34 © JAPI • mArch 2012 • VOL. 60

Review Article

Pharmacotherapy for Weight ManagementPrincy Louis Palatty*, Elroy Saldanha**

*Professor, **Intern, Department of Pharmacology, Fmmc, mangalore.received: 18.05.2009; revised: 27.10.2009; Accepted: 02.07.2011

AbstractWeight management means lifestyle modification, behavioral therapy, pharmacotherapy and surgery.Drugs have wide ranging side effects and contraindication for its widespread use. Orlistat and sibutramine are the most popular in the present day context. Anti depressants especially fluoxetine is a valuable adjunct for therapy of obesity. There are many newer concepts in weight management and these are mainly hormonal and receptor based, thereby reducing the uncalled adverse effects of drugs like orlistat and sibutramine. Anti-obesity vaccine, an immunotherapy to be looked out for.

IntroductionDefinition

Obesity is a chronic disease characterized by excessive body weight and unhealthy distribution of fat that pre-disposes to

various diseases and leads to increased mortality and morbidity. It is a combination of excessive calorie intake, inadequate exercise along with medical and genetic predisposition. It is one of leading public health problems affecting children and adults especially in developed countries. A leading non-communicable disease considered as a potential threat in reducing life expectancy by predisposing an individual to coronary vascular disease, diabetes, infertility, arthritis etc.Schematic Illustration of consequence of obesity (Table 1)

Obesity is a chronic metabolic disorder with many acquired and inherited factors.1,2 It is also considered as a mild inflammatory disease leading to significant morbid conditions.

Acquired InheritedExcessive intake of food cohen’s diseaseUnhealthy eating carpenter’s diseaseLack of physical activity

Table 1 : Schematic Illustration of consequence of obesity

Table 2 : Common diseases associated with obesity

1. Genetic Lawrence moon Biedl syndrome morgan Stuart syndrome carpenter’s syndrome cohen’s syndrome2. hypothalamic Trauma Inflammatory – Meningitis, TB, Syphilis Infiltration – Histiocytosis X, Sarcoidosis Leukanicdystrophy3. Physical disability Spina bifida Paraplegic4. mental retardation5. Down’s syndrome6. hunters disease7. Endocrine Pituitary: Lauren dwarf syndrome Kallaman’s syndrome cushing disease Thymus hypothyroidism8. metabolic Diabetes mellitus Insulinoma mesidioblastone Beckuth – Weedonan syndrome Decrun’s disease

HistoryIt was long known to the Greeks, Soranus advocated

massage, laxatives, exercise, fiber diet. The age old method of use of diuretics and laxatives still continues popularly. But this methodology surely has no effect on body fat. These are seemingly without any adverse effects but can cause hypokalemia, affect heart and other muscle adversely.

Pyruvate rich food such as red apples, red wine, cheese have not yet been established as an anti-obesity agent.3 It was noted in 1900’s that hypothyroidism leads to obesity and supplementation

Obesity

↓ ↓

a. Excessive weight b. Fat topography

↓ ↓

Increased prevalence of disease

E.g. Diabetes

Hypertension

Coronary Heart Disease

Increase Morbidity

↓

Increase Mortality

© JAPI • mArch 2012 • VOL. 60 35

with thyroid hormone was tried and continues to be used in addition to other agents not only for weight management but also in immortality clinics.3

Dinitrophenol uncoupled oxidative phosphorylation lead to products of heat rather than ATP in the mitochondria which lead to dramatic rise in body temperature and fizzled out of the market for its weight reducing propensity.3 Digitalis was also tried and discarded anti-obesity drug. 1930’s brought anorectics which still hold sway over celebrities and general public, alike.4

IncidenceIn USA, 1.5 billion people are obese. 30,000 deaths were

related to obesity or indwelling obesity. World over obesity totally amounts to 250 million.5, 6 According to WhO in the year 2000, 55% of adult population was obese, of which men and women constitute about 21% and 21.4% respectively.

