Antidiabetics drugs. Prof. Hanan Hagar

Transcription

1 Antidiabetics drugs Prof. Hanan Hagar

2 Outline of lecture What is diabetes? Types of diabetes Complications of diabetes Classification of antidiabetics Oral hypoglycemic drugs Insulin

3 Types of diabetes 1. Type I (formerly IDDM or Juvenile) due to autoimmune or viral diseases 2. Type II (formerly NIDDM or adult) due to genetic factors 3. Gestational diabetes Following pregnancy

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5 Characteristic Type 1 Type 2 Onset (Age) Usually < 30 Usually > 40 Type of onset Abrupt Gradual Nutritional status Usually thin Usually obese Clinical symptoms Polydipsia, polyphagia, polyuria, Wt loss Often asymptomatic Ketosis Frequent Usually absent Endogenous insulin Absent Present, but relatively ineffective Related lipid abnormalities Hypercholesterolemia frequent, all lipid fractions elevated in ketosis Hypoglycemic drugs Not indicated indicated Cholesterol & triglycerides often elevated; carbohydrateinduced hypertriglyceridemia common R Insulin therapy Required required in 20-30% of patients 5

6 Types of diabetes

7 Types II diabetes

8 Type II Diabetes Inadequate insulin secretion. Insulin resistance in target tissues.

9 Complications of diabetes Cardiovascular problems Renal failure (nephropathy). Blindness (retinopathy). Neuropathy (neuropathy). Risk of foot ambutation

10 Antidiabetics drugs 1. Oral hypoglycemic drugs 2. Insulin

11 Oral hypoglycemic drugs 1. Sulfonylurea drugs 2. Meglitinide analogues 3. Biguanides 4. alpha-glucosidase inhibitors. 5. Thiazolidinediones. 6. Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin

12 Oral hypoglycemic drugs Insulin secretagogues 1. Sulfonylurea drugs 2. Meglitinide analogues 3. D-phenylalanine derivatives Insulin sensitizers 1. Biguanides 2. Thiazolidinediones or glitazones

13 III. Alpha glucosidase inhibitors IV. Gastrointestinal hormones

14 Insulin secretagogues I. SULFONYLUREAS: First generation Second generation Tolbutamide Glipizide Tolazamide Glyburide Acetohexamide (Glibenclamide) Chlorpropamide Glimepiride

15 Mechanism of Action: Stimulate insulin release from functioning B cells by blocking of ATP-sensitive K channels resulting in depolarization and calcium influx. Reduction of serum glucagon concentration Increase tissue sensitivity to insulin.

16 Pharmacokinetics: Orally, well absorbed. Reach peak concentration after 2-4 hr. All are highly bound to plasma proteins. Duration of action is variable. Second generation has longer duration.

17 Pharmacokinetics: Metabolized in liver excreted in urine (elderly and renal disease) Cross placenta, stimulate fetal B cells to release insulin hypoglycemia at birth.

18 Sulfonylureas First generation second generation Short acting Intermediate acting Long acting Short acting Long acting Tolbutamide Acetohexamide Chlorpropamide Glipizide Tolazamide Glyburide (Glibenclamide) Glimepiride

19 First generation sulfonylurea Short: Tolbutamide (8 h) Intermediate: Tolazamide Acetohexamide (20 h) Long: Chlorpropamide (60 h)

20 First generation sulfonylurea Tolbutamid short-acting Acetohexamide intermediateacting Tolazamide intermediateacting Chlorpropamide long- acting Absorption Well Well Slow Well Metabolism Yes Yes Yes Yes Metabolites Inactive Active Active Inactive Half-life 4-5 hrs 6 8 hrs 7 hrs hrs Duration of action Short (6 8 hrs) Intermediate (12 20 hrs) Intermediate (12 18 hrs) Long ( hrs) Excretion Urine Urine Urine Urine

21 First generation sulfonylurea Tolbutamide safe for old patients or pts with renal impairment Chlorpropamide cause prolonged hypoglycemia (hepatic-renal disease-old patients) Dilutional hyponatremia Hyperemic flush after alcohol ingestion Leukopenia, thrombocytopenia

