www.youngpharmacists.

com

OBESITY:Obesity is a condition in which excess body fat has accumulated to such an extent that health may be negatively affected .It is commonly defined as a body mass index of 30 kg/m2 or higher.This distinguishes it from being overweight as defined by a BMI of 25 kg/m2 or higher Excessive body weight is associated with various diseases, particularly Cardiovascular diseases, Diabetes mellitus type 2, Obstructive sleep apnea, Certain types of cancer, Osteoarthritis. As a result, obesity has been found to reduce life expectancy. The primary treatment for obesity is dieting and physical exercise. If this fails, anti-obesity drugs and (in severe cases) bariatric surgery can be tried Obesity, in absolute terms, is an increase of body adipose tissue (fat tissue) mass. In a practical setting it is difficult to determine this directly. Therefore, obesity is typically assessed by BMI (body mass index)

Causes:Most researchers agree that a combination of excessive calorie consumption and a sedentary lifestyle are the primary causes of obesity.In a minority of cases, increased food consumption can be attributed to genetic, medical, or psychiatric A 2006 review identifies ten other possible contributors to the recent increase of obesity: (1) insufficient sleep, (2) endocrine disruptorsfood substances that interfere with lipid metabolism, (3) decreased variability in ambient temperature, (4) decreased rates of smoking as smoking suppresses appetite, (5) increased use of medication that leads to weight gain, (6) increased distribution of ethnic and age groups that tend to be heavier, (7) pregnancy at a later age, (8 ) positive natural selection of people with a higher BMI,

www.youngpharmacists.com

ANTIOBESITY DRUGS:Anti-obesity drugs or weight loss drugs refer to all pharmacological agents that reduce or control weight. These drugs alter one of the fundamental processes of the human body, weight regulation, by either altering appetite or metabolism. The main treatment modalities for overweight and obesity are dieting and physical exercise.

History:The first described attempts at producing weight loss are those of Soranus of Ephesus, a Greek physician, in the second century AD. He prescribed elixirs of laxatives and purgatives, as well as heat, massage, and exercise. This remained the mainstay of treatment for well over a thousand years. It was not until the 1920s and 1930s that new treatments began to appear. Based on its effectiveness for hypothyroidism, thyroid hormone became a popular treatment for obesity in otherwise healthy people. It had a modest effect but produced the symptoms of hyperthyroidism as a side effect, such as palpitations and difficulty sleeping. Dinitrophenol (DNP) was introduced in 1933; this worked by uncoupling the biological process of oxidative phosphorylation in mitochondria, causing them to produce heat instead of ATP. The most significant side effect was a dramatic rise in body temperature, frequently causing death. By the end of the 1930s DNP had fallen out of use. Amphetamines (marketed as Benzedrine) became popular for weight loss during the late 1930s. They worked primarily by suppressing appetite, and had other beneficial effects such as increased alertness. Use of amphetamines increased over the subsequent decades, culminating in the "rainbow pill" regime. This was a combination of multiple pills, all thought to help with weight loss, taken throughout the day. Typical regimens included stimulants, such as amphetamines and thyroid hormone, diuretics, digitalis, laxatives, and often a barbiturate to suppress the side effects of the stimulants. In 1967/1968 a number of deaths attributed to diet pills triggered a Senate investigation and the gradual implementation of greater restrictions on the market. This culminating in 1979 with the FDA banning the use of amphetamines, then the most effective of the diet drugs, in diet pills. Meanwhile, phentermine had been FDA approved in 1959 and fenfluramine in 1973. The two were no more popular then other drugs until in 1992 a researcher reported that the two caused a 10% weight loss which was maintained for over two years. [14] Fen-phen was born and rapidly became the most commonly prescribed diet medication. Dexfenfluramine (Redux) was developed in the mid-1990s as an alternative to fenfluramine with less side-effects, and received regulatory approval in 1996. However, this coincided with mounting evidence that the combination could cause valvular heart disease in up to 30% of those who had taken it, leading to withdrawal of Fen-phen and dexfenfluramine from the market in September 1997

www.youngpharmacists.com

Mechanisms of action:Anti-obesity drugs operate through one or more of the following mechanisms:

Suppression of the appetite. Catecholamines and their derivatives (such as amphetamine-based drugs) are the main tools used for this. Drugs blocking the cannabinoid receptors may be a future strategy for appetite suppression. Increase of the body's metabolism. Interference with the body's ability to absorb specific nutrients in food. For example, Orlistat (also known as Xenical and All) blocks fat breakdown and thereby prevents fat absorption. The OTC fiber supplements glucomannan and guar gum have been used for the purpose of inhibiting digestion and lowering caloric absorption

Anorectics (also known as anorexigenics) are primarily intended to suppress the appetite, but most of the drugs in this class also act as stimulants (dexedrine, e.g.), and patients have abused drugs "off label" to suppress appetite (e.g. digoxin).

