) Insulin used to control postprandial (after meals) hyperglycemia and emergency ketoacidosis • Ultra-short-acting( e.g. insulin lispro, insulin aspart) • Short-acting -Regular- (e.g. Novolin R, Humulin R) • B) Insulin used for maintenance treatment of type I DM • Intermediate-acting (NPH, Lente insulin) • 4. Long-acting (Glargine,Ultralente ) Clear liquid Turbid suspension عكر N.B. NPH = Neutral protamine Hagedorn

13. Advantages of Insulin Lispro (ultra-short) vs Regular Insulin (short acting) : • Rapid onset of action ( patients will not wait long before they eat ). • Its duration of action is no longer than 3-4 hrs regardless of the dose. • Decreased risk of postprandial hypoglycemia • Decreased risk of hyperinsulinemia

14. In emergency you can use either ultra-short or regular insulin (no difference in the duration of action because it is given IV) قواعد جوهرية In postprandial hyperglycemia you can use both but Ultra-short has less duration of action  no hypoglycemia Use ultra-short, wait for 5 minutes before having a meal while in regular, wait for 30 minutes

15. 3. Intermediate - acting insulins • Isophane (NPH) (Humulin N; Novolin N, etc.) • Turbid suspension (shaken before use) • Injected S.C. (Only) • Onset of action 1 - 2 hr • Peak serum level 5 - 7 hr • Duration of action 13 - 18 hr • Insulin mixtures • 75/25 70/30 50/50 ( mix isophane with ultra-short or short acting insulin). Isophane (NPH) Ultra-short or short acting Insulin mixture is given to patients with high postprandial hyperglycemia

16. (contd.) Lente insulin(Humulin L; Novolin L). Turbid suspension Mixture of 30% semilente insulin small crystals rapidly acting 70% ultralente insulin large crystals slow acting with prolonged duration Injected S.C. (only) Onset of action 1 - 3 hr Peak serum level 4 - 8 hr Duration of action 13 - 20 hr

17. Cont’d • Lente and NPH insulins • have the same effect. • given once or twice a day. • N.B: They are not used during emergencies • (e.g. diabetic ketoacidosis).

18. 4. Long – acting insulins e.g. Glargine ( Lantus ) Insulin glargine Onset of action: 2 hr Absorbed less rapidly than NPH or Lente insulins Duration of action up to 24 hr Advantages Constant circulating insulin over 24 hr with no pronounced peak (see next slide) Safer than NPH & Lente insulins ( less risk of nocturnal hypoglycemia) Clear solution(does not require resuspension before administration) Designed to overcome the disadvantages of intermediately acting insulins Nocturnal = أثناء النوم

19. Profile of Insulin Glargine vs NPH NPH Glargine glargine (plateau )

20. In the previous figure NPH gives a peak risk of hypoglycemia But glargine doesn’t give a peak risk of hypoglycemia N.B: intermediate & long acting use for maintenance of blood sugar during 24 hr in type I DM

21. Glargine

22. Methods of Adminisration • Insulin Syringes (most common) • Pre-filled insulin pens (expensive) • External insulin pump Under Clinical Trials • Oral tablets • Inhaled aerosol (still undergoing trials) • Intranasal, Transdermal • Insulin Jet injectors (needle less) • Ultrasound pulses

23. COMPLICATIONS OF INSULIN THERAPY 1. Severe Hypoglycemia (< 50 mg/dl ) life-threatening 2.Weight gain

24. Cont’d 3. Local or systemic allergic reactions (rare) 4. Insulin resistance (when the patient needs more than 200 units/day)(IgG anti-insulin antibodies, infection, expired insulin(rare)). 5. Lipohypertrophy at injection sites 6. Hypokalemia

26. Oral Hypoglycemics All taken orally in the form of tablets. Patients with type II diabetes have two physiological defects: • Abnormal insulin secretion (most important) • Resistance to insulin action in target tissues associated with decreased number of insulin receptors

27. Oral Anti-Diabetic Agents • Sulfonylureas e.g. Tolbutamide, Glyburide. • Meglitinides e.g. Repaglinide, Nateglinide. • Biguanides e.g. Metformin. • Alpha-glucosidase inhibitors e.g. Acarbose. • Thiazolidinedionese.g. Pioglitazone. • Dipeptidyl peptidase-4 inhibitorse.g. Sitagliptin, vildagliptin

28. More selective an smaller dose

29. FIRST GENERATION SULPHONYLUREA COMPOUNDS * Good for patients with renal impairment **Patients with renal impairment can expect long t1/2 ***Chlorpropamide isn’t well metabolized N.B. All 1stG Metabolized in liver.