22 Second generation sulfonylurea More potent have fewer adverse effects have fewer drug interactions has longer duration (24 h) e.g. Glipizide, glyburide (Glibenclamide), glimepiride Contraindicated in hepatic impairement or renal insufficiency

23 SECOND GENERATION SULPHONYLUREA Glipizide Glibenclamide (Glyburide) Glimepiride Absorption Well reduced by food Well Well Metabolism Yes Yes Yes Metabolites Inactive Inactive Inactive Half-life 2 4 hrs Less than 3 hrs 5-9 hrs Duration of hrs hrs hrs action short long long Doses Divided doses 30 min before meals Single dose Single dose 1 mg Excretion Urine Urine Urine

24 Unwanted Effects: 1. Hyperinsulinemia & Hypoglycemia: More in chlorpropamide & glibenclamide Less in tolbutamide. More in elderly and patients with renal disease. 2. Weight gain due to increase in appetite

25 Unwanted Effects: GIT upset. Dilutional hyponatremia, water intoxication (Chlorpropamide) vasopressin effect. Disulfiram-like reaction with alcohol (chlorpropamide). Tachyphylaxis (secondary failure).

26 Drug Interactions Drugs which augment hypoglycemic effect: NSAI: Phenyl butazone and salicylates Coumarin anticoagulants. Alcohol. Antibiotics: Sulphonamides Antifungal Drugs: Fluconazole.

27 Drugs which decrease hypoglycemic effect: Microsomal inducers. Thiazide diuretics Corticosteroids. Diazoxide. CONTRAINDICATIONS: Pregnancy (use insulin) Hepatic or renal insufficiency Type I diabetes

28 Meglitinide analogues are rapidly acting insulin secretagogues Repaglinide (Prandin) Nateglinide (Starlix)

29 Mechanism of Action: Stimulate insulin release from functioning B cells by modulating K efflux via blocking ATP-sensitive K channels resulting in depolarization and calcium influx.

30 Pharmacokinetics of Meglitinides Orally, well absorbed. Very fast onset of action, peak 1 h. short duration of action (4 h). Metabolized into inactive products in liver (CYP3A4).

31 Pharmacokinetics of Meglitinides excreted mainly in the bile Effective in early release of insulin after a meal (Post prandial glucose regulators) Taken just before each meal (3 times/day)

32 Uses of Meglitinides 1. Type II diabestes Monotherapy or combined therapy with metformin (better than monotherapy). 2. Patients allergic to sulfur or sulfonylurea

33 Adverse effects of Meglitinides less incidence than sulfonylureas Hypoglycemia (meal is delayed). Weight gain. Drug interactions. Contraindications Hepatic and renal impairment.

34 Drug Interactions 1. Enzyme inhibitors as cimetidine, fluconazole, erythromycin. 2. Enzyme inducers barbiturates, rifampicin and phenytoin. 3. Gemfibrozil augment action of repaglinide.

35 Insulin sensitizers 1. Biguanides 2. Thiazolidinediones or glitazones

36 Metformin BIGUANIDES

37 Mechanism of action of metformin Does not require functioning B cells. Does not stimulate insulin release. Increases peripheral glucose utilization (tissue glycolysis). Inhibits gluconeogenesis. Impairs glucose absorption from GIT. Reduces plasma glucagon level. LDL&VLDL. HDL

38 Pharmacokinetics of metformin orally. NOT bound to serum protein. NOT metabolized. t ½ 3 hours. Excreted unchanged in urine

39 Uses of metformin Has insulin sparing effect (insulin sensitizer). Obese patients with type II diabetes (with insulin resistance). Monotherapy or in combination. Advantages: No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia).

40 Adverse effects of metformin Metallic taste in the mouth GIT disturbances (nausea, vomiting, diarrhea). Lactic acidosis: Common in patients with renal disease, liver, pulmonary or cardiac disease. Long term use interferes with B 12 absorption.

41 Contraindications of metformin Pregnancy. Renal disease. Liver disease. Alcoholism. Conditions predisposing to hypoxia as cardiopulmonary dysfunction.