Table 3 : Drugs inducing obesitySulfonylureasInsulinOestrogenOral contraceptive pillsAlcoholSteroidscyproheptadineValproateTricyclic antidepressantsPhenothiazine

Table 4 : Investigations for an Over-weight Individual

a. clinical assessment: 1. Skin fold thickness with a spring loaded calliper • Biceps • Triceps • Subscapular • Suprailliac 2. Normal body fat content: Males – 20 %, Females – 30% 3. Index of intra-abdominal fat content17

• Ratio of waist circumference to height: Males> 0.95, Females>0.8

• Sagittal diameter of abdomen at L4, L5

Males ≥ 94cms = 37 weeks Females ≥ 80 cms = 32 weeksb. Laboratory investigations: 1. Blood sugar – Fasting, post-prandial, GTT, glycosylated Hb. 2. Lipid profile – Apolipoproteins, chylomicrons. 3. LFTs 4. S. GGT analysis (for alcoholic liver disease) 5. Kidney functions – S. Urea, S. Creatinine, S. Electrolytes 6. ccK mB. 7. Urine analysis 8. EcG 9. Thyroid function tests. 10. Isotopic measurement of whole body potassium content 11. Impedance analysis. 12. Abdominal fat can be measured by any cT or mrI 13. hydrostatic weighing. 14. Dual Energy X-Ray Absorptiometry (DEXA)

Assessment of ObesityDegree of obesity may be assessed early by the body mass

index which is taken as a reliable indicator for many disease states

Weight in kilograms BMI = (height in meters) 2

Significant obesity of males > 30 and females > 28.6.The fat distribution also predicts the complications of obesity.

Fat distribution above the hips (gynecoid, pear type) rather than abdomen (apple type) has a propensity of cardiovascular disease and diabetes mellitus.7, 8

Essential obesity is multifactorial e.g. racial and inheritance triats determine multifaceted of obesity. Persons with tendency for obesity have lower energy requirements.

moreover, obesity is observed predominantly in certain diseases (Table 2).2,9,10 Also drug intake can aid to the tendency of developing obesity (Table 3).11 All of the antecedent complications of obesity appear frequently and consequently, leading to morbidity and mortality.Investigations

There should be constant investigations, post clinical assessment or screening of obese individuals to pick up vital information of impending diseases so that drugs can be prescribed to the specific cause. Various methods can be employed to determine the obesity status starting from the simple clinical assessment like skin fold thickness, intra-abdominal fat content index12 to lab investigations like S.SGPT, S.SGOT. Apart from these various radiographic and research oriented tools like cT, mrI, impedance analysis, Dual Energy X-Ray Absorptiometry (DEXA), Hydrostatic weighing can be utilized in research institutions. comprehensive list of investigations (Table 4).

Sometimes stocky and muscular body have a BmI that appear to be in a higher range, but this is innocuous. So a constant array of investigations is indicated to know progress of disease and development of the complications. When obesity occurs with the continuing years many complications appear virtually ruining every aspect of our body (Table 5).13-15

The treatment of obesity borders on the main equation of a. calorie intake reduction.b. Excessive calorie expenditure.

The goal can be achieved only througha. Diet restrictionb. Exercise

Table 5 : Complications of obesity• hypertension• coronary Artery Disease• Type 2 Diabetes mellitus• Gall Stones• cancer• Arthritis• Infertility• Pregnancy complications – neural tube defects, pre-eclampsia,

perinatal mortality• Stress incontinence• Depression

36 © JAPI • mArch 2012 • VOL. 60

Infact there is no substitute for this mantra.16,17 But to add to this venture three options are available.a. Non-pharmacological measuresb. Surgeryc. Pharmacotherapya. Non-pharmacological measures: 1. Lifestyle changes: It requires the motivation to resist temptation and

the desire to continue when the going gets tough. Its difficult to take off weight and keep it that way. It is not as simple as it seems. help may be obtained from psychiatrist, psychologist or any other trained professional.

