OBESITY

Dr. Prashant ShuklaJunior ResidentDept of PharmacologySEMINAR

Contents

IntroductionEpidemiologyPatho-physiologyClassificationManagementRecent developmentsConclusions2

DEFINITIONLatin word OBESUS meaning stout, fat, plump.

It is defined as a state of excess adipose tissue.

Overweight Fat Fluid Muscle mass Bone Tumours

Obesity Fat ( adipose tissue )

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Epidemiology

GLOBESITY1.9 billion adults (39%) over weight600 million (13%) obese [2014]

42 million children under 5 overweight in 2013

4Obesity and overweight fact sheet. WHO. Accessed on 22/07/2016 from http://www.who.int/mediacentre/factsheets/fs311/en/

StatesMales (%)Males rankFemales (%)Females rankPunjab30.3137.51Kerala24.32342Goa20.83273Tamil Nadu19.8424.44Andhra Pradesh17.6522.710Sikkim17.36218Mizoram16.9720.317Himachal Pradesh16819.512Maharashtra15.9918.113Gujarat15.41017.77Haryana14.41117.66

5INDIAN FIGURESOBESE FEMALES > OBESE MALES

Etiology of obesityGenetic basis

Imbalance between energy intake and expenditure.

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Regulation of appetite7

Other centres in regulation of appetite :

Arcuate Nuclei- primary site for action of leptin and insulin.

Para Ventricular Nuclei- AMP kinase mediated appetite regulation

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Neuro-humoral factors in Obesity9

Pathophysiology of obesity10

Control of Energy expenditureNormal MetabolismPhysical activityThermogenesis11

OBESITY SYNDROMESLaurence Moon Biedl syndromeCongenital leptin deficiencyPrader Willi SyndromeBardet Biedl Syndrome

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Endocrinal Abnormalities-Cushing syndromeHypothyroidismInsulinomaMetabolic syndromePCOD13

Disorders of HypothalamusTumours- CraniopharyngiomaInflammationTraumaGH decreases but Somatomedin is normal.14

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

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Measurement Of ObesityBMIWaist hip ratioSkin fold thicknessBiometric impedanceUltrasoundDEXA (Dual Energy Xray AbsorptiometryCT / MRIAir displacement PlethysmographyTotal body electrical conductivityHydrometry (most accurate)16

Body Mass Index (BMI)Calculated as Weight(kg)/ Height(m2)

BMI can be misleading in certain casesBMI may be high in a very muscular personFor similar BMIs women have greater fat mass than their male counterparts

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Classification of Obesity (BMI)Underweight- BMI < 18.5

Normal weight- BMI 18.5 to 24.9

Overweight- BMI 25.0 to 29.9Obese grade I- BMI 30.0 to 34.9Obese grade II- BMI 35.0 to 39.0Obese grade III (morbid) BMI 4018

Recommendations for Asians (2002)WHO Expert Consultation. Appropriate-body mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157-6319

WHY DIFFERENT CUT-OFFS?

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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

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Co morbidities of Obesity

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Biomarkers for obesityImmunological (elevated C-reactive protein, TNF- 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--2, and genes related to cytokines.

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Management of Obesity24

Life Style Modification

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DietLow calorie dietLow in saturated fatsNormal protein intakeIncreased fibers in dietLow density foods1000 K cal deficit produces 1 kg wt loss per week

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Total FastingNot recommended (failure rate ~90%)There is diuresis, natriuresisProne to deficiencies

Re Feeding Syndrome-severe an potentially fatal electrolyte, fluid and metabolic abnormalities when feeding is resumed.27

Physical Activity

28To 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.

Pharmacotherapy29

PharmacotherapyIndications -

BMI > 30BMI > 27 with risk factors like HT, DM, CHD, Sleep Apnoea, Dyslipidemia.

