Drugs Acting on PPAR

PPAR Family

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. Issemannand Green discovered Peroxisome
proliferatoractivated receptors (PPAR).
The different types of PPAR initially identified in
xenopusfrog.
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
Ligandsnot
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 & Signal Transduction. In: Robert K. Murray, Daryl K. Granner, Peter A. Mayes, Victor W. Rodwell
editors. Harper’s Illustrated Biochemistry. 26
th
ed. NewYorkMcGraw-Hill

6. Plays a central role in the regulation of
Storage and catabolism of dietary fats and
carbohydrates
Adipocytedifferentiation
Inflammatory responses
Cancer
Types :
PPAR α
PPARβ / δ
PPARγ
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 PartnerLigand
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 catalaseand oxidaseare 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, Peter A. Mayes, Victor W. Rodwell. Harper’s Illustrated Biochemistry. 26
th
ed. NewYork
McGraw-Hill.

12. PPAR α agonists : Fibrates-Hyperlipidaemia
PPAR γ agonists : Thiazolidinediones-
Hyperglycaemia
PPAR dual agonists (α ,γ) : Glitazars–
Hyperlipidaemia& Hyperglycaemia
PPAR δagonists : 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. 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.
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
ODwith
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.
Fenofibrateis uricosuric-given in coexisting
hyperuricaemia
ADR : GI, skin rashes, body ache, myalgia, reversible
myopathy.
Eosnophilia, Impotence, Blurred Vision, cholelithiasiswith
Gemfibrozil
↑ Aminotransferases& Alk. Phosphatase–Fenofibrate
DI : with statinsincrease 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,
Immunomodulatoryeffects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemicindividuals
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
Rosiglitazonehas 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 : Rosiglitazonein urine
Pioglitazonein 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 PPARγtarget
genes involved in adipogenesisand 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
pioglitazoneor placebo.
Aliglitazar Side effect proflieon kidneys
and heart
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 34

34. The first Glitazarto be approved in India-2013
Indication : diabetic dyslipidemiaor
hypertriglyceridemiain type-2 diabetes not
controlled by statinsalone.
Development of saroglitazar
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 35

35. Chemical structure : aryl alkoxypropionicacid
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 δregulates fatty acid metabolism in the brain,
skeletal muscle and adipose tissue.
Actions : improves insulin sensitivity and ↑HDL in T2DM,
dyslipidemia& obesity.
Cancer
Atherosclerosis
Enhance oligodendrocytematuration and
differentiation & regulates myelinationof 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, γreceptors
Being developed for type 2 diabetes and
dyslipidemia
*Bezafibratefound to have pan agonist action
3/23/2015 39Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*TenenbaumA, MotroM, FismanEZ. Dual and pan-peroxisomeproliferator-activated
receptors (PPAR) co-agonism: the bezafibratelessons. CardiovascDiabetol2005 ;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 agonismor pan-
agonismare 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. 11
th
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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:MacGrawHill’s Companies;2010.
Kumar A, HasamnisA. A clinical update on peroxisomeproliferator-
activated receptors. SystRev Pharm2010;1:175-81.
V. A. Javiya, J. A. Patel. The role of peroxisomeproliferator–
activated receptors in human disease. Indian J Pharmacol
2006;38:243-53
TaygerlyJP,McGee LR,Rubenstein SM,HouzeJB,Cushing TD,Li
Y.Discovery of INT131: a selective PPARγ modulator that enhances
insulin sensitivity. BioorgMed Chem2013;21:979-92.
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 43

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