A simple easily modifiable flow chart for weight management (Table 6)

2. Psychological therapy hypnosis: hypnosis by a psychologist helps to aid

the suggestibility that remain with the patient to help overcome temptation and maintain weight loss.18

3. Dietary therapy A low fat and low calorie diet is ideal to obtain weight

loss and to maintain lean body. Naturopathy also has lot to offer in this regard. It is advocated to drink lemon juice with one ounce of honey, first thing in the morning. The rationale being lime is an anti-oxidant and aids dissolution of the fat while honey prevents eating tendency as the fructose etc as it will stimulate the satiety center.

Low fat, low carbohydrate nutritionally balanced diet is advocated. It is also advised not to sleep immediately after meals as there is lesser tendency for fat deposition.16,19

4. Physical activity: Warm up exercises, high energy impact activities

for calorie expenditure, stretches, yoga, abdominal workouts. regular exercises to lose and maintain weight is necessary. cycling, skipping, brisk walking are other useful exercises.17, 20

5. Behaviour therapy: Lifestyle modifications cannot be made without a

behavioural change and such a change does contribute to weight management. Some of the methods are

• Improving self esteem • Enhance self confidence • Understanding health • Changing to healthy food stuff • Changing to healthy food practices • Recording daily diet • Recording daily weight • Rewards for losing weight • Selling realistic short term goals • Avoiding crash diet • Adopting moderate and sustained weight loss

program • Enlisting social support network involving family,

friends, colleagues • Joining and supporting other people in a similar

situationb. Surgery: • Weight loss surgery: Consists of gastric bypass ( Roux

en y type) and banding surgery to aid weight loss in those with BMI > 36. Although it leads to 60% of weight loss, it can be maintained by reduced calorie intake and exercise. It may end up in complications like gall stone formation, malabsorption and other nutrition deficiency.21, 22

• Wiring of teeth is advised. • Cosmetic surgery: Abdominoplasty or apronectomy are

various surgeries undertaken to immediately prune the misshapen body.

c. Pharmacotherapy

Anti-obesity Drugs The availability of drugs for any disease condition, itself

brings with it a sense of relief. Drugs are last ditch effort in maintaining optimal weight. Weight creeps on insidiously, so also it should be taken off in a slow and steady manner rather than suddenly. Drugs aid in management. The physician takes a judicious decision after completely reviewing the investigations, patient’s needs and status.

Drugs alter the fundamental metabolic process of the human body and thereby regulate weight. The benefits are out weighted by their adverse effects. Anti-obesity drugs are long term solution for obesity.23, 24 combination of drugs may be effective by regulating multiple pathways and possibly inhibiting feedback pathways. The comprehensive list of drugs presently available is charted in Table 7.

The mechanistics of drugs in weight management is represented in Table 8.

Table 6 : A simple easily modifiable flow chart for weight management

Analyze your food intake

calorie count i.e. Intake + expenditure

Identify habits causative for weight increase

Change of attitude

Yes to healthy foods. No to unhealthy foods

Set goals

Eat only when hungry

Water, vegetables, fresh fruits in daily diet

maintain daily record of food with weight and abdominal girth

Enhance calorie expenditure

regular exercise

© JAPI • mArch 2012 • VOL. 60 37

OrlistatMechanism of action: reduces fat absorption from the

intestine by inhibiting pancreatic lipase and reduces triglyceride hydrolysis.

Low fat diet is generally advised.Adverse effects: Steatorrhoea (oily stools).Newer analogues have lesser degree of steatorrhoea. A well

balanced low calorie diet is advocated with vitamin supplements especially fat soluble vitamins A, D, E and K.25 Orlistat on long term treatment basis had lesser mortality and morbidity incidence and was particularly useful to the patients with impaired glucose tolerance.26,27

SibutramineMechanism of action: centrally acting sympathomimetic

amine that enhances satiety by inhibiting non-selective uptake of nor adrenaline, serotonin and dopamine. It mainly acts on β1, 5hT2a, and 5hT2c. In addition, peripheral D3 receptor are stimulated enhancing metabolic rate, thermogenesis and reduces energy expenditure.28

Efficacy of the drug was found to be better when life style modification was implemented along with the drug intake.29

Adverse effects: hypertension, serotonin syndrome,30 dry mouth, insomnia, headache, constipation, seizures, fatal pulmonary hypertension may occur.31

MetforminBiguanide used in type II diabetes mellitus is also used for

weight reduction. It is the drug of choice in obese patients with type II diabetes when its found to be associated with heart failure or polycystic ovarian disease.32

Mechanism of action: It activates cAmP-activated protein kinase and suppresses hepatic gluconeogenesis activity.

