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.
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
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4. Epidemiology
GLOBESITY 1.9 billion adults
(39%) – over weight
600 million (13%) –
obese [2014]
42 million children
under 5 – overweight
in 2013
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Obesity and overweight fact sheet. WHO. Accessed on 22/07/2016
from http://www.who.int/mediacentre/factsheets/fs311/en/
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
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14. Disorders of Hypothalamus
Tumours- Craniopharyngioma
Inflammation
Trauma
GH decreases but Somatomedin is
normal.
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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
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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)
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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
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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
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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
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
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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.
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28. Physical Activity
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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.
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.
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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 %
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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.
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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.
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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.
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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
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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.
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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
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!
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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)
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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
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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
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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.
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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'.
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SUMMARY...
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/
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