Obesity Its pathophysiology and management

1. OBESITY Pathophysiology
and Management
Fardan Qadeer
Resident, Department of
Pharmacology
ELMC&H
Moderator:
Dr. Ali Ahmad

2. OVERVIEW
EPIDEMIOLOGY
CLASSIFICATION OF OBESITY
MEDICAL COMPLICATIONS OF OBESITY
ETIOLOGY
MANAGEMENT OF OBESITY
PHARMACOTHERAPY

3. According to the WHO(2014) more than 1.9
billion adults, 18 years and older, were
overweight. Of these over 600 million were
obese.
Overall, about 13% of the world’s adult
population (11% of men and 15% of women)
were obese in 2014.

5. WHO defines obesity as “abnormal or excessive fat
accumulation.”
The Obesity is classified according to the BMI:

6. COMPLICATIONS:

7. ETIOLOGY
It may be simply attributed as the imbalance between energy intake
and energy output however it has a more complex and multifactorial
etiology. Possible factors in the development of obesity include the
following:
Race, sex, and age factors
Ethnic and cultural factors
Metabolic factors
Genetic factors
Psychological factors
Endocrine factors
Dietary habits
Level of inactivity
Psychological factors

9. THE REGULATION OF BODY
WEIGHT
This process is tightly regulated by a homeostatic system that
integrates inputs from a number of internal sensors and
external factors.
Important components of the system include the following:
•Hormones that signal the status of fat stores (e.g. leptin).
•Hormones released from the gut during feeding that convey
sensations of hunger (e.g. ghrelin), satiety (e.g. CCK) or
satiation (e.g. PYY3-36).

10. THE REGULATION OF BODY
WEIGHT
•This hormonal information together with neural gustatory,
olfactory and viscerosensory input is integrated in the
hypothalamus.
•Two groups of opposing neurons in the arcuate nucleus
sense hormonal and other signals. Those secreting
POMC/CART products promote feeding while those
secreting NPY/AgRP inhibit feeding.
•The net output from this process is relayed to other sites
in the brain stem motor nuclei that control feeding
behaviour.

11. LEPTIN: ITS ROLE IN OBESITY
Friedman and his colleagues in 1994 identified a protein leptin.
When recombinant leptin was administered in animals it strikingly
reduced food intake and body weight.
It had a similar effect when injected directly into the lateral or the third
ventricle, implying that it acted on the regions of the brain that control
food intake and energy balance.
LEPTIN ARCUATE NUCLEUS
Glucocorticoi
ds insulin
oestrogens
Beta
adrenergic
stimulation
+
-

12. ADIPONECTIN
A peptide hormone made by adipocytes in response to
high fat reserves:
Increases FA uptake by myocytes and the rate of FA
oxidation.
Slows FA synthesis in the liver.
Slows gluconeogenesis in the liver.
Adiponectin is the only adipose-specific protein known to
date that is negatively regulated in obesity
Adiponectin levels are significantly reduced among obese
subjects in comparison with lean control subjects

14. GUT HORMONES
PYY- Peptide YY
1. Secreted from L cells of GI tract
2. Reduces food intake
Ghrelin
1. Mainly secreted from stomach
2. A potent Orexigenic
Cholecystokinin
1. Mainly secreted in duodenum
2. Decreasing meal size and duration both

17. THE PATHOGENESIS
LEPTIN DISORDER
 Insufficient amounts of this hormone.
 resistance to leptin
 Defect in leptin carriage, transport into the CNS,
 Leptin receptor defect in the hypothalamus (as occurs
in db/db mice)
 Postreceptor signalling

18. Mediators other than leptin are certainly implicated
in obesity. TNF-α, and cytokines that can relay
information from fat tissue to brain, is increased in
the adipose tissue of the obese individuals.
Reduced insulin sensitivity of muscle and fat,
alterations in the function of specific nuclear
receptors, such as PPARα, β and γ, may play a role
in obesity.