Adverse effects: Lactic acidosis, Gastro-intestinal upset.

ExenatideMechanism of action: It is long acting analogue of the

hormone GLP-1, which the intestine secretes in response to the presence of food which in turn is responsible for the delaying of gastric emptying time and gives the sense of satiety. It is often noticed that obese individuals are deficient in GLP-1 which

Table 7 : Anti obesity drugs1. Diet Supplements: Fiber diet hydrogel2. reduced fat absorption: Orlistat3. reduced carbohydrate absorption: Acarbose4. Appetite Suppressants: • Sympathomimetic: Benzamphetamine Phendimetrazone Diethyl propranolol mazindol Phenylpropanolamine • Serotonergic: Dexfenfluramine Fenfluramine • Both sympathomimetic and serotonergic: Phenteramine Phendimetrazine5. Antidepressants: a. Tricyclic antidepressants: • NA and 5HT receptor reuptake inhibitor: Doxepin Trimipramine • NA receptor inhibitor: Amoxepine b. Selective Serotonin reuptake Inhibitor: Sertraline Fluoxetine c. Atypical: mirtazapine Buspropione6. GABA potentiator and glutamate receptor antagonist: Topiramate7. Opioid antagonist: Naltrexone8. Anti-diabetic drug: metformin Pramlintide Exenatide9. cannabinoid receptor antagonist: rimonabant10. Leptin and neuropeptide Y11. cholecystokinin receptor anatagonist12. Breakthrough treatment options: OB receptor modulating drugs Neuropeptide inhibitors Insulotropin cytokine regulators Uncoupling protein Z Β3 agonists Dopamine antagonists

Individual AgentsA brief description of each of the agents will be described

with supporting evidence.

Table 8 : Schematic representation of general mechanism of action of anti-obesity drugs

Food Items

Lipids Glucose Amino acid

Food Intake

Acarbose Orlistat

Bran, dietary fibre Appetite

Nutritional status

Body – Stores Feeding Mechanistic Centre

Feedback from Alimentary Tract

Satiety Centre α1, α2, β3, MAO D

α1, α2, β3, MAO D

α α β , MAO D

Psychotherapy

Hypothalamus Para vertebral Nucleii

Dorsa Ventricular Nuclei

Brainstemmm

Area Postrema

Nucleus of Tractus solitarus Vagal Tone

Fat Topography

Body Weight

Rimonabant Antidepressants

Mazindol

Long term Anorexiants

Short Term

Insulin tropin CCK receptor Antagonists

Hunger X

X

X

X X

X

X

38 © JAPI • mArch 2012 • VOL. 60

reduces even further when dieting is resorted to.33 For the effective weight reduction, the drug has to be taken for atleast but the benefits of glycemic control was found to be higher than weight loss.

Adverse effects: Injected twice daily and severe nausea during initial therapy. Oxyntomodulin: It is pro-glucagon gene product with actions similar to exenatide.

Amylin: It is a hormone co-released with insulin reduces glucagon secretion. It is advocated as a therapeutic agent, surprisingly.34, 35

PramlintideMechanism of action: It is a synthetic analogue of amylin

secreted by pancreas. It produces a feeling of satiety and delays gastric emptying. It inhibits hepatic gluconeogenesis by inhibiting glucagon synthesis and thereby reduces blood glucose levels. Treatment started with 60µg and increased as needed. Injected subcutaneously twice a day prior to food intake.

It is advocated for obese diabetic with type 1 or type 2 with uncontrolled sugar levels.

