Drugs acting on ppar

what are the various types of PPAR receptors, how do they act. what drugs act through PPAR recptors i.e., agonists and antagonists

1. Peroxisome Proliferator – Activated Receptors : Role in Pharmacotherapy Dr Karuna Sree P Asst. Professor Dept. Of Pharmacology Kamineni Institute of Medical Sciences

2. Contents Introduction PPAR receptors – types Mechanism of action Role of PPARS Clinical significance Conclusion 7/26/2014 2 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

3. History Issemann and Green discovered Peroxisome proliferator activated receptors (PPAR). The different types of PPAR initially identified in xenopus frog. Belongs to nuclear receptor family. 7/26/2014 3 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

4. Nuclear receptor family 7/26/2014 4 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

5. Nuclear receptor* Binds to response elements on DNA Ligands bind Co-activators Co-regulator proteins 7/26/2014 5 Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Daryl K Granner . Hormone Action & Signal Transduction. In: Robert K. Murray, Daryl K. Granner , Peter A. Mayes, Victor W. Rodwell editors. Harper’s Illustrated Biochemistry. 26 th ed. NewYork McGraw-Hill

6. PPAR Plays a central role in the regulation of Storage and catabolism of dietary fats and carbohydrates Adipocyte differentiation Inflammatory responses Cancer Types : PPAR α PPAR β / δ PPAR γ 7/26/2014 6 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

7. Tissue Expression of PPAR Ubiquitous but predominant in α - Liver, kidney, heart, muscle, adipose tissue. β / δ - Brain, adipose tissue, and skin. γ - three forms: γ 1 - Heart, muscle, colon, kidney, pancreas & spleen. γ 2 - Adipose tissue. γ 3 - Macrophages, large intestine, white adipose tissue. 7/26/2014 7 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

8. Ligands of PPAR - Function PPAR Partner Ligand Process affected Related disease process PPAR α Active state -fasting Retinoic acid X receptor Fatty acids(FA) Fibrates Peroxisome proliferation Dyslipidaemia PPAR - β / δ FA Proteins Dyslipidaemia Obesity PPAR - γ Active state -fed FA, TZD Lipid & CHO metabolism Insulin resistance Obesity, Metabolic syndrome PCOS, NAFLD Cardiac steatosis 7/26/2014 8 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

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10. PPAR regulated genes 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 10

11. Peroxisomes * Cellular organelle More than 50 enzymes are present in it, among which catalase and oxidase are important Role : In the metabolism of fatty acids and other lipids (cholesterol, bile acids) Purines Aminoacids Hydrogen peroxide 7/26/2014 11 Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Robert K. Murray, Daryl K. Granner , Peter A. Mayes, Victor W. Rodwell . Harper’s Illustrated Biochemistry. 26 th ed. NewYork McGraw-Hill.

12. Potential therapeutic indications of PPAR PPAR α agonists : Fibrates - Hyperlipidaemia PPAR γ agonists : Thiazolidinediones - Hyperglycaemia PPAR dual agonists (α ,γ) : Glitazars – Hyperlipidaemia & Hyperglycaemia PPAR δ agonists : under investigation for obesity, cancer PPAR pan agonists 7/26/2014 12 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

13. PPAR α agonists Fibrates 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13

14. Fibric acid derivatives 1 st generation fibrates : Clofibrate 2 nd generation : Gemfibrozil , Fenofibrate , Bezafibrate , ciprofibrate Lowers VLDL, TG by 50% & ↑ HDL-C by 15 % & ↓ fibrinogen levels & LDL-C by 15-20% Effect mediated through PPAR∝ receptor expressed in liver, fat & muscles. 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 14

15. Fibrates : MOA 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 15 Activates peroxisome proliferation activated receptor factor (PPAR-∝) ↓ TG, VLDL & ↑ HDL ↑ fatty acid oxidation ↑ LPL activity ↑ Apo A I & II, hepatic SREBP-1 production ↓ Apo CIII

16. Fibrates :Hepatic & peripheral effects 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 16

17. Pk Dose uses Gemfibrozil T1/2 : 1-2hrs, High efficacy in Type III & ↓CH, Factor VII-PL complex & promotes fibrinolysis Absorption : Oral - Complete Metabolism: Glucuronidation Excretion: urine 600mg BD before meals Type III Type IV,V And as adjuvant in Type II 200mg TDS Bezafibrate Dose reduction needed in elderly / renal insufficiency ↑action of warfarin 200mg OD with meals Fenofibrate T1/2 : 20 hrs Greater ↓ in CH & ↑ HDL Most suitable combination with statins 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 17

