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Dr Karuna Sree P
Asst. Professor
Dept. Of Pharmacology
Kamineni Institute of Medical Sciences
 Introduction
 PPAR receptors – types
 Mechanism of action
 Role of PPARS
 Clinical significance
 Conclusion
3/23/20...
 Issemann and Green discovered Peroxisome
proliferator activated receptors (PPAR).
 The different types of PPAR initiall...
Nuclear Receptor Superfamily
Type 1
Receptors
Eg. GR, MR,
AR,ER,PR
Steroids
Type 2 Receptors
Eg. TR, VDR, RAR,
PPAR
Thyroi...
Binds to response
elements on DNA
Ligands
bind
Co-activators
Co-regulator
proteins
3/23/2015 5Dr Karuna Sree P, Dept. of P...
 Plays a central role in the regulation of
 Storage and catabolism of dietary fats and
carbohydrates
 Adipocyte differe...
Ubiquitous but predominant in
 α - Liver, kidney, heart, muscle, adipose tissue.
 β / δ - Brain, adipose tissue, and ski...
PPAR Partner Ligand
Process
affected
Related
disease process
PPAR α
Active state -
fasting
Retinoic
acid X
receptor
Fatty
...
3/23/2015 9Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 10
 Cellular organelle
 More than 50 enzymes are present in it, among
which catalase and oxidase are important
 Role : In ...
 PPAR α agonists : Fibrates - Hyperlipidaemia
 PPAR γ agonists : Thiazolidinediones -
Hyperglycaemia
 PPAR dual agonist...
PPAR α agonists
Fibrates
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13
 1st generation fibrates : Clofibrate
 2nd generation : Gemfibrozil, Fenofibrate,
Bezafibrate, ciprofibrate
 Lowers VLD...
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 15
Activates peroxisome proliferation activated
receptor factor (P...
3/23/2015
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
16
Pk Dose uses
Gemfibrozil
T1/2 : 1-2hrs, High efficacy
in Type III & ↓CH, Factor
VII-PL complex & promotes
fibrinolysis
Abs...
 Uses : Hypertriglyceridaemias.
 Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
 ADR : GI, skin rashes,...
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 19
 These are insulin-sensitizing drugs
 Rosiglitazone
 Pioglitazone
 TZDs have also effects on TG, FFA, and ketone
body ...
 Because of Antiproliferative, Anti-inflammatory,
Immunomodulatory effects
 Have potential role
 In the treatment of di...
Rosiglitazone
Pioglitazone
3/23/2015 22Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Activate insulin responsive genes -
r...
 Pioglitazone has no effect on LDL levels, ↓
triglyceride & ↑ HDL
 Rosiglitazone has inconsistent effect on lipid
profil...
 Absorption : Completely absorbed from GIT
 Distribution : >95% bound to plasma proteins
 Metabolism : Rosiglitazone - ...
 Pt who benefit most are type II DM with
substantial amount of insulin resistance
 Also used in PCOD
 Monotherapy – Hyp...
 Weight gain: due to fluid retention & edema
 ↑ Extracellular fluid volume
 Worsening of CHF
 ↑ Deposition of subcutan...
 Liver disease
 Congestive heart failure
 Pregnancy
 Lactating mother
 Children
3/23/2015 27Dr Karuna Sree P, Dept. o...
3/23/2015 28Dr Karuna Sree P, Dept. of Pharmacology, KIMS
 Rosiglitazone banned in India* - GSR NO. 910(E) on
12.11.2010, as well in European medicines agency
 US FDA# – in Nov 2...
 Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones.
 SPPARM have partially act...
 These are termed as glitazars, several
dual PPAR-α/γ agonists have been
developed.
3/23/2015 32Dr Karuna Sree P, Dept. o...
3/23/2015 33Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Drug Reasons for stopping the
trials
Ragaglitazar, MK-0767,
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
...
 The first Glitazar to be approved in India-2013
 Indication : diabetic dyslipidemia or
hypertriglyceridemia in type-2 d...
 Chemical structure : aryl alkoxy propionic acid
 Strong PPAR-α effect with moderate PPAR-γ
effect
 Pk : well absorbed,...
 PPAR δ regulates fatty acid metabolism in the brain,
skeletal muscle and adipose tissue.
 Actions : improves insulin se...
3/23/2015 38Dr Karuna Sree P, Dept. of Pharmacology, KIMS
 Agonist actions on PPAR α, β/δ, γ receptors
 Being developed for type 2 diabetes and
dyslipidemia
 *Bezafibrate found ...
 Type 2 Diabetes mellitus
 Atherosclerosis, Dyslipidaemia
 Obesity
 Metabolic syndrome
 Cardiovascular diseases
 Can...
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 41
 Inflammation & Neurology
 Alzheimers disease
 Multiple scle...
 PPARs are interesting pharmaceutical targets.
 They have multiple beneficial effects.
 New PPAR drugs showing co agoni...
 Guyton AC, Hall JE. Text book of Medical physiology. 11th ed.
Philadelphia (Pa): Saunders; 2006.
 Laurence L. Brunton, ...
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 44
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 45
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Drugs acting on ppar

