Oral Hypoglycemic Agents

Dr.Bindu Susan Varghese

These drugs lower the blood glucose and are
effective orally.
Classification:
first generation
Sulfonylureas
second generation
Biguanides
Meglitinides
Thiazolidinediones
glucosidase inhibitors
Sulfonylureas
They reduce blood glucose in normal subjects
as well as in Type II diabetics, not in Type I
diabetics.
Mechanism of action:
1. They provoke a quick release of insulin.
They act on specific receptors on the cell
causing K
+
channel blockade leading to calcium
channel opening which later causes release of
insulin.
Mechanism of action of sulfonylureas
sulfonylurea
receptor
Sulfonylureas
2. They increase the number of insulin receptors
and sensitize the target tissue to insulin.
3.They reduce glucagon secretion. This is only a
minor mechanism.
4. Hepatic degradation of insulin is slowed.
Sulfonylureas
Pharmacokinetics:
All are absorbed orally.
Mostly are 90% bound to plasma proteins.
Adverse effects:
Hypoglycemia
Nausea,vomiting,diarrhoea,constipation (nonspecific)
Safety in pregnancy not established
Drug interactions are common with I generation
sulfonylureas.

First generation sulfonylureas
Chlorpropamide,tolbutamide
Low specificity of action
Delay in onset of action
Longer duration of action
Drug interactions are more
Hence not preferred now.
Sulfonylureas - drug interactions
(1
st
generation)
Displaced from protein binding site. Eg;
salicylates
Metabolism is inhibited by enzyme inhibitors.
Eg; Erythromycin
Metabolism is enhanced by enzyme inducers
Eg; phenobarbitone,phenytoin
Drugs that oppose action or inhibit insulin
release. Eg; steroids,thiazide diuretics,
furosemide etc.

Second generation sulfonylureas
Glyburide (glibenclamide) most commonly
prescribed member.
Glipizide is preferred in the elderly because it
has short duration of action.
Glimeperide is the most potent,1mg dose is
effective, long duration of action. Hence need to
be given once daily only.
Gliclazide has additional antiplatelet and free
radical scavenging effect, hence useful in
diabetic retinopathy. Also effective in renal
impairment.


Biguanides
They do not lower blood glucose in normoglycemic
patients; only lower in hyperglycemics.
Phenformin and metformin

Mechanism of action:
-Suppress hepatic gluconeogenesis and glucose
output from the liver.
-Enhances peripheral utilisation of glucose.
Enhances insulin mediated glucose disposal in
muscle and fat.
Improves lipid profile in Type-II diabetes.

Biguanides
Metformin is the only member used now.
Useful in delaying insulin resistance.
Postponement of diabetes
Obesity and PCO
Adverse effects:
Anorexia, nausea, metallic taste in the mouth.
Lactic acidosis is common with phenformin,
hence not used now.
Hypoglycemia is rare.

Meglitinides
Repaglinide,nateglinide
Releases insulin through a mechanism similar to
sulfonylureas.
Rapid onset and short lasting action.
No food no drug because causes hypoglycemia
Used only in Type-II DM.

Thiazolidinediones
Called insulin sensitizers.
A selective agonist for PPAR gamma receptor.
This receptor
Enhances transcription of several insulin
responsive genes.
Reverses insulin resistance by stimulating
GLUT4 expression and translocation
Regulates fatty acid metabolism and lipogenesis
in adipose tissue.
Thiazolidinediones-contd
Pioglitazone and Rosiglitazone
Well tolerated after taking orally.
Few cases of hepatic dysfunction
Causes water retention; few cardiovascular
events reported - heart failure may be worsened.

Pioglitazone is banned.
Thiazolidinediones-contd
Therapeutic uses:
Type 2 DM
Supplement biguanides in insulin resistance.
May prevent development of type 2 diabetes in
prediabetics.

Glucosidase inhibitors
Acarbose
Complex oligosaccharide
MOA: Inhibits glucosidase the enzyme in
digestion of carbohydrates, so digestion is
reduced.
Acarbose is a mild antihyperglycemic and not a
hypoglycemic.
Flatulence,abdominal discomfort ,loose stools
and sometimes constipation are adverse effects.
Therapeutic use: Supplement with other oral
hypoglycemics.
Newer drugs
Amylin analogue
Pramlinitide
Injectable along with insulin in both type1 &2
Anorexia, reduces glucagon and delay gastric
emptying
Hypoglycemia side effect
Incretin based therapy
Sitagliptin (oral) insulin, glucagon (US)
Exenetide (inj) analogue of GLP-1, pancreatitis
is reported