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Oral hypoglycemic agents Biguanides Sulfonylureas α- glucosidase inhibitors Thiazolidinediones Prandial glucose regulator

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Page 1: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator
Page 2: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Oral hypoglycemic agents

Biguanides

Sulfonylureas

α- glucosidase inhibitors

Thiazolidinediones

Prandial glucose regulator

Page 3: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- 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.

Page 4: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Biguanides

Indication:

Type 2 diabetes failed on diet

Metformin can be given alone

or in combination with

sulfonylureas or Insulin

Page 5: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

BiguanidesMode 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 .

Page 6: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

BiguanidesMode of action:

Decreases the intestinal absorption of CHO

Increases glucose uptake (GLUT 4)

Increases glucose utilization (glycogensynthase)

Increases glycolysis via anaerobic pathway (lactic acidosis)

Page 7: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Biguanides

Pharmacokinetics: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

Page 8: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Biguanides

Side effects:

occur in 20-25 % of patients .

include.. Diarrhea, abdominal discomfort, nausea, metallic

taste and decreased

absorption of vitamin B12 .

Page 9: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

BiguanidesContraindications

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 .

Page 10: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

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

Page 11: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREASTypes:

First generation ,ChlorpropamideTolbutamide

Second generation,GliclazideGlibenclamideGlipizide

Third generation,Glimepiride

Page 12: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREAS

Mechanism of action:

Pancreatic effect

Extra-pancreatic effect

Page 13: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Pancreatic effect:

•Increase insulin release

from pancreas

•Suppress secretions of

Glucagon

SULFONYLUREAS

Page 14: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREASExtra pancreatic effect:

Increases the number of insulin receptors

Increases post-receptor insulin sensitivity

Increases glucolysisIncreases glycogen storage

in muscle and liverDecreases the hepatic

output of glucose

Page 15: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREASPharmacokinetics:

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.

Page 16: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREASPharmacokinetics:

1st generation members have short half lives.

2nd generation is

administered once, twice or

several times daily.

3rd generation is

administered once daily.

Page 17: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREASPharmacokinetics:

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.

Page 18: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

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 .

Page 19: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

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.

Page 20: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREASDrug interactions:

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

affecting:Their metabolism and

excretion The concentration of free

sulfonylureas in plasma through competing them on

plasma proteins.

Page 21: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Drug – Drug interaction

NSAIDs

Salicylates

Sulfonamide

ß-blockers

Chloramphenicol

Diazepam

MAOI

Barbiturates

Thiazide and loop diuretics

Sympathomimetics

Corticosteroids

Oestrogen / Progesterone combinations

Page 22: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

SULFONYLUREAS

Contraindications :

Type 1 DM

Pregnancy and Lactation .

Significant hepatic or renal

failure .

Page 23: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

α Glucosidase Inhibititor

Acarbose

Indicated for type 2

diabetesIn addition with diet

In addition with other

anti-diabetic therapies

Page 24: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Acarbose (Glucobay)

Mode of action:Poorly absorbed 1% (act

locally in G.I.T.)Inhibits α glucosidase, so

inhibits CHO degradationDose:

50mg to 100mg 3 times daily before meals

Page 25: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Acarbose (Glucobay)

Side effects:

Flatulence (77%)

Diarrhea

Abdominal pain (21%)

Decreased iron absorption

Page 26: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Thiazolidenedione

Rosiglitazone

Pioglitazone

Page 27: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Thiazolidenedione

Mode of action:Insulin sensitizer (increase

insulin sensitivity in muscle, adipose tissue & liver)

They are not insulin

secretagogues (Not insulin

releasers)

Page 28: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

ThiazolidenedioneDrawbacks:

They are not effective alone in case of severe insulin deficiency

and should be combined with sulfonylurea or metformin or

bothSide effects:

Hepatotoxicity weight gainDyslipidaemia (increases LDL)

Page 29: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Prandial glucose regulators (Meglitinide)

Example:Repaglinide

Rational:Fast acting, short duration

non-sulfonylureaDesigned to minimize

mealtime blood glucose peaks

Page 30: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

Repaglinide

Mechanism of action:Stimulation of pancreatic

insulin release by closing ß-cells KATP channels

Very rapid onset of action and short duration (TMAX = 1

hour, metabolized by liver T1/2 = 70 minutes)

No hypoglycemic metabolites

Page 31: Oral hypoglycemic agents  Biguanides  Sulfonylureas  α- glucosidase inhibitors  Thiazolidinediones  Prandial glucose regulator

RepaglinideClinical efficacy:

Improves postprandial glycemia Less effective in decreasing

fasting blood glucose levels and HbA1C

drawbacks:Fails to provides a stable 24 hours

blood glucose controlComplicated dosage style (3-8

tablets/daily)How to adapt the dosage to the

meal volume?