diabetes mellitus and oral antidiabetic agents - quick review
TRANSCRIPT
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
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