Oral hypoglycemic agents

Biguanides Sulfonylureas

- glucosidase inhibitors
Thiazolidinediones Prandial glucose regulator

Biguanides
Biguanides are derivatives of the antimalarial agent Chloroguanide. Which is found to have hypoglycemic

action.
The most commonly used member of

biguanides is Metformin.

Biguanides
Indication:
Type 2 diabetes failed on diet Metformin can be given alone or in combination with sulfonylureas or

Insulin

Biguanides
Mode of action
Biguanides [Metformin] is an Antihyperglycemic and not Hypoglycemic agent.
It does not stimulate pancreas to secrete insulin and does not cause hypoglycemia (as a side effect) even in large doses. Also it has no effect on secretion of Glucagon or Somatostatin.

Biguanides
Mode of action:
Decreases the intestinal absorption of CHO

Increases glucose uptake (GLUT 4)

Increases glucose utilization (glycogensynthase)

Increases glycolysis via anaerobic pathway (lactic acidosis)

Biguanides
Metformin is well absorbed from small intestine, stable, does not bind to plasma proteins, excreted unchanged in urine. Half life of Metformin is 1.5 - 4.5 hours, taken in three doses with meals

Pharmacokinetics:

Biguanides
Side effects: occur in 20-25 % of patients. include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B12.

Biguanides
Contraindications
Patients with renal or hepatic impairment. Past history of lactic acidosis. Heart failure, Chronic lung disease. .. These conditions predispose to increased lactate production which causes lactic acidosis which is fatal.

SULFONYLUREAS
SUs., have been discovered during
the 2nd. World war (sulfonamide).

SUs are drugs that used orally to

control blood glucose levels of type

2 diabetes.

SULFONYLUREAS
Types:
First generation, Chlorpropamide Tolbutamide Second generation, Gliclazide Glibenclamide Glipizide Third generation, Glimepiride

SULFONYLUREAS
Mechanism of action:
Pancreatic effect

Extra-pancreatic effect

SULFONYLUREAS
Pancreatic effect:
Increase insulin release from

pancreas
Suppress secretions of Glucagon

SULFONYLUREAS
Increases the number of insulin receptors Increases post-receptor insulin sensitivity Increases glucolysis Increases glycogen storage in muscle and liver Decreases the hepatic output of glucose

Extra pancreatic effect:

SULFONYLUREAS
Pharmacokinetics: They are effectively absorbed from gastrointestinal tract. Food can reduce the absorption of sulfonylurea. Sulfonylureas are more effective when given 30 minutes before eating. Plasma protein binding is high 90 99 % .. mainly bind to albumen.

SULFONYLUREAS
1st
Pharmacokinetics: generation members have short half lives.

2nd generation is administered once, twice or several times daily.

3rd generation is administered

once daily.

SULFONYLUREAS
Pharmacokinetics:
All sulfonylurea are metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged.
Sulfonylurea should be administered with caution to patients with either renal or hepatic insufficiency.

SULFONYLUREAS
Adverse Reactions :
Very few adverse reactions [4 %] in the first generation and rare in the 2nd and 3rd generation. SUs may induce hypoglycemia especially in elderly patients with impaired hepatic or renal functions-These cases of hypoglycemia are treated by I/V glucose infusion.

SULFONYLUREAS
Adverse Reactions :
First generation may induce other side effects as nausea and vomiting & dermatological reactions These side effects are fewer in

the 2nd generation and rare in the 3rd generation.

SULFONYLUREAS
Some drugs may enhance or suppress the actions of sulfonylureas Either by affecting:

Drug interactions:

Their metabolism and excretion The concentration of free sulfonylureas in plasma through competing them on plasma proteins.

Drug Drug interaction

NSAIDs
Salicylates Sulfonamide -blockers Chloramphenicol Diazepam MAOI

Barbiturates
Thiazide and loop diuretics

Sympathomimetics
Corticosteroids Oestrogen / Progesterone combinations

SULFONYLUREAS
Contraindications :
Type 1 DM

Pregnancy and Lactation.

Significant hepatic or renal

failure.

 Glucosidase Inhibititor
Acarbose
Indicated for type 2

diabetes
In addition with diet

In addition with other anti- diabetic therapies

Acarbose (Glucobay)
Mode of action:
Poorly absorbed 1% (act locally in G.I.T.) Inhibits glucosidase, so inhibits CHO degradation

Dose:
50mg to 100mg 3 times daily before meals

Acarbose (Glucobay)
Side effects:
Flatulence (77%)

Diarrhea Abdominal pain (21%) Decreased iron absorption

Thiazolidenedione
Rosiglitazone Pioglitazone

Thiazolidenedione
Mode of action:
Insulin sensitizer (increase insulin sensitivity in muscle, adipose tissue & liver) They are not insulin secretagogues (Not insulin releasers)

Thiazolidenedione
Drawbacks:
They are not effective alone in case of severe insulin deficiency and should be combined with sulfonylurea or metformin or both Hepatotoxicity weight gain Dyslipidaemia (increases LDL)

Side effects:

Prandial glucose regulators (Meglitinide)

Example:
Repaglinide

Rational:
Fast acting, short duration non- sulfonylurea Designed to minimize mealtime blood glucose peaks

Repaglinide
Mechanism of action:
Stimulation of pancreatic insulin release by closing -cells KATP channels Very rapid onset of action and short duration (TMAX = 1 hour, metabolized by liver T1/2 = 70 minutes) No hypoglycemic metabolites

Repaglinide
Improves postprandial glycemia Less effective in decreasing fasting blood glucose levels and HbA1C

Clinical efficacy:

Fails to provides a stable 24 hours blood glucose control Complicated dosage style (3-8 tablets/daily) How to adapt the dosage to the meal volume?

drawbacks: