Obesity is one of the most common factor which underlies the pathophysiology of many other non- communicable diseases. In recent years, its prevalence has blown out of proportions. The term GLOBESITY signfies that. Newer pharmacological developments will definitely play a crucial role in containing this epidemic. This seminar is my attempt this interesting topic with all the latest data I could collect on the internet.

1. Dr. Prashant Shukla
Junior Resident
Dept of Pharmacology
SEMINAR

2. Contents
 Introduction
 Epidemiology
 Patho-physiology
 Classification
 Management
 Recent
developments
 Conclusions
2

3. DEFINITION
 Latin word “OBESUS” meaning stout, fat,
plump.
 It is defined as a state of excess adipose
tissue.
Overweight – Fat
Fluid
Muscle mass
Bone
Tumours
3

4. Epidemiology
GLOBESITY 1.9 billion adults
(39%) – over weight
600 million (13%) –
obese [2014]
42 million children
under 5 – overweight
in 2013
4
Obesity and overweight fact sheet. WHO. Accessed on 22/07/2016
from http://www.who.int/mediacentre/factsheets/fs311/en/

5. States
Males
(%)
Males
rank
Females
(%)
Females
rank
Punjab 30.3 1 37.5 1
Kerala 24.3 2 34 2
Goa 20.8 3 27 3
Tamil Nadu 19.8 4 24.4 4
Andhra Pradesh 17.6 5 22.7 10
Sikkim 17.3 6 21 8
Mizoram 16.9 7 20.3 17
Himachal
Pradesh
16 8 19.5 12
Maharashtra 15.9 9 18.1 13
Gujarat 15.4 10 17.7 7
Haryana 14.4 11 17.6 6
5
INDIANFIGURES
OBESE FEMALES > OBESE MALES

6. Etiology of obesity
 Genetic basis
 Imbalance between energy intake and
expenditure.
6

7. Regulation of appetite
7

8. Other centres in regulation of
appetite :
1. Arcuate Nuclei-
primary site for action of leptin and
insulin.
2. Para Ventricular Nuclei-
AMP kinase mediated appetite
regulation
8

9. Neuro-humoral factors in Obesity
9

10. Pathophysiology of obesity
10

11. Control of Energy expenditure
 Normal Metabolism
 Physical activity
 Thermogenesis
11

12. OBESITY SYNDROMES
1. Laurence Moon Biedl syndrome
2. Congenital leptin deficiency
3. Prader Willi Syndrome
4. Bardet Biedl Syndrome
12

13. Endocrinal Abnormalities-
 Cushing syndrome
 Hypothyroidism
 Insulinoma
 Metabolic syndrome
 PCOD
13

14. Disorders of Hypothalamus
 Tumours- Craniopharyngioma
 Inflammation
 Trauma
 GH decreases but Somatomedin is
normal.
14

15. Viral Etiology ??
 Virus Ad-36 found almost exclusively in
obese human beings
 Role of Ad-36 in obesity is unclear.
 Possibility: Virus induced hypothalamic
damage
15

16. Measurement Of Obesity
 BMI
 Waist hip ratio
 Skin fold thickness
 Biometric impedance
 Ultrasound
 DEXA (Dual Energy Xray Absorptiometry
 CT / MRI
 Air displacement Plethysmography
 Total body electrical conductivity
 Hydrometry (most accurate)
16

17. Body Mass Index (BMI)
 Calculated as Weight(kg)/ Height(m2)
 BMI can be misleading in certain cases
1. BMI may be high in a very muscular
person
2. For similar BMIs women have greater fat
mass than their male counterparts
17

18. Classification of Obesity (BMI)
 Underweight- BMI < 18.5
 Normal weight- BMI 18.5 to 24.9
 Overweight- BMI 25.0 to 29.9
 Obese grade I- BMI 30.0 to 34.9
 Obese grade II- BMI 35.0 to 39.0
 Obese grade III (morbid) BMI ≥ 40
18

19. Recommendations for Asians
(2002)
WHO Expert Consultation. Appropriate-body mass index for Asian populations
and its implications for policy and intervention strategies. Lancet 19

20. WHY DIFFERENT CUT-
OFFS?
20

21. Classification of Obesity (clinical)
 Stage 0: no apparent obesity-related risk factors
 Stage 1: presence of obesity-related sub-clinical risk
factors, mild physical symptoms.
 Stage 2: presence of established obesity-related
chronic disorders
 Stage 3: established end-organ damage
 Stage 4: severe (end-stage?) disabilities
21

22. Co morbidities of Obesity
22

23. Biomarkers for obesity
 Immunological (elevated C-reactive protein,
TNF-α and IL-6)
 Biochemical (glucose, lipids, satiety-related
hormones)
 Microbiological (the fecal microbial
composition)
 Genetic markers: genes coding adrenergic
receptors (ADBRs), uncoupling proteins
(UCPs), leptin (LEP), leptin receptor (LEPR),
melanocortin pathways genes (MC3R, POMC),
serotonin receptor, peroxisome proliferator-
activated receptor PPAR-γ-2, and genes related23

24. Management of Obesity
24
Management
Lifestyle modification
Pharmacologic Therapies
Surgical treatment

25. Life Style Modification
25

26. Diet
 Low calorie diet
 Low in saturated fats
 Normal protein intake
 Increased fibers in
diet
 Low density foods
 1000 K cal deficit
produces 1 kg wt loss
per week
26

27. Total Fasting
 Not recommended (failure rate ~90%)
 There is diuresis, natriuresis
 Prone to deficiencies
 Re Feeding Syndrome-severe an
potentially fatal electrolyte, fluid and
metabolic abnormalities when feeding
is resumed.
27

28. Physical Activity
28
To stay at a healthy
weight, or to lose
weight, most people
will need more
physical activity-at
least an hour a day-to
counteract the effects
of increasingly
sedentary lifestyles.

29. Pharmacotherapy
29

30. Pharmacotherapy
 Indications -
1. BMI > 30
2. BMI > 27 with risk factors like HT, DM,
CHD, Sleep Apnoea, Dyslipidemia.
30

31. Pharmacotherapy
31

32. Pharmacotherapy
32
2014: Contrave (Bupropion + Naltrexone ) and
Liraglutide

33. Phenteramine
 Amphetamine like drug
 Act centrally to reduce appetite
 Low addictive potential
 Modest efficacy
 CVS side effects
33

34. Fenfluramine
 Inhibit serotonin uptake
 Modest efficacy as single agent
34

35. Fen Phen
 Combination fenfluramine and
phentermine
 drugs exerted independent actions on
brain satiety mechanisms
 Primary Pulmonary hypertension
increases 20 fold in this patients.
 Drug was withdrawn in 1997.
35

36. Sibutramine
 Originally an anti depressant
 Mechanism of action –
Mono amine reuptake inhibitor (primarily
serotonin and norepinephrine )
 Site of action - Central nervous system
 Absorption – 77 %
 Protein binding – 94 %
36

37. Sibutramine
 Metabolism – Hepatic enzymes,
Cytochrome 3A4 to active metabolites
M1 and M2
 FDA Approval – for adults and
adolescents.
 Side Effects – hypertension ( DBP
increases by 2 to 3 mm ) and
tachycardia ( 3/ min), sweating, dizziness
and headache.
37

38. Orlistat
 Mechanism of action – non systemic reversible
inhibitor of gastric and pancreatic lipases by
forming a covalent bond with serine residue
 Site of action - stomach and intestine
 FDA Approval – for adults and adolescents as
well as children.
 Side Effects – flatulence, defecation increases,
oily evacuation, rectal leakage, steatorrhoea.
 Contraindications – cholestasis,
hypersensitivity, pregnancy, nursing mothers, 38

39. Orlistat
 Precautions –
1. Patient should take 3 main meals into
which dietary constituents are equally
divided.
2. Multivitamins are to be added
3. High fat diet should be avoided as it will
lead to fatty large stools.
 Pellets – pelletized formulations
increasing surface area of the drugs are
also available. 39

40. Rimonabant
 Mechanism of action –
Endocannabinoid (CB1) receptor
blocker.
 Site of action – CNS
 FDA approval – BANNED
 Side effects – depression, anxiety,
suicidal tendencies. 40

41. Metformin
 Decreases appetite and thereby
reduces weight
 Since most DM II patients are Obese
this is a good choice in DM II.
41

42. Olestra
 Olestra is synthesized using a sucrose
molecule, which can support from 6-8
fatty acid chains arranged radially.
 Too large to move through the intestinal
wall and be absorbed.
 Same taste and mouth feel as fat
 Approval as a food additive upto 35%
replacement of fats in home cooking
and 75% in commercial uses.
42

43. Olestra
 Decline in blood cholesterol levels
 Side effects-
1. abdominal cramping
2. loose stools.
3. Vitamins A, D, E, and K deficiency
4. anal leakage
5. increase in bowel movement
frequency
43

44. Lorcaserin
 Selective 5 HT2C receptor agonist
44

45. Liraglutide
Liraglutide is a long-acting glucagon-
like peptide-1 receptor agonist,
binding to the same receptors as does
the endogenous metabolic hormone
GLP-1 that stimulates insulin
secretion.
45