18. Fibric acid derivatives cont… Uses : Hypertriglyceridaemias . Fenofibrate is uricosuric - given in coexisting hyperuricaemia ADR : GI, skin rashes, body ache, myalgia , reversible myopathy . Eosnophilia , Impotence, Blurred Vision, cholelithiasis with Gemfibrozil ↑ Aminotransferases & Alk . Phosphatase – Fenofibrate DI : with statins increase myositis , potentiates affect of warfarin 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 18

19. PPAR γ agonists Thiazolidinediones ( Glitazones ) 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 19

20. thiazolidinediones These are insulin-sensitizing drugs Rosiglitazone Pioglitazone TZDs have also effects on TG, FFA, and ketone body level in several animal models of T2DM* 7/26/2014 20 Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Caring for diabetes. Treatment and prevention : Emerging therapies. Available at www.caring for diabetes.com.

21. Thiazolidinediones cont… Because of Antiproliferative , Anti-inflammatory, Immunomodulatory effects Have potential role In the treatment of diabetic complications inflammatory-proliferative diseases in non-insulin-resistant euglycaemic individuals Autoimmune Atopic and inflammatory diseases sepsis and reperfusion injury. 7/26/2014 21 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

22. Glitazones : MOA Rosiglitazone Pioglitazone 7/26/2014 22 Dr Karuna Sree P, Dept. of Pharmacology, KIMS Activate insulin responsive genes - regulate carbohydrate & lipid metabolism Sensitize the peripheral tissues to insulin ↑ Glucose transport into muscle & adipose tissue Inhibit hepatic gluconeogenesis Promote lipogenesis ↓ Blood Glucose Selective agonists of PPAR  - bind to the receptor

23. TZD : role in lipid metabolism Pioglitazone has no effect on LDL levels, ↓ triglyceride & ↑ HDL Rosiglitazone has inconsistent effect on lipid profile it ↑ HDL & LDL levels The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues. 7/26/2014 23 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

24. Pharmacokinetics Absorption : Completely absorbed from GIT Distribution : >95% bound to plasma proteins Metabolism : Rosiglitazone - CYP2C8 Pioglitazone - CYP2C8 & CYP3A4 Excretion : Rosiglitazone in urine Pioglitazone in bile Drug interactions less with rosiglitazone 7/26/2014 24 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

25. Uses & dose Pt who benefit most are type II DM with substantial amount of insulin resistance Also used in PCOD Monotherapy – Hypoglycemia rare Slow acting – takes 1 month for its action Dose Pioglitazone : 15 to 45 mg once daily orally Rosiglitazone : 4 to 8 mg once daily orally 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 25

26. Adverse effects Weight gain: due to fluid retention & edema ↑ Extracellular fluid volume Worsening of CHF ↑ Deposition of subcutaneous fat Mild anemia: due to hemodilution Hepatotoxicity : rare Rosiglitazone : ↑ risk of fractures especially in elderly women 7/26/2014 26 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

27. Contraindications Liver disease Congestive heart failure Pregnancy Lactating mother Children 7/26/2014 27 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

28. PPAR γ : Actions & Side effects 7/26/2014 28 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

29. Manufactute & sale Rosiglitazone banned in India* - GSR NO. 910(E) on 12.11.2010, as well in European medicines agency US FDA # – in Nov 2013 removed the warnings/ restrictions on Rosiglitazone initially put in 2010 for causing heart failure. Pioglitazone : Banned in India & reintroduced- 2011. ^US FDA drug safety communication recommend – Not to use / use with caution in patients with active / prior h/o bladder cancer 7/26/2014 29 Dr Karuna Sree P, Dept. of Pharmacology, KIMS *www.cdsco.nic.in/writereaddata/prohibition_rosiglitazone.pdf # http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm376365.htm ^http://www.fda.gov/Drugs/DrugSafety/ucm266555.htm

30. SPPARM Selective PPAR Modulators gained importance to combat the side effect profile of glitazones . SPPARM have partially activated PPARγ target genes involved in adipogenesis and more agonistic activity on target genes influencing insulin sensitivity. INT131, MBX-102, antihypertensive drug - Telmisartan 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 30

31. PPAR RECEPTOR LOCATION FUNCTION DRUGS AS AGONISTS PPAR- α Skeletal muscle, liver, kidney and Vascular endothelial cells. Controls LP metabolism, FA oxidation and cellular uptake of fat. Regulation of adipocyte gene expression and differentiation Regulation of target genes involved in glucose and lipid metabolism Fibrate class of lipid-lowering agents ( ie , clofibrate , fenofibrate , and gemfibrozil ). PPARs- β/ δ Oligodendrocytes & spermatocytes . Muscle,adipocytes , macrophages, etc Oligodendrocyte differentiation and Spermatogenesis. Increases FA oxidation and serves as an anti-inflammatory factor PPAR- γ Adipocytes , skeletal muscle, and cardiac muscle. Improvements in insulin sensitivity and glycemic control. Adipocyte differentiation and fat deposition. Oral hypoglycemics like, pioglitazone and rosiglitazone . angiotensin II Type1 receptor antagonists has selective PPAR- γ- modulating activity. PPAR- α + PPAR- γ Combined treatments with PPAR gamma and alpha agonists improve insulin resistance and alleviate atherogenic dyslipidemia . The new generation of dual-action PPARs—the glitazars :- muraglitazar , aleglitazar . 7/26/2014 31 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