19. Proopiomelanocorti
n (POMC)
Alpha-MSH
melanocor
tin
receptor 4
Genetic defects in POMC
production and mutations in
the MC4 gene are described as
monogenic causes of obesity in
humans
Reduce dietary
intakeData suggest that up to 5% of children who are morbidly obese have MC4 or POMC mutations
Most common identifiable genetic defects
associated with obesity in humans
Prohormone convertase
Genetic factors are presumed to explain
40-70% of the variance in obesity.
Genome-wide association studies have
found a robust number of genetic
susceptibility loci associated with
obesity.
THE GENETIC FACTORS

20. Leptin deficiency
Rare cases of humans with congenital leptin deficiency
caused by mutations in the leptin gene have been
identified. (The involved band is at 7q31.)
PPAR-gamma
PPAR-gamma is a transcription factor that is involved
in adipocyte differentiation. All humans with mutations
of the receptor (at band 3p25) described so far have
had severe obesity.

21. DRUG INDUCED OBESITY

22. DIET AND OBESITY
Various animal models have
shown that high fat diet causes
obesity.
Similar observations are seen
with High carbohydrate diet
Hence, a diet rich in
carbohydrate plus fats in
definitely implicated for obesity.

23. OBESITY IN DISEASE
Obesity is a common feature in various endocrine
disorders:
Hypothyroidism
Cushing’s Syndrome
Pseudohypoparathyroidism
Growth hormone deficiency

24. TREATMENT OF OBESITY
The first weapons in the fight against obesity are diet
and exercise. Unfortunately, these often fail or show only
short-term efficacy, leaving only surgical techniques
(such as gastric stapling or bypass) or drug therapy as a
viable alternative. Surgery is much more effective than
currently licensed drugs.

25. DIETARY MODIFICATION
Ensure low calorie diet for moderate weight loss:
Nutrient Recommended Intake
Calories Approximately 500 to 1,000
kcal/day reduction from usual
intake
Total fat 30 percent or less of total calories
Saturated fatty acids 8 to 10 percent of total calories
Monounsaturated fatty acids Up to 15 percent of total calories
Polyunsaturated fatty acids Up to 10 percent of total calories
Carbohydrate 55 percent or more of total calories
Protein Approximately 15 percent of total
calories

26. PHYSICAL ACTIVITY
Physical activity should be an integral part of weight loss
therapy and weight maintenance. Initially, moderate
levels of physical activity for 30 to 45 minutes, 3 to 5 days
per week, should be encouraged.
Example
Walking 13/4 miles in 35 minutes (20
min/mile)
Bicycling 5 miles in 30 minutes
Running 11/2 miles in 15 minutes(15
min/mile)
Swimming laps for 20 minutes

27. PHARMACOTHERAPY
Currently, the 3 major groups of drugs used to
manage obesity are as follows:
Centrally acting medications that
impair dietary intake
Medications that act peripherally to
impair dietary absorption
Medications that increase energy
expenditure

28. ORLISTAT
Orlistat is a gastrointestinal and
pancreatic lipase inhibitor that induces
weight loss by inhibiting dietary fat

29. ORLISTAT
Indication: Indicated in patients with pretreatment BMI >30
kg/m², or BMI >27 kg/m² in presence of other risk factors
or diseases (eg, HTN, DM, hyperlipidemia)
Dose:120 mg PO q8hr with each fat-containing meal
Side effects:
Oily spotting (5%)
Flatulence, Fatty/oily stool ,Increased defecation, Fecal
incontinence, Nausea, Vomiting, Reduced absorption of
fat soluble vitamins and beta-carotene
Serious interaction: Orlistat decreases levels of
cyclosporine by inhibition of GI absorption

30. LORCASERIN
It decrease food consumption and promote
satiety by selectively activating 5-HT2C
receptors on anorexigenic pro-
opiomelanocortin neurons located in the
hypothalamus.

31. LORCASERIN
Indication: Indicated in patients with pretreatment BMI >30 kg/m²,
or BMI >27 kg/m² in presence of other risk factors or diseases
(eg, HTN, DM, hyperlipidemia)
Dose: 10 mg PO q12h
Side effects:
Interactions:Almotriptan, Amitriptyline, bupropion
>10% Uncommon
Headache (16.8%)
Upper respiratory tract
infection (13.7%)
Nasopharyngitis (13%)
Dizziness (8.5%)
Nausea (8.3%)
Fatigue (7.2%)
Diarrhea (6.5%)
Urinary tract infection
(6.5%)
Back pain (6.3%)
Constipation (5.8%)

32. SYMPATHOMIMETIC AMINE
Phentermine
Diethylpropion
Phendimetrazine
Benzphetamine
Phentermine/topiram
ate
Sympathomimetic
amine increases the
release and reuptake of
norepinephrine and
dopamine.
Its anorexiant effect
occurs as a result of
satiety-center
stimulation in
hypothalamic and limbic
areas of the brain.

