ANTIDIABETIC DRUGS

Dr. Manjunatha.C.H Asst. Professor, Dept. of Pharmacology

LEARNING OBJECTIVES
At the end of the class the students should be able to mention various classes of antidiabetic drugs

Explain their mechanism of action Choose appropriate drug for management of Diabetes

OUTLINE
INTRODUCTION VARIOUS ANTIDIABETIC DRUGS INSULIN ORAL ANTIDIABETIC DRUGS

 Mr.ramesh, 45 yr old accountant, has been newly diagnosed of DM type 2. he weighs 100 kilos and has increased increased LDL. Which group of antidiabetic drug would be appropriate in his case?

INTRODUCTION

Diabetes mellitus (DM) type 1 and type 2 Persistently elevated plama glucose leads to various micro and macrovascular complications

ANTIDIABETIC DRUGS
INSULIN AND ORAL ANTIDIABETIC DRUGS  InsulinHuman and animal insulin and their analogues

Oral antidiabetic drugs  Sulfonylureas  Meglitinides  Biguanides  thiazolidinediones

 Others  -Glucosidase inhibitor  Incretin analogues  Dipeptidyl peptidase-4 inhibitors

INSULIN

SOURCES OF INSULIN
Bovine and pork insulin Human insulins-

 Produced by modification of porcine insulin or by recombinant DNA technology

Advantages of human insulin Diminished antibody production  Less allergic reactions  Less lipodystrophy

 Insulin analogues-

 Insulin lispro  Insulin aspart  Insulin glargine

INSULIN RECEPTOR AND MECHANISM OF ACTION

ACTIONS OF INSULIN
Target cells-liver, skeletal muscles and adipose tissue Reduction in blood glucose Transit of amino acids and potassium into cells

 Enhances protein synthesis Inhibits lipolysis

PHARMACOKINETICS
Naturally insulin secreted- enters liver through portal vein and then to systemic circulation When administered (SC or IV) both liver and other organs receive the same concentration Route- Subcutaneous, Inhalational Intravenous

 Plasma t1/2 is 5-9 mins

 INSULIN DELIVERY SYSTEMS Syringes Insulin pens External infusion Implantable pumps

Various insulin preparations

ULTRASHORT-ACTING Insulin lispro

 Insulin aspart
SHORT-ACTING  Soluble insulin

 INTERMEDIATE ACTING-

 Isophane (NPH) insulin  Lente insulin

 LONG ACTING-

 Ultralente insulin  Insulin glargine  Insulin detemir

 Strength of insulin-100u/ml Chemical assay using HPLC has replaced bioassay.

Insulin regimens
FLEXIBLE  Multiple injections of short-acting and single night time dose of long-acting insulin CONVENTIONAL Two injections a day of biphasic insulin(combination of short and long-acting insulins)

Adverse effects
Mainly because of overdose Hypoglycemia- coma and convulsions and even death Lipodystrophy- rare with purified insulin and patient education to rotate injection site

USES
Diabetes mellitus Hyperkalemia Testing of anterior pituitary function

ORAL ANITDIABETIC DRUGS

NO ROLE IN TYPE 1 DM SOME (30%)ENDOGENOUS INSULIN SECRETION MUST FOR THEIR ACTION Two major groups-Hypoglycemic drugs and Antihyperglycemic drugs

Hypoglycemic drugs
SULFONYLUREAS (2nd generation)-

 Glibenclamide  Glipizide  Gliclazide  glimipiride

 MOA Increase insulin secretion and decease glucagon secretion Inhibition of ATP-sensitive potassium channels- increased amount of insulin released

 Increase only pulsatile secretion Increased insulin and somatostatin- decreased glucagon (normalize insulin glucagon ratio) Extra-pancreatic- insulin sensitization

 PHARMACOKINETICS Orally well absorbed

 ADVERSE EFFECTS- Hypoglycemia, skin rashes, nausea , vomiting , cholestasis and blood dyscrasias

 DRUG INTERACTIONS Decrease effectiveness- thiazide diuretics, corticosteroids, estrogen Increase effectiveness- ACE inhibitors, sulfonamides, salicylates and NSAID s

 INDICATIONS First line therapy in type 2 DM Used as monotherapy or in combination with metformin or thiazolidinediones

MEGLITINIDES
 Repaglinide  Nateglinide
MOA- similar to sulfonylureas PHARMACOKINETICSt1/2- 1-1.5, short and rapid acting

 Orally well absorbed Taken before food Completely metabolized in liver in 4hrs.

 ADVERSE EFFECTS Hypoglycemia-less frequent Dizziness, dyspepsia, arthralgia

ANTIHYPERGLYCEMIC DRUGS
BIGUANIDEmetformin MOA- Not completely known

AMPK activation

 Suppresses hepatic glucose output Enhance insulin mediated glucose uptake Reduced intestinal glucose absorption

 PHARMACOKINETICS- well absorbed, not metabolized

t1/2 1.5 to 3 hrs

ADVERSE EFFECTS- abdominal pain, anorexia, metallic taste

 INDICATIONS

 First-line therapy for type 2 DM  Particularly appropriate- obese diabetics with insulin resistance and hyperlipidemia  Single or in combination with sulfonylureas

THIAZOLIDINEDIONES
 Rosiglitazone  Pioglitazone

MOA- Stimulate PPAR- - enhances transcription of several insulin responsive genes.

 Suppression of hepatic gluconeognesis Insulin sensitizing action- stimulates GLUT-4 expression and translocation Activation of genes regulating FA metabolism and lipogenesis in adipose tissue Pioglitazone lowers serum TG s and raises HDL

 PHARMACOKINETICS t 3-5 hrs Metabolized in Liver

 ADVERSE REACTIONS Usually well tolerated Weight gain and edema Headache, myalgia, hepatic dysfunction

 DRUG INTERACTION Failure of oral contraception due to pioglitazone therapy  Ketoconazole inhibits pioglitazone metabolism

 INDICATIONS Mainly used to supplement sulfonylureas or biguanides and in case of insulin resistance. Particularly in patients with insulin resistance

OTHERS
-Glucosidase inhibitors- Acarbose, Miglitol

Inhibits alpha glucosidase- prevents digestion of polysaccharides and sucrose. Postprandial glycaemia is reduced Taken at the beginning of meal

 Mild hyperglycemic and used mainly as adjuvant in obese diabetics Flatulence , abdominal discomfort and loose stools

 INCRETIN ANALOGUES- Exenatide GLP-1 enhances insulin release in response to raised plasma glucose concentration Adjunctive therapy in type 2 DM

 DIPEPTIDYL PEPTIDASE (DPP) 4 INHIBITORS Sitagliptin and Vildagliptin DDP 4 breaksdown GLP-1 and its inhibition improves glucose control