Thiazolidinediones

July 19, 2020 Rima Pharmacology 0

  • Thiazolidinedione (TZDs) or glitazones are an important class of insulin sensitizers used in treatment of type 2 diabetes.
  • Their introduction in the late 1990s was breakthrough since the introduction of sulfonylureas in 1950s. They are a class of heterocyclic compound consisting of 5 membered C3NS ring.
  • Two glitazones available are:
    • Pioglitazone and
    • Rosiglitazone

Mechanism of action of Thiazolidinediones

Figure 1- Mechanism of action of Thiazolidinediones

  • TZDs bind to peroxisome-proliferator activated receptor gamma (PPARϒ), a nuclear hormone receptor present in adipose tissues, liver, heart and skeletal muscle. Activation of PPARϒ regulates gene expression involved in glucose and lipid metabolism, insulin signal transduction, and adipocyte differentiation and proliferation. These results in increased insulin sensitivity in adipose tissues, skeletal muscle and liver.
  • Its action is seen after weeks or months because of its action on genetic regulation. It is effective only in presence of insulin.
  • It can be used alone or in combination with insulin or other anti-diabetic agents.

Pharmacological Actions of Thiazolidinediones

  • They are insulin sensitizers. They reduce peripheral resistance to insulin and increase insulin sensitivity of adipose tissue, skeletal muscle and liver. This property helps to protect body from damaging effect of chronic endogenous hyperinsulinemia.
  • They lower hepatic fat content.
  • Thiazolidinediones lower hepatic glucose production and increase glucose uptake by skeletal muscle.
  • They reduce production of pro-inflammatory cytokines by adipocytes and increase adipose tissue production of adiponectin which is antiatherogenic
  • They decrease level of PAI-1 and fibrinogen and hence lower procoagulant state.
  • Thiazolidinediones protect and enhance pancreatic beta cells by reducing FFA and cytokine induced islet cell damage to the body.
  • They don’t cause hypoglycemia by themselves.

Pharmacokinetics of Thiazolidinediones

  • Both rosiglitazone and pioglitazone are well absorbed after oral administration. They are absorbed within 2 hours and maximum clinical effect requires 6-12 weeks.
  • They bind to plasma proteins, mainly albumin.
  • Both of them are extensively metabolized in liver. Rosiglitazone is metabolized by hepatic CYP2C8 and pioglitazone is metabolized by CYP3A4 and CYP2C8. The metabolites of pioglitazone are active.
  • Metabolites of rosiglitazone are excreted from urine. Renal elimination of pioglitazone is negligible. Most of its active form and metabolites are excreted from bile in the form of feces.

Therapeutic uses

  • To treat type 2 diabetes mellitus (T2DM). When used as monotherapy, they are less effective than sulfonylurea or metformin. They are used in diabetic patients who cannot take sulfonylurea and metformin. They may be used in combination with other oral hypoglycemic agents.
  • In Polycystic ovary syndrome (PCOS).
  • In non-alcoholic steatohepatitis (NASH).

Adverse effect

  • Hepatotoxicity may occur rarely. Periodic monitoring of liver function is recommended in patients taking these drugs.
  • They cause weight gain due to proliferation of new adipocytes, redistribution of fat stores and fluid retention.
  • Cardiac toxicity is questionable. Rosiglitazone was removed from market as it was found to be associated with significant increase in risk of death from myocardial infarction and stroke. This restriction was removed by FDA in 2013 after re-evaluation.
  • They also cause osteopenia, increased fracture risk, anemia, very unpleasant hunger sensation (when used in combination with other anti-hyperglycemic agents).
  • Pioglitazone may increase risk of bladder cancer.

Note- It is necessary to check for cardiac, renal and hepatic status of patient before prescribing glitazones.

Contraindication

  • They are avoided in pregnancy and nursing mothers.
  • They should be avoided in hepatic patients.
  • Should be avoided or used with caution in patients with New York Heart Association class 3 or 4 heart failure.

References

  1. Nanjan MJ, Mohammed M, Kumar BRP, Chnadrasekar MJN. Thiazolidinediones as antidiabetic agents: A critical review. Bioorg Chem. 2018; 77: 548-567.
  2. Mankovsky B, Kurashvili RB. Glitazones: Beyond glucose lowering! Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2007; 1(3): 197-207.
  3. Reynaert H, Geerts A, Henrion J. Review article: the treatment of non‐alcoholic steatohepatitis with thiazolidinediones. Aliment Pharmacol Ther. 2005; 22: 897-905.
  4. Pladevall M, Guardia NR, Margulis AV, Lorenzo CV, Calingaert B, Gutthann SP. Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC Cardiovascular Disorders. 2016; 16(14).
  5. Daniel K. The glitazones proceed with caution. West J Med. 2000; 173(1): 54-57.
  6. Pharmacology and Pharmacotherapeutics. 24th edition.
  7. Goodman and Gillman Manual of Pharmacology and Therapeutics.
  8. Lippincott Illustrated Reviews Pharmacology, 6th edition.