33. SYMPATHOMIMETIC AMINE
Side effects:
Dysuria, Excitement, Hair loss, Headache, Hypertension,
Tremor, Urticaria, Primary pulmonary hypertension,
Psychotic disorder
Serious interaction: Amoxapine, Cabergoline, Citalopram,
Clomipramine
Contraindication: Arteriosclerosis, cardiovascular disease,
moderate-to-severe hypertension, glaucoma, agitation,
hyperthyroidism, history of drug abuse
Not approved for long-term use

34. BUPROPION AND
NALTREXONE
Combination may regulate activity in the dopamine reward
system of the brain that helps control food cravings and
overeating behaviours
Bupropion Increases dopamine activity
in the brain, which appears to
lead to a reduction in
appetite and increase in
energy expenditure by
increasing activity of pro-
opiomelanocortin (POMC)
neurons
Naltrexone Blocks opioid receptors on
the POMC neurons,
preventing feedback
inhibition of these neurons
and further increasing POMC
activity

35. LIRAGLUTIDE
Liraglutide was approved by the FDA on December 23,
2014 for treatment for obesity in adults with some
related comorbidity.
Liraglutide (NN2211) is a long-acting glucagon-like
peptide-1 receptor agonist.
Thyroid cancer concern:
Liraglutide caused a statistically
significant increase in thyroid
tumors in rats. The clinical
relevance of these findings is
unknown.

36. DRUGS WITHDRAWN BY FDA

37. DRUGS UNDER TRIAL

38. Target Drug Company
Mechanism of
action
Status
Central
neuropeptide
signaling
Melanocortin
receptor
MK-0493 Merck
Selective
MC4R agonist,
increasing
MC3/4R
signaling
Phase II
completed
RM-493 Rhythm
Selective
MC4R agonist,
increasing
MC3/4R
signaling
Phase II
NPY
MK-0557 Merck
Y5 receptor
antagonist,
NPY blocker
Phase II
completed
Velneperit (S-
2367)
Shionogi USA
Y5 receptor
antagonist,
NPY blocker
Phase III

39. Target Drug Company
Mechanism of
action
Status
Monoamine
neurotransmis
sion
Dopamine /
norepinephrin
e / serotonin
Contrave
(bupropion /
naltrexone)
Orexigen
Norepinephrin
e/dopamine
reuptake
inhibitor
Phase III
completed
NDA
submission
Intestinal
peptide
hormone
signaling
GLP
Byetta®
(exenatide)
Amylin
GLP1R
agonist, GLP-
1 mimicking
Phase III
OXM
Qxyntomoduli
n (OXY-RPEG)
Prolor
GLP1R
agonist, OXM
mimicking
Phase I
recruiting
Thiakis /
GLP1R

40. Target Drug Company
Mechanism of
action
Status
Pancreatic
hormone
signaling
PP PP1420
Wellcome
Trust
Pancreatic
polypeptide
analog
Phase I
completed
Amylin
Davalintide
(AC2307)
Amylin
Amylin
mimicking
Phase II
Adipose tissue
hormone
signaling
Leptin Metreleptin
Amylin /
Takeda
Leptin
receptor
agonist
Phase III
recruiting
Inhibition of
lipase
Pancreatic
lipase
Cetilistat
(ATL-962)
Alizyme /
Takeda /
Norgine
Pancreatic
lipase
inhibitor,
inhibiting
Phase III
completed

41. SURGICAL MANAGEMENT
Weight loss surgery is an option for weight reduction in
patients with clinically severe obesity, i.e., a BMI ≥40, or a
BMI ≥ 35 with comorbid condition(morbid obesity)

42. THANK YOU
Eat and drink, but be not excessive. Indeed, He does
not like those who commit excess.”
[Quran Sûrah al-A`râf: 31]