Diabetes Mellitus and Oral antidiabetic agents - quick review

Oral Anti-DiabeticAgents

Dr. Amna AmirBDS

Graduated from AMC, Rawp, Pakistan

Introduction to Diabetes Mellitus Oral antidiabetic agents Classification Sulfonyl ureas in detail

Contents

DIABETES = diabainein ‘to go through’ or

‘excessive discharge of urine’ MELLITUS = mell ‘honey-sweet’

What is Diabetes Mellitus?

Definition : “It ‘s a chronic disorder of carbohydrate,

protein, and fat metabolism resulting from insulin deficiency or Insulin resistance ,

that results into high blood gulucose levels”.

Diabetes Mellitus

Normal glucose levels Fasting plasma glucose 82-110 mg/dl Plasma gulucose after meals upto 140 mg/dl

In diabetic patients Fasting plasma glucose levels above 126mg/dl Plasma glucose after meals above

200mg/dl

i) Insulin dependent diabetes mellitus (IDDM) ii) Non-insulin dependent diabetes mellitus (NIDDM) iii) Other iv) Gestational diabetes

Types

FEATURES TYPE 1 DM TYPE 2 DMFrequency 10-20% 80-90%Age at onset Early (below 30) Late (above 30)Type of onset Acute ChronicBody weight Normal Obese HLA association Yes No

Family history Uncommon CommonPathogenesis Autoimmune

destruction of beta pancreatic cells

Insulin resistance

by Islet cell antibodies

-

Decreased insulin increased insuline

Management Insulin & diet Diet,exercise,oral antidiabetics,insulin

Acute complications

Ketoacidosis Hyperosmolar coma

Islet cell antibodies

Autoimmune destruction of beta pancreatic cells

Type 1 Diabetes

Type 2 Diabetes

Other Insuline deficiency because of pancreatectomy,

pancreatitis and nonpancreatic diseases .

Type 3 DM

Gestational diabetes “High blood sugar that develops at any

time during pregnancy in a woman who does not have diabetes, because of Increased level of certain hormones made in placenta during pregnancy”.

It resembles type 2 diabetes .

Type 4 DM

?

Who is at risk?

NO INSULIN

MARKED HYPERGLYCEMIA

GLUCOSURIA

WEIGHT LOSS

OSMOTICDIURESIS

POLYURIA

CELLULAR HUNGER

POLYPHAGIA

POLYDIPSIA

LIPOLYSIS

OSMOTICDEHYDRATION

KETOACIDOSIS

Urine tastes like sweet!

Treatment

• Diet and ExerciseA• Oral antidiabetic

therapyB

• Insulin TherapyC

Definition: “Agents which are given orally to reduce

the blood glucose levels in diabetic patients ”. The oral antidiabetic drugs are given only in

the treatment of type 2 (NIDDM) diabetes mellitus which cannot be controlled by diet alone.

Use of an oral antidiabetic drug with insulin may decrease the insulin dosage in some individuals.

Oral Antidiabetics

Are known as insulin secretagogues,

because they increase insulin release from the β cells of the pancreas.

The primary drugs used today are tolbutamide and the second-generation derivatives, glyburide, glipizide, and glimepiride.

Sulfonyl Ureas

I Generation

Tolbutamide (Orinase) short acting (6-12h) / Safest

Chlorpropamide (Diabinese) longest acting (60h)

Acetohexamide Tolazamide

II Generation Glipizide (Glucatrol) short acting (7h) Gliclazide Glibenclamide (Glyburide) Glimepiride (Amaryl)

Intermediate acting

long acting

Sulfonyl Ureas

Structure

All sulfonylureas contain a central S-phenylsulfonylurea structure with a p- substituent on the phenyl ring (R) and various groups terminating the urea N′ end group (R2).

1) Stimulation of insulin-release from the β

cells of the pancreas by blocking the ATP-dependent K+ channels leads to depolarization and Ca2+ influx .

2) Decrease gluconeogenesis by ↓ glucagon secretion

3) Extra pancreatic action: ↑sensitivity of peripheral tissue to insulin by ↑insulin receptors

Mechanism of Action

Mechanism of Action

Drugs Bioavailabili

ty (Oral)Half Life

Duration of action (hrs)

Urinary Excretion

Chlopropamide

90% 32 Upto 60 20%

Glibenclamide(Glyburide)

>90% 10 10-24 Negligible

Tolbutamide 93% 5-9 6-12 0%

Glipizide 95% 2-4 10-24 10%

Glimepiride 100% 3-4 - 0.5%

Pharmacokinetics

Highly plasma protein binding i.e. > 90% low volume of distribution i.e. 0.2-0.4 L/kg Cross placenta C/I in pregnancy Metabolized by the liver Excreted by the liver or kidney Tolbutamide has the shortest duration of

action (6-12 hours), whereas Chlopropamide has longest upto 60 h

Pharmacokinetics

SU + other Antidiabetic

Agents SU + Metformin (best) SU + Glitazones (best) SU + Insulin (good) SU + Meglitinides (bad) SU + SU (worst)

Contraindications

Patients allergic to SU Renal compromised hepatic dysfunction Pregnancy (except Glibenclamide ) Type 1 DM

Drugs that ↑ SU action Displace them from plasma proteinsdecrease

metabolismSynergistic actione.g. Aspirin, sulfonamides ,Cimetidine ,

warfarin ,PAS & Propranolol

Drugs that ↓ SU action Increase metabolismAntagonistic action

e.g. Phenytoin, phenobarbitone , rifampicin, corticosteroids, thiazides, furosemide, OCP’s

Drug Interacations

Weight gain Hyperinsulinemia Hypoglycemia (commonest) GI upsets: Nausea, vomiting, metallic

taste, diarrhoea & flatulence Hypersensitivity In hepatic or renal insufficiency may cause

hypoglycemia because of delayed excretion (accumulation) .

Adverse Effects

Renal impairment (mainly with glyburide) If given in pregnancy causes fetal

hypoglycemia (except glibenclamide or glyburide)

Chlorpropamide: cholestatic jaundice, dilutional

hyponatremia, disulfuram like reaction Tolbutamide: Reduces iodine uptake by thyroid

(doesn’t cause hypothyroidism)

Adverse Effects

THANK YOU

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