Adverse effects: Apart from redness, pain at injection site, it causes hypoglycemia, headache, abdominal pain, fatigue, weight loss.

Drug interactions: Atropine, acarbose, miglitol that slow gastric emptying time and absorption. Insulin and pramlintide should not be mixed in the same syringe.36

RimonabantMechanism of action: It is an approved but infrequently used

drug. It is a canabinoid cB1 receptor antagonist . It selectively acts on cB1 receptor in brain and peripheral organs. It potentiates satiety feeling along with increase peripheral glucose uptake in muscle. It increases insulin sensitivity and reduces lipogenesis in liver.37 They not only cause weight loss but in addition reverse metabolic effects of obesity.38 Some studies concluded that it causes dose dependent restriction in food intake.39

Adverse effects: Severe depression and predisposes to neurodegenerative diseases E.g. Alzheimer’s disease, amylotropic sclerosis.40

MazindolNonamphetamine, an indole derivative. It acts peripherally

by increasing metabolic rate and preferred as an adjunct with other anti-obesity drugs, to enhance over all effectiveness. Mazindol is found to be effective in initial weeks of treatment and their response tends to decline later. So it’s used as a short term treatment regimen.

PhendimetrazineSympathetic agonist that shows potential as anti-obesity agent

because of lesser tendency for addiction liability. Few cases of cardiac ischemia and interstitial nephritis have been reported. 41 Other adverse effects are hyperpyrexia, mydriasis, arrhythmias, rhabdomyolysis. 42 cardiomyopathies are noted on long term usage which is reversible on discontinuation. 43

Fenfluramine has tendency to produce heart valve damage and fatal pulmonary hypertension due to action on 5hT2b receptors.44

combinations approved are

a. SSrI + phenteramine b. Topiramate + phenteramine c. Buproprion + zonisamide d. Buproprion + naltrexone

Peptide YY3-36It is secreted neuro-endocrine cells of ileum and colon,

acts via neuropeptide Y receptors leading to suppression of pancreatic secretion and inhibition of gastric motility along with increased water and electrolyte absorption. Its concentration is found to be reduced in obese individuals.45 Peripheral infusion or nasal spray before meals, with high plasma concentration found to be effective in reducing weight. 46, 47 It brings about appetite suppression.

RNAi TherapyThe ribonucleic acid interface (rNAi) is a nuclear hormone

co-repressor and helps to maintain lean profile thought out their life. Development of ribonucleic acid interface series is the only long term approach to obesity. The experimental evidence proves that its action manifests by silencing rIP140 a nuclear hormone co-repressor, which regulates fat accumulation.48

New Hydrogel – diet PillIt consists of bio-degradable polycellulose that imbibes water

which is flushed out in a few hours giving dieters a feeling of satiety and has no major adverse effects except for flatulence, it is a good alternative to drugs with higher adverse effects like sibutramine.

DiazoxideAffects potassium channels and enhances potassium release

leading to suppression of insulin secretion. It is used in treatment of obesity and hyper insulin states.49 A 6 month study concluded that a high dose of diazoxide along with calorie restriction and life style modification brought about significant insulin suppression and weight reduction.50 But efficacy of diazoxide is better in non-obese than obese individuals and therefore dosages based weight of an individual played an important role.51

NaltrexoneAn opiod antagonist often used to reduce craving, as with

substances of abuse. It selectively antagonizes opioid receptors in central nucleus of amygdala and paraventricular nucleus of hypothalamus leading to diet selection and regulation of food intake.52 certain studies showed that Buproprion action was potentiated with use of naltrexone.53 So the combination is preferred rather than the monotherapy.

TopiramateAntiepileptic, has promising effect by an unknown

mechanism. Acts mainly by inactivating sodium channel, potentiates GABA and some glutamate receptors. It has got varied uses. Apart from treatment of nocturnal and binge eating disorders,54 it is also used in treatment of SSrI induced weight gain.55 Topiramate has a wide range of use.

Antidepressants: They most inhibit the receptors of biogenic amines NA, 5hT at neurons and potentiate their action. common antidepressants preferred are buproprion and diethylpropion.