46. 46
Bariatric surgical techniques
 Divided into two groups
1. Malabsorptive procedures - Induce
decreased absorption of nutrients by
shortening the functional length of the
small intestine
2. Restrictive procedures - Reduce the
storage capacity of the stomach and as
a result early satiety arises, leading to a
decreased caloric intake

47. 47
DRUGS IN THE PIPELINE

48. 48
PHASE I PHASE II PHASE IIIDrugsinClinicaltrials
DRUG NAME CLASS STATUS
GT389-225 conjugate of pancreatic
lipase inhibitor & fat-
binding hydrogel polymer
Phase I
BVT 74316,
PRX 07034
5HT-6-R antagonist Phase I
TKS1225 GLP-1-R agonist Phase I
Remogliflozin
etabonate
SGLT-2 Inh. (↑ urinary
excretion of glucose)
Phase I
Buproprion
Zonisamide
FDC Suspended

49. 49
PHASE I PHASE II PHASE IIIDrugsinClinicaltrials
DRUG NAME CLASS STATUS
Tesofensine NE, DA and serotonin
reuptake inhibitor
Phase IIb
Pramlintide,
Davalintide
Amylin agonist Phase II
S-2367 Neuropeptide Y blocker Phase IIb
Beloranib Methionine
aminopeptidase II inh.
Phase II
Semaglutide GLP-1-R agonist Phase II
RM-493, Mk-
0493
Melanocortin-4 receptor
agonist
Phase II

50. 50
PHASE I PHASE II PHASE IIIDrugsinClinicaltrials
DRUG NAME CLASS STATUS
Cetilistat Pancreatic lipase inhibitor Phase III
Metreleptin Leptin analog Phase III
Velneprit NPY-5 inhibitor Phase III
Exenatide GLP-1 agonist Phase III

51. HYDROGEL POLYMERS
(PHASE II)
 Capsule containing salt like granules
swallowed 20 mins before meal
 In stomach, absorb water 100 times its dry
weight
 After several hours – particles shrink
releasing water
 In small intestine rehydrate & elasticity /
viscosity
 In Large intestine, enzymes cleave cross-
linkers of hydrogel & release water for
reabsorption
 Particles become small & excreted
 EG: Gelesis 100 & GT389-225 51

52. PHARMACOGENOMICS
 Polymorphism in CB1 receptor gene &
serotonin transporter (SLC6A4) –
development of side effects
 Genetic screening can personalise
choice of medication
 Pharmacogenomics + newer highly
selective drugs – Anti-obesity Rx with
greater efficacy & low side effect profile
will soon be a reality!
52

53. FAILED DRUG
53

54. β3 ADRENERGIC RECEPTORS
AGONISTS
 Actions of the β3 receptor include:
◦ Enhancement of lipolysis in white fat.
◦ Thermogenesis in skeletal muscle/brown fat
 Agonists: Mirabegron (marketed –
overactive bladder - OAB), Solabegron
(Phase II – OAB, IBS), Amibegron, BTA243
(discontinued – Obesity)
 Selective β3 agonist - potential weight loss
effects through modulation of lipolysis
(Animal studies)
54

55. Taranabant
 Taranabant is a cannabinoid receptor
type 1 inverse agonist that was
investigated as a potential treatment
for obesity due to its anorectic effects.
 In October 2008, Merck has stopped
its phase III clinical trials with the drugs
due to high level of central side effects,
mainly depression and anxiety
55

56. SUMMARY
56

57. SUMMARY...
 Obesity –abnormal excessive fat
accumulation that harms.
 WHO cut off points BMI >25 kg/m2 &
>30 kg/m2 for obesity & overweight.
 Asian Population is at high risk.
 Physiology of feeding regulated by
multiple peptides – potential drug
targets
57

58. SUMMARY...
 Lifestyle management & exercise
precedes drug therapy.
 Drug therapy indications - obesity /
overweight (BMI >27) with related
comorbidity.
 Bariatric surgery should be used only
when BMI >40.
58

59.  Next generation of weight-loss drugs
will be based on combination
treatments with gut hormones in a
manner that mimics the changes
underlying surgically induced weight
loss thus introducing the so called
'bariatric pharmacotherapy'.
59
SUMMARY...

60. 60
The Indian Way!!!

61. 61

62. 62
THANK YOU FOR YOUR
PATIENCE

63. References
 Dale, M. M., Rang, H. P., & Dale, M.
M. (2007). Rang & Dale's
pharmacology. Edinburgh: Churchill
Livingstone.
 Caballero B (March
2001). "Introduction. Symposium:
Obesity in developing countries:
biological and ecological factors". J.
Nutr. (Review) 131 (3): 866S–870
 http://www.ncbi.nlm.nih.gov/pmc/articl
es/PMC4054704/table/T1/
63