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Pharmacotherapy31

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Pharmacotherapy32

2014: Contrave (Bupropion + Naltrexone) and Liraglutide

PhenteramineAmphetamine like drugAct centrally to reduce appetiteLow addictive potentialModest efficacyCVS side effects33

FenfluramineInhibit serotonin uptakeModest efficacy as single agent

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Fen PhenCombination fenfluramine and phenterminedrugs exerted independent actions on brain satiety mechanismsPrimary Pulmonary hypertension increases 20 fold in this patients.Drug was withdrawn in 1997.35

SibutramineOriginally 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

SibutramineMetabolism 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.

Contraindications coronary artery disease, cardiac arrythmias, uncontrolled HT

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OrlistatMechanism 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,

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OrlistatPrecautions Patient should take 3 main meals into which dietary constituents are equally divided.Multivitamins are to be addedHigh 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

RimonabantMechanism of action Endocannabinoid (CB1) receptor blocker.

Site of action CNS

FDA approval BANNED

Side effects depression, anxiety, suicidal tendencies.

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MetforminDecreases appetite and thereby reduces weightSince most DM II patients are Obese this is a good choice in DM II.41

OlestraOlestra 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 fatApproval as a food additive upto 35% replacement of fats in home cooking and 75% in commercial uses.42

OlestraDecline in blood cholesterol levels

Side effects-abdominal crampingloose stools.Vitamins A, D, E, and K deficiencyanal leakageincrease in bowel movement frequency43

LorcaserinSelective5 HT2C receptoragonist

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LiraglutideLiraglutide 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

46Bariatric surgical techniquesDivided into two groups

Malabsorptive procedures - Induce decreased absorption of nutrients by shortening the functional length of the small intestine

Restrictive procedures - Reduce the storage capacity of the stomach and as a result early satiety arises, leading to a decreased caloric intake

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DRUGS IN THE PIPELINE

48Drugs in Clinical trialsDRUG NAMECLASSSTATUS GT389-225conjugate of pancreatic lipase inhibitor & fat-binding hydrogel polymerPhase IBVT 74316, PRX 070345HT-6-R antagonistPhase ITKS1225GLP-1-R agonistPhase IRemogliflozin etabonateSGLT-2 Inh. ( urinary excretion of glucose)Phase I Buproprion ZonisamideFDCSuspended

49Drugs in Clinical trialsDRUG NAMECLASSSTATUS TesofensineNE, DA and serotonin reuptake inhibitorPhase IIbPramlintide, DavalintideAmylin agonistPhase IIS-2367Neuropeptide Y blockerPhase IIbBeloranibMethionine aminopeptidase II inh. Phase IISemaglutideGLP-1-R agonistPhase IIRM-493, Mk-0493Melanocortin-4 receptor agonistPhase II

50Drugs in Clinical trialsDRUG NAMECLASSSTATUS CetilistatPancreatic lipase inhibitorPhase IIIMetreleptinLeptin analogPhase IIIVelnepritNPY-5 inhibitorPhase IIIExenatideGLP-1 agonistPhase III

HYDROGEL POLYMERS (PHASE II)Capsule containing salt like granules swallowed 20 mins before mealIn stomach, absorb water 100 times its dry weightAfter several hours particles shrink releasing waterIn small intestine rehydrate & elasticity / viscosityIn Large intestine, enzymes cleave cross-linkers of hydrogel & release water for reabsorptionParticles become small & excretedEG: Gelesis 100 & GT389-225

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

FAILED DRUG53

3 ADRENERGIC RECEPTORS AGONISTSActions of the 3 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 3 agonist - potential weight loss effects through modulation of lipolysis (Animal studies)

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TaranabantTaranabantis acannabinoid receptor type 1inverse agonistthat was investigated as a potential treatment forobesitydue to itsanorecticeffects.

In October 2008, Merck has stopped itsphase IIIclinical trialswith the drugs due to high level ofcentralside effects, mainly depressionandanxiety

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SUMMARY

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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 targets57

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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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'.

59SUMMARY...

60The Indian Way!!!

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THANK YOU FOR YOUR PATIENCE

ReferencesDale, 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): 866S870http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054704/table/T1/63