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INSULIN & ORAL HYPOGLYCEMIC AGENTS
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INTRODUCTION Diabetes or Diabetes Mellitus Vascular Abnormalities
Chronic Metabolic Disorder Vascular Abnormalities Characterized by Hyperglycemia Glycosuria Polydipsia Polyphagia Ketoacidosis
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Characteristic Type 1 ( 10% ) Type 2 Onset (Age) Usually < 30 Usually > 40 Type of onset Abrupt Gradual Nutritional status Usually thin Usually obese Clinical symptoms Polydipsia, polyphagia, polyurea, 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 Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia common Insulin therapy Required Required in only % of patients Hypoglycemic drugs Should not be used Clinically indicated Diet Mandatory with insulin Mandatory with or without drug
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2 hrs after consuming glucose
BLOOD GLUCOSE LEVELS category Fasting values (mg/dL) Post prandial Minimum value Maximum value 2 hrs after consuming glucose Normal 70 100 <140 Early diabetes 101 126 Established diabetes >126 - >200
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Pancreatic Hormone
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Regulation
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Regulation of Insulin and Glucagon
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Action of Insulin on Various Tissues
Liver Muscle Adipose ↓ glucose production ↑ Glucose transport ↑ glucose transport ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis ↑ Protein synthesis ↑ protein synthesis
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INSULIN
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Degradation of Insulin
Liver and Kidney are two organ remove insulin from circulation by hydrolysis of disulfide connection between A & B chains. Liver remove 60% of insulin. Kidney remove 35-40% of insulin.
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INSULIN RECEPTOR Binding sites Cell membrane Intracellular space Tyrosin kinase
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Amino Acid Substitutons
A- chain Position B- chain Position Source/ Type A21 B3 B28 B29 B30 B31 And B32 Human Asn Pro Lys Thr Aspart Aspartic acid Lispro Glulisine Glu Glargine Gly Arg Detemir Myristic rapid-acting long-acting
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TYPES OF INSULIN PREPARATIONS
Ultra-short-acting (Rapid acting) Short-acting (Regular) Intermediate-acting Long-acting
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Short-acting (regular) insulins
e.g. Humulin R, Novolin R Uses Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis Physical characteristics Clear solution at neutral pH Chemical structure Hexameric analogue Route & time of administration S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action 30 – 45 min ( S.C ) Peak serum levels 2 – 4 hr Duration of action 6 – 8 hr Usual administration 2 – 3 times/day or more Ultra-Short acting insulins e.g. Lispro, aspart, glulisine Similar to regular insulin but designed to overcome the limitations of regular insulin 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) 0 – 15 min ( S.C ) 30 – 90 min 3 – 4 hr 2 – 3 times / day or more
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3. Intermediate - acting insulins
e.g. Isophane (NPH) Turbid suspension Injected S.C.(Only) Onset of action hr Peak serum level hr Duration of action hr Insulin mixtures 75/ /30 50/50 ( NPH / Regular )
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Turbid suspension Lente insulin Mixture of 30% semilente insulin
70% ultralente insulin Injected S.C. (only) Onset of action hr Peak serum level hr Duration of action hr
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4. Long – acting insulins e.g. Insulin glargine Onset of action 2 hr
Absorbed less rapidly than NPH & Lente insulins. Duration of action - 24 hr Designed to overcome the deficiencies of intermediate acting insulins Advantages over intermediate-acting insulins: More safe than NPH & Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia). Clear solution that does not require resuspension before administration.
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Glargine
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Oral HypoGLYCaEMIC AGENTS
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Classification Sulfonylurea drugs Meglitinide analogues Biguanides
α -glucosidase inhibitors. Thiazolidinediones. Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin
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Classification based on MOA
Insulin secretagogues Sulfonylurea drugs Meglitinide analogues D-phenylalanine derivatives Insulin sensitizers Biguanides Thiazolidinediones or glitazones
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First generation Second generation
SULFONYLUREAS : First generation Second generation Tolbutamide Glipizide Tolazamide Glyburide Acetohexamide (Glibenclamide) Chlorpropamide Glimepiride
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MEGLITINIDE ANALOGUES
Rapidly acting insulin secretagogues Repaglinide (Prandin) Nateglinide (Starlix)
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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.
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BIGUANIDES MECHANISM OF ACTION
Metformin Phenformin BIGUANIDES MECHANISM OF ACTION 1. Increase peripheral glucose utilization 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut
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Thiazolidinediones (Glitazones)
Insulin Sensitizers Activation of Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). Do not promote Insulin secretion from β-cells Two agents are : Pioglitazone Rosiglitazone
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Mechanism of Action
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α-Glucosidase Inhibitors
Competitive inhibitor of Intestinal α- Glucosidase . Delays carbohydrate absorption . Agents are : - Acarbose - Miglitol
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Mechanism of Action Acarbose
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Incretin Therapy or Dipeptidyl-Peptidase 4 Inhibitors
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Glance at Diabetes 2 therapy
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