32. PPAR Dual agonists ( α , γ ) These are termed as glitazars , several dual PPAR-α/γ agonists have been developed. 7/26/2014 32 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

33. 7/26/2014 33 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

34. PPAR Dual agonists Drug Reasons for stopping the trials Ragaglitazar , MK-0767, Naveglitazar bladder cancer and hyperplasia in rodent studies Tesaglitazar renal dysfunction Muraglitazar – completed phase III studies increased risk of death, myocardial infarction, or stroke when compared with patients who received either pioglitazone or placebo. Aliglitazar Side effect proflie on kidneys and heart 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 34

35. Saroglitazar The first Glitazar to be approved in India-2013 Indication : diabetic dyslipidemia or hypertriglyceridemia in type-2 diabetes not controlled by statins alone. Development of saroglitazar 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 35

36. Saroglitazar Chemical structure : aryl alkoxy propionic acid Strong PPAR-α effect with moderate PPAR-γ effect Pk : well absorbed, nearly 96% plasma protein bound, metabolism by oxidation & excreted in bile Dose : 4mg oral tablet OD Adverse effects : gastritis, asthenia and pyrexia 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 36

37. PPAR δ agonists PPAR δ r egulates fatty acid metabolism in the brain, skeletal muscle and adipose tissue. Actions : improves insulin sensitivity and ↑ HDL in T2DM, dyslipidemia & obesity. Cancer Atherosclerosis Enhance oligodendrocyte maturation and differentiation & regulates myelination of neurons Drugs under development for treating obesity, cancer, Infertility GW501516 GW0742 7/26/2014 37 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

38. Functions of PPAR δ 7/26/2014 38 Dr Karuna Sree P, Dept. of Pharmacology, KIMS

39. PPAR pan agonists Agonist actions on PPAR α , β / δ , γ receptors Being developed for type 2 diabetes and dyslipidemia * Bezafibrate found to have pan agonist action 7/26/2014 39 Dr Karuna Sree P, Dept. of Pharmacology, KIMS * Tenenbaum A, Motro M, Fisman EZ. Dual and pan- peroxisome proliferator -activated receptors (PPAR) co- agonism : the bezafibrate lessons. Cardiovasc Diabetol 2005 ;16:4-14.

40. Therapeutic role of PPARs Type 2 Diabetes mellitus Atherosclerosis, Dyslipidaemia Obesity Metabolic syndrome Cardiovascular diseases Cancers – colon, breast, prostate, lung, blood Assisted reproductive technology, PCOS Retinopathy Viral infections 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 40

41. Therapeutic role of PPARs 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 41 Inflammation & Neurology Alzheimers disease Multiple sclerosis Parkinson's disease Ischemic stroke Spinal cord Injury Psoriatic arthritis Chronic obstructive pulmonary disease / Br. Asthma Inflammatory bowel disease Rheumatoid arthritis

42. Conclusion PPARs are interesting pharmaceutical targets. They have multiple beneficial effects. New PPAR drugs showing co agonism or pan- agonism are expected to show synergistic effects on various metabolic and inflammatory diseases. Long-term trials are needed to evaluate the efficacy and safety of these wonder agents. 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 42

43. References Guyton AC, Hall JE. Text book of Medical physiology. 11 th ed. Philadelphia (Pa): Saunders; 2006. Laurence L. Brunton , Keith L. Parker, editors. Textbook of Goodman and Gillman’s Manual of Pharmacology and therapeutics, 12 th ed. New York:Mac Graw Hill’s Companies;2010. Kumar A, Hasamnis A. A clinical update on peroxisome proliferator -activated receptors. Syst Rev Pharm 2010;1:175-81. V. A. Javiya , J. A. Patel. The role of peroxisome proliferator –activated receptors in human disease. Indian J Pharmacol 2006;38:243-53 Taygerly JP ,  McGee LR ,  Rubenstein SM ,  Houze JB ,  Cushing TD ,  Li Y .  Discovery of INT131: a selective PPAR γ modulator that enhances insulin sensitivity. Bioorg Med Chem 2013;21:979-92. 7/26/2014 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 43

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