Drugs that were initially used for obesity and later

© JAPI • mArch 2012 • VOL. 60 39

withdrawn from use by the FDA are fenfluramine, dexflurane, phenylpropanolamine and troglitazone.

SertralineAn SSrI often used in the treatment of nocturnal and binge

eating disorders.56 It is also used in bulimia nervosa treatment. 57

New ConceptsAs obesity is considered to be a mild chronic inflammatory

disease, along with weight reducing drugs anti-inflammatory drugs is also advocated. Since obesity has a tendency to develop leptin insensitivity,58 to overcome the resistance, ciliary neurotrophic factor, a glial cytokine was developed. It brought about weight loss in individuals with diet and leptin resistance induced obesity via melanocortin independent pathway.59,60 however, the trial had to be called off since the patients developed antibodies against ciliary neurotrophic factor.61

The unexpected fall out of anti–obesity drugs could be in the prevention of HIV, influenza and hepatitis which rely on metabolic processes for enhancing viral load. rimonabant may also be given to maintain smoking cessation and has potential to improve short term memory, anti-inflammatory and anti-hyperalgesic effect. Since obesity is associated with depression tri-cyclic anti-depressants can be given. But they have an added disadvantage of weight gain on long term dosage. Various trials are being carried out to provide better drug, some of them are worth a mention.

OlestraIt is polyester of sucrose used as a fat substitute which is

neither digested nor absorbed and therefore has no role in production of energy. It is considered as a tool for weight loss and maintenance. On a long term usage, it is associated with decreased absorption of fat soluble vitamins and steatorrhoea.

AtomoxetineA central nor-epinephrine uptake inhibitor. A 10-week,

double-blind, clinical trial found it to be effective in reducing binge eating episode along with weight and body metabolic index.62 Another 12-week, double-blind, randomized controlled trial with 30 obese women (average BMI = 36) concluded that atomoxetine reduced 5% of body mass when compared to placebo with minimal adverse effects.63

Melanin-concentrating Hormone Receptors (MCHR)

mchr are G protein-coupled receptors involved in regulation of appetite. mchr1 antagonists bring reduced food intake and elevation of body metabolic rate.64,65 GW-803,430 and T-226,296 drugs come under this group and presently under trial.66, 67

Melanocortinsmelanocortin receptor 4 antagonists bring about anorectic

effects by mediating its action by leptin-melanocortin pathway similar to MCHR antagonists except for the latter’s thermogenic effects. 68

P57A steroidal glycoside, hoodia gordonii plant extract brings

about appetite suppression by increasing ATP content in hypothalamus. 69

Apart from these, clinical trials are being done on 5hT6 receptor ligands,70 human steroidal hormone rF1051, amylase inhibitors AZM-140, β3 adrenergic receptor agonists L 755,507 and SB 418790, cholecystokinin A agonists GI 181771, corticotropin releasing factor agonists NBI-30326, leptin promoters and leptin receptor agonists may serve a potential benefit in years to come.

Anti-obesity VaccineAn innovative unexpected method in weight management

and is said to be ideal to yoyo dieters, the cycle of repeated loss and regain of weight which inhibits a naturally occurring hormone ghrelin for regulating energy balance in the body, this immunotherapy comes to the rescue. It is expected to reduce fat stores inspite of not reducing food intake.71,72

Anti-cellulite CreamAnti-cellulite creams are said to increase the metabolism of

the local area using local energy and leads to increased blood circulation, sweating that is helpful in burning and dissolving fats.73,74

most commonly the herbal ingredients used in anti-obesity creams are myrica cerifera, cyperus rotundus, prunes amygladus, ocimum sanctum, piper nigram (Table 8).

ConclusionObesity can be adequately managed by just dietary restriction

and life style modification. It is only rarely that drugs are to be used. Moreover, only a befitting patient that is cleared of contraindications can be given drugs.

Surgery is rarely used for weight management in Indian scenario.

Lifestyle modifications and behavioural therapy has an integral part to play in weight management.

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