42 Insulin sensitizers Thiazolidinediones (glitazones) Pioglitazone (Actos)

43 Mechanism of action Activate nuclear receptors (peroxisome proliferator-activated receptor - ) (PPAR- ). Increase sensitivity of target tissues to insulin. Increase glucose uptake and utilization in muscle and adipose tissue. Increase insulin sensitivity (decrease insulin resistance).

44 Mechanism of actionof pioglitazone PPAR- α and Nuclear receptors. Liver, skeletal muscles, adipose tissue. control genes involved in glucose (PPAR- ) and lipid metabolism (PPAR- α). Increase insulin sensitivity in muscle and adipose tissue. triglycerides. HDL

45 Pharmacokinetics of pioglitazone Orally (once daily dose). Highly bound to plasma albumins (99%) Slow onset of activity Half life 3-4 h Metabolized by CYP450. Give active metabolites Excreted in urine 64% & bile

46 Uses of pioglitazone Type II diabetes with insulin resistance. Used either alone. Combined with sulfonylurea, biguanides or insulin. Anovulatory women (polycystic ovarian syndrome). No risk of hypoglycemia when used alone

47 Contraindications of pioglitazone Heart failure. Pregnancy. Significant liver disease.

48 Adverse effects of pioglitazone Fluid retention (Edema). Weight gain. Headache. Liver function tests for 1 st year of therapy. Failure of estrogen-containing oral contraceptives.

49 -Glucosidase inhibitors Acarbose (Precose). Miglitol (Glyset).

50 -Glucosidase inhibitors Reversible inhibitors of intestinal -glucosidases in intestinal brush border responsible for degradation of oligosaccharides to monosaccharides. include sucrase, maltase, dextranase, glycoamylase.

51 -Glucosidase inhibitors decrease carbohydrate digestion and absorption in small intestine. Decrease postprandial hyperglycemia. Taken just before meals. No hypoglycemia if used alone.

52 Kinetics of -glucosidase inhibitors Acarbose Given orally, poorly absorbed. Metabolized by intestinal bacteria. Excreted in stool and urine. Miglitol well absorbed, no systemic effects. Excreted unchanged in urine. 6 times more potent inhibitor for sucrase.

53 Uses of -glucosidase inhibitors Type II diabetics inadequately controlled inadequately controlled by diet with or without other agents ( SU, Metformin) alone or combined with insulin or sulfonylurea.

54 Adverse effects of -glucosidase inhibitors GIT: Flatulence, diarrhea, abdominal pain, bloating, increase in liver enzymes.

55 contraindications of -glucosidase inhibitors Inflammatory bowel disorders (IBD). Renal disease. Hepatic disease (used with caution). Intestinal obstruction.

56 Dipeptidyl peptidase-4 inhibitor (DPP- 4 inhibitors) e.g. Sitagliptin, vildagliptin

57 (DPP- 4 inhibitors) Sitagliptin Orally Given once daily half life 8-14 h Dose is reduced in pts with renal impairment

58 Mechanism of action of sitagliptin Inhibit DPP-4 enzyme (GLP-1, glucagon like peptide-1) and leads to an increase in incretin hormones level (gastrointestinal hormone secreted in response to food). This results in an increase in insulin secretion & decrease in glucagon secretion.

59 Mechanism of action

60 Clinical uses Type 2 DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects Nausea, abdominal pain, diarrhea Nasopharyngitis

61 INSULIN HISTORY: The hypoglycemic effects of pancreatic extract were first published by Kleiner in 1919.

62 The isolation of insulin in 1921 by Frederick Grant Banting and Charles H. Best ( in collaboration with JJR Macleod and James B. Collip) led to a revolution in the management of diabetes.

63 Chemistry of insulin: Polypeptide hormone MW Contains 51 amino acids arranged in two chains A (21) & B (30) linked by two disulphide bridges. B cells of pancreatic islets synthesize insulin from a precursor called proinsulin.

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65 Proinsulin is hydrolyzed into insulin & C- peptide. Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues. Proinsulin might have mild hypoglycemic action but C-peptide is inactive.

