OBESITY Pathophysiology and Management Fardan Qadeer Resident, Department of Pharmacology ELMC&H Moderator: Dr. Ali Ahmad
OBESITYPathophysiology and Management
Fardan QadeerResident, Department of PharmacologyELMC&H
Moderator:Dr. Ali Ahmad
OVERVIEW
EPIDEMIOLOGY
CLASSIFICATION OF OBESITY
MEDICAL COMPLICATIONS OF OBESITY
ETIOLOGY
MANAGEMENT OF OBESITY
PHARMACOTHERAPY
According to the WHO(2014) more than 1.9billion adults, 18 years and older, wereoverweight. Of these over 600 million wereobese.
Overall, about 13% of the world’s adultpopulation (11% of men and 15% of women)were obese in 2014.
WHO defines obesity as “abnormal or excessive fataccumulation.”
The Obesity is classified according to the BMI:
COMPLICATIONS:
ETIOLOGYIt 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
THE REGULATION OF BODY WEIGHT
This process is tightly regulated by a homeostatic system thatintegrates inputs from a number of internal sensors andexternal 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 conveysensations of hunger (e.g. ghrelin), satiety (e.g. CCK) orsatiation (e.g. PYY3-36).
THE REGULATION OF BODY WEIGHT
•This hormonal information together with neural gustatory,olfactory and viscerosensory input is integrated in thehypothalamus.
•Two groups of opposing neurons in the arcuate nucleussense hormonal and other signals. Those secretingPOMC/CART products promote feeding while thosesecreting NPY/AgRP inhibit feeding.
•The net output from this process is relayed to other sitesin the brain stem motor nuclei that control feedingbehaviour.
LEPTIN: ITS ROLE IN OBESITY
Friedman and his colleagues in 1994 identified a protein leptin.
When recombinant leptin was administered in animals it strikinglyreduced food intake and body weight.
It had a similar effect when injected directly into the lateral or the thirdventricle, implying that it acted on the regions of the brain that controlfood intake and energy balance.
LEPTIN ARCUATE NUCLEUS
Glucocorticoids insulin
oestrogens
Beta adrenergic stimulation
+
-
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
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
THE PATHOGENESISLEPTIN 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
Mediators other than leptin are certainly implicatedin obesity. TNF-α, and cytokines that can relayinformation from fat tissue to brain, is increased inthe adipose tissue of the obese individuals.
Reduced insulin sensitivity of muscle and fat,
alterations in the function of specific nuclearreceptors, such as PPARα, β and γ, may play a rolein obesity.
Proopiomelanocortin (POMC)
Alpha-MSH
melanocortin
receptor 4
Genetic defects in POMCproduction 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
Leptin deficiency
Rare cases of humans with congenital leptin deficiencycaused by mutations in the leptin gene have beenidentified. (The involved band is at 7q31.)
PPAR-gamma
PPAR-gamma is a transcription factor that is involvedin adipocyte differentiation. All humans with mutationsof the receptor (at band 3p25) described so far havehad severe obesity.
DRUG INDUCED OBESITY
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.
OBESITY IN DISEASE
Obesity is a common feature in various endocrinedisorders:
Hypothyroidism
Cushing’s Syndrome
Pseudohypoparathyroidism
Growth hormone deficiency
TREATMENT OF OBESITY
The first weapons in the fight against obesity are dietand 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.
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
Fiber 20 to 30 g/day
PHYSICAL ACTIVITY
Physical activity should be an integral part of weight losstherapy and weight maintenance. Initially, moderatelevels of physical activity for 30 to 45 minutes, 3 to 5 daysper 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
PHARMACOTHERAPY
Currently, the 3 major groups of drugs used tomanage obesity are as follows:
Centrally acting medications that impair dietary intake
Medications that act peripherally to impair dietary absorption
Medications that increase energy expenditure
ORLISTAT
Orlistat is a gastrointestinal and pancreatic lipase inhibitor that induces
weight loss by inhibiting dietary fat absorption.
ORLISTAT
Indication: Indicated in patients with pretreatment BMI >30kg/m², or BMI >27 kg/m² in presence of other risk factorsor 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, Fecalincontinence, Nausea, Vomiting, Reduced absorption offat soluble vitamins and beta-carotene
Serious interaction: Orlistat decreases levels ofcyclosporine by inhibition of GI absorption
LORCASERIN
It decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus.
LORCASERINIndication: 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%)
SYMPATHOMIMETIC AMINE
Phentermine
Diethylpropion
Phendimetrazine
Benzphetamine
Phentermine/topiramate
Sympathomimetic amine increases the release and reuptake of norepinephrine and dopamine.
Its anorexiant effect occurs as a result of satiety-centerstimulation in hypothalamic and limbic areas of the brain.
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
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
LIRAGLUTIDELiraglutide 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.
DRUGS WITHDRAWN BY FDA
DRUGS UNDER TRIAL
Target Drug CompanyMechanism of
actionStatus
Central neuropeptide signaling
Melanocortinreceptor
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 MerckY5 receptor antagonist, NPY blocker
Phase II completed
Velneperit (S-2367)
Shionogi USAY5 receptor antagonist, NPY blocker
Phase III
Target Drug CompanyMechanism of
actionStatus
Monoamine neurotransmission
Dopamine / norepinephrine / serotonin
Contrave (bupropion / naltrexone)
Orexigen
Norepinephrine/dopamine
reuptake inhibitor
Phase III completed
NDA submission
Intestinal peptide hormone signaling
GLPByetta®
(exenatide)Amylin
GLP1R agonist, GLP-1 mimicking
Phase III
OXM
Qxyntomodulin (OXY-RPEG)
ProlorGLP1R
agonist, OXM mimicking
Phase I recruiting
TKS1225Thiakis /
Wyeth / Pfizer
GLP1R agonist, OXM Phase I
Target Drug CompanyMechanism of
actionStatus
Pancreatic hormone signaling
PP PP1420Wellcome
Trust
Pancreatic polypeptide
analog
Phase I completed
AmylinDavalintide (AC2307)
AmylinAmylin
mimickingPhase II
Adipose tissue hormone signaling
Leptin MetreleptinAmylin / Takeda
Leptin receptor agonist
Phase III recruiting
Inhibition of lipase
Pancreatic lipase
Cetilistat (ATL-962)
Alizyme / Takeda / Norgine
Pancreatic lipase
inhibitor, inhibiting
intestinal lipid
Phase III completed
SURGICAL MANAGEMENT
Weight loss surgery is an option for weight reduction inpatients with clinically severe obesity, i.e., a BMI ≥40, or aBMI ≥ 35 with comorbid condition(morbid obesity)
THANK YOU
Eat and drink, but be not excessive. Indeed, He does not like those who commit excess.”
[Quran Sûrah al-A`râf: 31]