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

1. Dr Karuna Sree P
Asst. Professor
Dept. Of Pharmacology
Kamineni Institute of Medical Sciences

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.  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. 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. 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.  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. 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. 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. 3/23/2015 9Dr Karuna Sree P, Dept. of Pharmacology, KIMS

10. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 10

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.  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. PPAR α agonists
Fibrates
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13

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. 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. 3/23/2015
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:
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.  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. PPAR γ agonists
Thiazolidinediones
(Glitazones)
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 19

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.  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. 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.  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.  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.  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.  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.  Liver disease
 Congestive heart failure
 Pregnancy
 Lactating mother
 Children
3/23/2015 27Dr Karuna Sree P, Dept. of Pharmacology, KIMS

28. 3/23/2015 28Dr Karuna Sree P, Dept. of Pharmacology, KIMS

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.  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.  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. 3/23/2015 33Dr Karuna Sree P, Dept. of Pharmacology, KIMS

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.  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.  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.  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. 3/23/2015 38Dr Karuna Sree P, Dept. of Pharmacology, KIMS

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.  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. 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.  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.  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. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 44

44. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 45