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

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Drugs acting on ppar

  1. 1. Dr Karuna Sree P Asst. Professor Dept. Of Pharmacology Kamineni Institute of Medical Sciences
  2. 2.  Introduction  PPAR receptors – types  Mechanism of action  Role of PPARS  Clinical significance  Conclusion 3/23/2015 2Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  3. 3.  Issemann and Green discovered Peroxisome proliferator activated receptors (PPAR).  The different types of PPAR initially identified in xenopus frog.  Belongs to nuclear receptor family. 3/23/2015 3Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  4. 4. Nuclear Receptor Superfamily Type 1 Receptors Eg. GR, MR, AR,ER,PR Steroids Type 2 Receptors Eg. TR, VDR, RAR, PPAR Thyroid hormone Vitamin D Retinoic acid Lipid derivatives Orphan receptors Ligands not known Eg. SF-1, HNF4 3/23/2015 4Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  5. 5. Binds to response elements on DNA Ligands bind Co-activators Co-regulator proteins 3/23/2015 5Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Daryl K Granner. Hormone Action & SignalTransduction. In: Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell editors. Harper’s Illustrated Biochemistry. 26th ed. NewYork McGraw-Hill
  6. 6.  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 3/23/2015 6Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  7. 7. Ubiquitous but predominant in  α - Liver, kidney, heart, muscle, adipose tissue.  β / δ - Brain, adipose tissue, and skin.  γ - three forms: γ1 - Heart, muscle, colon, kidney, pancreas & spleen. γ 2 - Adipose tissue. γ 3 - Macrophages, large intestine, white adipose tissue. 3/23/2015 7Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  8. 8. 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 3/23/2015 8Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  9. 9. 3/23/2015 9Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  10. 10. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 10
  11. 11.  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 3/23/2015 11Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell. Harper’s Illustrated Biochemistry. 26th ed. NewYork McGraw-Hill.
  12. 12.  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 3/23/2015 12Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  13. 13. PPAR α agonists Fibrates 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13
  14. 14.  1st generation fibrates : Clofibrate  2nd 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. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 14
  15. 15. 3/23/2015 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. 16. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 16
  17. 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: Glucuronida tion 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 mealsFenofibrate T1/2 : 20 hrs Greater ↓ in CH & ↑ HDL Most suitable combination with statins 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 17
  18. 18.  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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 18
  19. 19. PPAR γ agonists Thiazolidinediones (Glitazones) 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 19
  20. 20.  These are insulin-sensitizing drugs  Rosiglitazone  Pioglitazone  TZDs have also effects on TG, FFA, and ketone body level in several animal models of T2DM* 3/23/2015 20Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Caring for diabetes.Treatment and prevention : Emerging therapies. Available at www.caring for diabetes.com.
  21. 21.  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. 3/23/2015 21Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  22. 22. Rosiglitazone Pioglitazone 3/23/2015 22Dr 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. 23.  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. 3/23/2015 23Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  24. 24.  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 3/23/2015 24Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  25. 25.  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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 25
  26. 26.  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 3/23/2015 26Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  27. 27.  Liver disease  Congestive heart failure  Pregnancy  Lactating mother  Children 3/23/2015 27Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  28. 28. 3/23/2015 28Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  29. 29.  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 3/23/2015 29Dr Karuna Sree P, Dept. of Pharmacology, KIMS *www.cdsco.nic.in/writereaddata/prohibition_rosiglitazone.pdf #http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/ucm376365.htm ^http://www.fda.gov/Drugs/DrugSafety/ucm266555.htm
  30. 30.  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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 30
  31. 31.  These are termed as glitazars, several dual PPAR-α/γ agonists have been developed. 3/23/2015 32Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  32. 32. 3/23/2015 33Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  33. 33. 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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 34
  34. 34.  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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 35
  35. 35.  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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 36
  36. 36.  PPAR δ regulates 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 3/23/2015 37Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  37. 37. 3/23/2015 38Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  38. 38.  Agonist actions on PPAR α, β/δ, γ receptors  Being developed for type 2 diabetes and dyslipidemia  *Bezafibrate found to have pan agonist action 3/23/2015 39Dr 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.
  39. 39.  Type 2 Diabetes mellitus  Atherosclerosis, Dyslipidaemia  Obesity  Metabolic syndrome  Cardiovascular diseases  Cancers – colon, breast, prostate, lung, blood  Assisted reproductive technology, PCOS  Retinopathy  Viral infections 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 40
  40. 40. 3/23/2015 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
  41. 41.  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. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 42
  42. 42.  Guyton AC, Hall JE. Text book of Medical physiology. 11th ed. Philadelphia (Pa): Saunders; 2006.  Laurence L. Brunton, Keith L. Parker, editors. Textbook of Goodman and Gillman’s Manual of Pharmacology and therapeutics, 12th 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 PPARγ modulator that enhances insulin sensitivity. Bioorg Med Chem 2013;21:979-92. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 43
  43. 43. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 44
  44. 44. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 45

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