66 Storage Formed insulin is stored within granules of β cell in the form of crystals consisting of 2 atoms of zinc and 6 molecules of insulin which is equal to 8 mg or 200 biologic units. One milligram contains 28 units.

67 Insulin secretion

68 1. Stimulants of insulin secretion Insulin is secreted at low basal rate Its secretion can be stimulated by: Glucose, mannose Vagal stimulation. Amino acids (arginine) Gastrointestinal Hormones Secretin Gastrin- Cholecystokinin -adrenergic agonists.

69 2. inhibitors of insulin secretion α-sympathomimetics Somatostatin. Drugs: Diazoxide.

70 Insulin secretion by glucose Glucose is taken up by glucose transporter in cells glucose metabolism ATP block of K channels depolarization & Ca influx insulin release by exocytosis.

71 Mechanisms of Insulin secretion

72 Sources of Insulin Beef Insulin Differs by 3 AA from human insulin (more antigenic). It is isolated and purified from beef insulin. Porcine Insulin Differs by one AA.

73 Human Insulin. Recombinant DNA techniques. Less immunogenic. It contains a threonine molecule, allows more rapid absorption and short duration of action. Mixing with phosphate buffer reduces aggregation of regular insulin in infusion pumps.

74 Insulin degradation 1. Basal level of insulin is 5-15 µu/ml. 2. Half life of circulating insulin is 3-5 min. 3. Cleared by 60% liver, 40% kidney (endogenous insulin) 4. 60% kidney & 40% liver (exogenous insulin)

75 Insulin receptors Present on cell membranes of most tissues. Liver, muscle and adipose tissue glycogen in liver and skeletal muscles.

76 Pharmacodynamics of insulin: Lowering of blood glucose by: glucose uptake by peripheral tissues. synthesis and storage of glycogen in liver and skeletal muscles.

77 I. Carbohydrate Metabolism: glycogen synthesis (glycogen synthase) gluconeogenesis. glycogenolysis (liver). Glycolysis (muscle). glucose uptake & utilization. Conversion of carbohydrate to fats.

78 II. Fat Metabolism: Liver: triglyceride synthesis. Inhibits conversion of fatty acids to keto acids. Adipose Tissue: Triglycerides storage. Fatty acids synthesis.

79 III. Protein Metabolism: Liver: protein catabolism. Muscle: amino acids Uptake. protein Synthesis. glycogen synthesis

80 IV. potassium potassium uptake into cells.

81 Types of insulin preparations Vary in onset and duration of action. Ultrashort acting very fast onset and short duration Short acting (regular). fast onset and short duration. Intermediate acting. Long acting. Slow onset and long duration.

82 Ultra-short rapid-acting insulins 1. Insulin lispro, insulin aspart, insulin glulisine (injection) 2. Do not aggregate or form complexes 3. Fast onset of action (5-15 min) 4. Short duration of action (3-5 h) 5. Reach peak level min after injection.

83 Ultra-short Rapid-acting insulins Insulin Lispro, insulin aspart, insulin glulisine Clear solutions at neutral ph. Monomeric analogue. S.C. (5 min no more than 15 min before meal). I.V. emergency (only insulin lispro). 2-3 times/day. Mimic the prandial mealtime release of insulin

84 Ultra-short rapid-acting insulins insulin lispro, insulin aspart, insulin glulisine Have the lowest variability of absorption Preferred for external insulin pump (does not form hexamer) used to control post-prandial hyperglycemia and emergency ketoacidosis

85 Short acting insulins regular insulins Regular humulin R regular novolin R Soluble crystalline zinc insulin (stability shelf half life) Recombinant DNA technology Clear solutions at neutral ph. Hexameric analogue. Onset of action min (s.c.). Peak 2-4 h. Duration 6-8 h.

