Saturday, January 31, 2009

Glitazones (Thiazolidinediones)

Introduction

The thiazolidnediones reduce peripheral insulin resistance, leading to a reduction of blood glucose concentration. Either drug may be used alone or in combination with metformin or with a Sulphonylurea. Following are the examples for thiazolidnediones;

1. Rosiglitazones
2. Pioglitazones
3. Ciglitazones (not in use due to the hepatotoxicity)
4. Troglitazones (not in use due to the hepatotoxicity)

Mechanism of actions

Glitazones bind with a nuclear receptor called Peroxisomal Proliferator-Activated Receptor Gamma (PPARγ), which is complexed with retinoid X-receptor (RXR). This binding will cause a conformational change in the PPARγ-RXR complex. Thus, this complex binds with DNA and promotes transcription of several genes. Therefore following proteins result. These are important in insulin signaling.

Lipoprotein lipase
Fatty acid transporter protein
Adipocytes fatty acid binding protein
Glut 4 receptors
Phophoenolpyruvate carboxykinase

PPARγ is mainly found adipose tissue, muscles and liver. It mediates differentiation of adipocytes, increase lipogenesis and enhances uptake of fatty acid and glucose.

Effects of Glitazones

1. reduce hepatic glucose out put
2. increase glucose uptake into muscles
3. enhances the effectiveness of endogenous insulin
4. reduce the amount of exogenous insulin needed to maintain a given blood sugar level by 30%
5. reduce circulating insulin and fatty acids
6. reduce small density LDL, which is more atherogenic
7. increase weight gain
8. cause fluid retention
9. increase extravascular fluids
10. increase deposition of subcutaneous fat.

Pharmacokinetics

Oral absorption is rapid and complete. They achieve peak plasma concentration within 2 hours. They are highly bound to plasma protein. They undergo hepatic metabolism. Half life is less than 7 hours for parent drug but the half life of rosiglitazone is 150hous whereas the half life of pioglitazone is 24 hours. Rosiglitazone is excretd via urine whereas pioglitazone is excreted via bile.

Side effects

1. hepatotoxicity ( uncommon with newer drugs)
2. weight gaining and fluid retention
3. headache
4. fatigue
5. gastrointestinal disturbances
6. may resume ovulation in women who are anovulatory. This is due to the reduction insulin resistance. Therefore precautions should be taken
7. teratogenic

Drug interaction

1. additive with other oral hypoglycemic agents
2. increase the risk of heart failure with insulin

Clinical uses

1. useful in type 2 diabetes mellitus
2. good for patient who cannot tolerate metformin
3. can be combined with other oral hypoglycemic agents
4. monotherapy or polytherapy is possible

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