Oral Hypoglycaemic agents

Definition : These are the drugs which lower blood glucose levels when taken orally.

Classification: oral hypoglycaemic agents are chemically classified into different classes.

1. Sulfonylurea derivatives
 First generation:

Carbutamide Tolbutamide

 Second generation:

Glibenclamide

Glipizide
2. Biguanides

Phenformin Metformin

3. Thiazolidinediones

Ciglitazone
 Rosiglitazone
4. Aldose reductase inhibitors

Sorbinil Tolrestat
5. α-D-Glucosidase inhibitors

Acarbose, Miglitol

Glibenclamide
Tolbutamide

Mechanism of action of sulfonylurea derivatives (Glibenclamide / Tolbutamide):

 The principal action of the sulphonylureas is on the β-cells of the islets stimulating insulin secretion
and thus reducing plasma glucose concentration.
 They act on the so called sulfonylurea receptors present on the pancreatic β cell membrane
and cause depolarization by reducing the conductance of ATP sensitive K+ channel.
 It leads to opening of voltage sensitive calcium channel which produces influx of calcium
ions, that results in production of insulin from β cells.

SAR of sulphonylurea derivatives

 The general structure of sulphonylureas is represented as

                                
 The benzene ring should contain one substituent, preferably at the para position. The substituents
like methyl, amino, acetyl, chloro, bromo, methylthio, and trifluoromethyl enhance hypoglycemic
activity.
 Compounds with p-(-β-arylcarboxamidoethyl) substituents (the second generation agents) are better
than the first generation agents.
 The group attached to the terminal nitrogen should be of certain size and should impart lipophilic
properties to the molecule. The N-methyl are inactive, N-ethyl have low activity, while N-propyl to
N-hexyl are most active. Activity is lost if N-substituent contains 12 or more carbons.

PPAR-γ modulators as antidiabetic agents / Thiazolidinediones

PPAR -γ modulators are drugs which act upon the peroxisome proliferator-activated receptor. They are used
for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar.
e.g.

Ciglitazone
 Rosiglitazone

Mode of action

 This class of drugs are act as agonist of peroxisome proliferator activated receptor γ (PPAR- γ).
 The receptor complex binds with DNA activating transcription of a wide variety of metabolic
regulator. They expresses various genes involved in metabolism of glucose and lipid.
 They express and translocate GLUT4 which leads to improved glucose entry into muscle and
fat.
 They suppress hepative gluconeogenesis in liver.

Insulin preparations
The commercial preparations of insulin are derived from beef and pork pancrease. According to
onset/ duration of action insulin preparation are categorised as

1. Short acting insulin preparation

a. Regular insulin
 Regular insulin is a clear, colourless solution with rapid onset of action and short
duration of action.
 It is administered intravenous, subcutaneous or intramuscular route.
 It’s onset of action is 0.5-1 h and duration of action is 6-8 h.
b. Prompt insulin zinc suspension
 It a sterile suspension of insulin in buffer water for injection modified by the addition
of zinc chloride in a manner such that the solid phase of the suspension is
predominately amorphous.
 It’s onset of action is 1-1.5 h and duration of action is 12-16 h.
2. Intermediate acting insulin preparation
a. Insulin zinc suspension / Lente insulin
 It a sterile suspension of insulin in buffer water for injection modified by the addition
of zinc chloride in a manner such that the solid phase of the suspension consists of a
mixture of crystalline and amorphous in 7:3 ratio.
 It’s onset of action is 1-2 h and duration of action is 20-24 h.
 It is administered only by subcutaneous route.
b. Neutral protamine hagedron (NPH) / Isophane insulin
 It a sterile suspension of zinc insulin crystals and protamine phosphate in buffer water
for injection, combined in a manner such that the solid phase of the suspension
consists of crystals composed of insulin, protamine and zinc.
 It’s onset of action is 1-2 h and duration of action is 20-24 h.
3. Long acting insulin preparation
a. Extended insulin zinc suspension / Ultralente insulin
  It a sterile suspension of insulin in buffer water for injection modified by the addition
of zinc chloride in a manner such that the solid phase of the suspension is
predominately crystalline.
 It’s onset of action is 4-6 h and duration of action is 24-36 h.
b. Protamine zinc insulin (PZI)
 It a sterile suspension of insulin in buffer water for injection modified by the addition
of zinc chloride and protamine sulfate.
 It’s onset of action is 4-6 h and duration of action is 24-36 h.