30. SECOND GENERATION SULPHONYLUREA COMPOUNDS

31. MECHANISM OF ACTION OF SULPHONYLUREAS (SU) 1) Release of insulin from β-cells*(hence, no use in type 1 DM). 2) Reduction of serum glucagon concentration.(in long term use) 3) Potentiation of insulin action on target tissues. - SU’s binds to k+ channel  no efflux  depolarization Opening of voltage gated Calcium channel  insulin release

32. Sulphonylureas ( Cont.) • CLINICAL USE: • Approved for monotherapy and in combination with metformin or thiazolidinediones in type II DM • Taken before each meal, 1-2 times/day

33. SIDE EFFECTS OF SULPHONYLUREAS 1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycaemia 3) Dilutionalhyponatraemia & water intoxication (Chlorpropamide) because it ↑ADH 4) Disulfiram*-like reaction with alcohol (Chlorpropamide) “contain sulfur” Disulfiram R: Ingestion of chlorpropamide with alcohol  hyperemic flush 5) Weight gain alcoholism * Disulfiram is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol.

34. CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney. metabolism excretion 3) Pregnancy, lactation (due to the physiologic stress, not teratogenicity) 4) Major stress.

35. DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS Sulfonamides (increase insulin secretion) Warfarin(displace the drugs  ↑t1/2 ) Salicylates(displace the drugs  ↑t1/2 ) Propranolol(mask the hypoglycemia) Alcohol (acute) Liver enzymes inhibitors ↑SU conc.

36. DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS Thiazide diuretics (a K+ opener hyperpolarization no release of insulin) Corticosteroids Epinephrine Liver enzymes inducers e.g. alcohol (in chronic alcohlic patients ) ↓sensitivity of insulin

37. MEGLITINIDES e.g. Repaglinide, Nateglinide (SU without sulfur) • PKs: • Taken orally • Rapidly absorbed ( Peak approximately 1hour ) • Metabolized by liver • t1/2 = 1 hr • Duration of action 4-5 hr

38. MEGLITINIDES (Contd.) MECHANISM OF ACTION Bind to the same KATP Channel as do Sulfonylureas, to cause insulin release from β-cells. They bind to K channels  no K efflux  depolarization of β cells  opens Ca channel  influx  release of insulin

39. MEGLITINIDES (Contd.) CLINICAL USE Approved for monotherapy and in combination with metformin in type 2 diabetes Taken before each meal, 3 times / day Does not offer any advantage over sulfonylureas SIDE EFFECTS: Hypoglycemia Weight gain( less than sulfonylureas ) Caution in patients with renal & hepatic impairement. We can use it if the patient is allergic to sulfonylurea

40. BIGUANIDES • e.g. Metformin • PKs: • Given orally • Do not bind to plasma proteins • Not metabolized • Excreted unchanged in urine • t 1/2 2 hr

41. BIGUANIDES (Contd.) MECHANISM OF ACTION 1. Increase peripheral glucose utilization (increase insulin receptor sensitivity thus is insulin dependent) 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut

42. Advantages of Metformin over SUlfonylurea • Does not cause hypoglycemia because they don’t stimulate the release of insulin from pancreas  no hypoglycemia • Does not result in weight gain because they ↓appetite.

43. BIGUANIDES (Contd.) SIDE EFFECTS 1. Metallic taste in the mouth 2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use) 4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal failure) (they ↑anerobicglycolysis ↑lactic acid) this phenomenon is treated with NaHCO3.

44. BIGUANIDES (Contd.) CONTRAINDICATIONS • Hepatic impairment • Heart failure • 3. Renal impairment • 4. Alcoholism In these situations the body is more sensitive to lactic acidosis

45. BIGUANIDES (Contd.) INDICATIONS • Obese patients with type II diabetes • 2. Alone or in combination with sulfonylureas or meglitinides.

46. α-GLUCOSIDASE INHIBITORS • e.g. Acarbose • PKs: • Given orally. • Not absorbed from intestine except small amount (hence, no systemic effect). • t1/2 3 - 7 hr. • Excreted with stool.

47. α-GLUCOSIDASE INHIBITORS (Contd.) MECHANISM OF ACTION With the use of drugs, there is no sharp rise in blood sugar (مايشطح السكر بعد الأكل) They delay the absorption but don’t inhibit it

48. α-GLUCOSIDASE INHIBITORS (Contd.) • It is a competitive inhibitor of glucosidase enzyme (has more affinity than sugar ). • It used as supportive not as treatment . • Also can be used in border line patients. • It can be use with type I DM but not alone.

49. α-GLUCOSIDASE INHIBITORS (Contd.) SIDE EFFECTS • Flatulence • sugar fermentation • Loose stool or diarrhea results in gas formation • Abdominal pain • Alone does not cause hypoglycemia

50. α-GLUCOSIDASE INHIBITORS (Contd.) INDICATIONS Patients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin to reduce postprandial hyperglycemia Maybe helpful in obese Type II patients (similar to metformin) α-GLUCOSIDASE INHIBITORS can also be used with type I DM with meals.