86 Regular insulins humulin R novolin R I.V. emergency. Management of ketoacidosis After surgery During acute infection 2-3 times/day. Control postprandial hyperglycemia & ketoacidosis. Pregnancy

87 Uses Short-acting (regular) insulins e.g. Humulin R, Novolin R postprandial hyperglycemia & emergency diabetic ketoacidosis Ultra-Short acting insulins e.g. Lispro, aspart, glulisine postprandial hyperglycemia & emergency diabetic ketoacidosis Physical characteristics chemistry Route & time of administration Clear solution at neutral ph Hexameric analogue S.C min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Clear solution at neutral ph Monomeric analogue S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action min ( S.C ) 0 15 min ( S.C ) Peak level Duration Usual administration 2 4 hr 6 8 hr 2 3 times/day or more min 3 5 hr 2 3 times / day or more

88 Advantages of Insulin Lispro vs Regular Insulin Rapid onset of action ( pts will not wait long before they eat ). Decreased risk of postprandial hypoglycemia Decreased risk of hyperinsulinemia.

89 Intermediate acting insulins Isophane (NPH) (Humulin N, Novolin N) Lente insulin (Humulin L, Novolin L)

90 Isophane (NPH) (Humulin N, Novolin N) NPH, a neutral protamine hagedorn in phosphate buffer is combination of protamine & crystalline zinc insulin (1: 6 molecules). proteolysis release insulin. Turbid suspension at neutral ph Given S.C. only Onset of action 1-2 h.

91 Isophane (NPH) (Humulin N, Novolin N) Peak serum level 5-7 h. Duration of action h. Insulin mixtures 75/25-70/30-50/50 (NPH/regular). (NPL= NPH / lispro)(npa= NPH / aspart) NPL& NPA have the same duration as NPH 70/30 50/50 NPL/insulin lispro

92 Lente insulin (Humulin L, Novolin L) Mixture of 30% semilente insulin (amorphous precipitate of insulin with zinc in acetate buffer) + 70% ultralente insulin (poorly soluble crystal of zinc insulin) Turbid suspension at neutral ph Given S.C.

93 Lente insulin (Humulin L, Novolin L) onset of action (1-3 h) Peak serum level 4-8 h. Duration of action h. Lente and NPH insulins are equivalent in activity. Lente and NPH are Not used in emergencies (diabetic ketoacidosis). Require several hours to reach therapeutic levels

94 Long acting insulin Insulin glargine (lantus) Slow onset of action 2 h. Clear solution Forms precipitate (depot) at injection site. absorbed less rapidly than NPH & Lente insulin. Given s.c.

95 Long acting insulin Insulin glargine (lantus) Maximum effect after 4-5 h produce broad plasma concentration plateau (low continous insulin level). Prolonged duration of action (24 h). Once daily Should not be mixed with other insulin

96 Advantages over intermediate-acting insulins: Constant circulating insulin over 24 hr with no pronounced peak. More safe than NPH & Lente insulins ( reduced risk of hypoglycemia).

97 Insulin preparations

98 Routes of administrations of exogenous insulin 1. Given subcutaneously by syringes (arms, abdomen, thighs). 2. Portable pin injector. 3. Continuous S.C. insulin infusion (pump). Under Clinical Trials 4. Inhaled aerosols, transdermal, intranasal.

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100 Adverse effects of Insulin Therapy: Hypoglycaemia: Manifested by:- Coma due to blood glucose to the brain. sympathetic: tachycardia, sweating, anxiety. parasympathetic: Nausea, Vomiting

101 Treated by Sugar containing beverage or food ml of 50% glucose solution I.V. or glucagon 1 mg S.C. or I.M.

102 Adverse effects of Insulin Therapy: Weight gain Hypersensitivity reactions. Lipodystrophy at injection site Insulin resistance Hypokalemia

103 Hypoglycemic coma Diabetic coma Diabetic ketoacidosis Onset Rapid Slow- Over several days Insulin Excess Too little Acidosis & dehydration Signs and symps No Ketoacidosis B.P. Normal or elevated Subnormal or in shock Respiration Normal or shallow Deep & air hunger Skin Pale & Sweating Hot & dry CNS Tremors, mental confusion, sometimes convulsions General depression Blood sugar Lower than 70 mg/100cc Elevated above 200 mg/100cc Ketones Normal Elevated