Available anti-obesity drugs:If diet and exercise are ineffective alone, anti-obesity drugs are a choice for some patients. Some prescription weight loss drugs are stimulants, which are recommended only for short-term use, and thus are of limited usefulness for extremely obese patients, who may need to reduce weight over months or years.

Orlistat:Orlistat (Xenical) reduces intestinal fat absorption by inhibiting pancreatic lipase. Originally available only by prescription, it was approved by the FDA for over-thecounter sale in February 2007..Orlistat may cause frequent, oily bowel movements (steatorrhea), but if fat in the diet is reduced, symptoms often improve.

Sibutramine:Sibutramine (Reductil or Meridia) is an anorectic or appetite suppressant, reducing the desire to eat. Both drugs have side effects. Sibutramine may increase blood pressure and may cause dry mouth, constipation, headache, and insomnia.

Metformin:In people with Diabetes mellitus type 2, the drug metformin (Glucophage) can reduce weight.

www.youngpharmacists.com

Byetta:Byetta (Exenatide) is a long-acting analogue of the hormone GLP-1, which the intestines secrete in response to the presence of food. Among other effects, GLP-1 delays gastric emptying and promotes a feeling of satiety. Some obese people are deficient in GLP-1, and dieting reduces GLP-1 further. Byetta is currently available as a treatment for Diabetes mellitus type 2. Some, but not all, patients find that they lose substantial weight when taking Byetta. Drawbacks of Byetta include that it must be injected twice daily, and that it causes severe nausea in some patients, especially when therapy is initiated. Byetta is recommended only for patients with Type 2 Diabetes. A somewhat similar drug, Symlin, is currently available for treating diabetes and is in testing for treating obesity in non-diabetics.

Symlin:Symlin (Pramlintide) is a synthetic analogue of the hormone Amylin, which in normal people is secreted by the pancreas in response to eating. Among other effects, Amylin delays gastric emptying and promotes a feeling of satiety. Many diabetics are deficient in Amylin. Currently, Symlin is only approved to be used along with insulin by Type 1 and Type 2 diabetics. However, Symlin is currently being tested in non-diabetics as a treatment for obesity. A drawback is that Symlin must be injected at mealtimes.

Rimonabant:Recent pharmaceutical research has produced potential obesity combating drugs. The discovery of cannabinoid receptors in the brain, liver and muscle has stimulated research in a new class of drugs, namely cannabinoid (CB1) receptor antagonists. These drugs not only causes weight loss, but prevent or reverse the metabolic effects of obesity, such as insulin resistance and hyperlipidemia, and may also decrease the tendency to abuse substances such as alcohol and tobacco.

Side effects:Some anti-obesity drugs have severe and often life-threatening side effects. These side effects are often associated with their mechanism of action. In general, stimulants carry a risk of high blood pressure, faster heart rate, palpitations, closed-angle glaucoma, drug addiction, restlessness, agitation, and insomnia.

www.youngpharmacists.com

ORLISTAT:Orlistat marketed under the trade name Xenical by Roche; or over-the-counter as Alli by GlaxoSmithKline also known as tetrahydrolipstatinis a drug designed to treat obesity. Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physiciansupervised reduced-calorie diet. Orlistat is the saturated derivative of lipstatina potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.

IUPAC name

1-(3-hexyl-4-oxo-oxetan-2-yl)tridecan2-yl 2-formylamino-4-methylpentanoate

Therapeutic Indications
Xenical is for weight control, including weight loss, weight maintenance and prevention of weight regain in adults with an initial body mass index (BMI) of 30 or more. Xenical should be used in conjunction with a low fat, calorie controlled diet

www.youngpharmacists.com

History: Orlistat (Xenical) for Management of Adolescent Obesity in Approved in European Union:On June 28, the European Commission approved an expanded indication for orlistat (Xenical 120-mg capsules, made by Roche Pharma), allowing its use for the management of obesity in adolescents aged 12 years and older, rather than in adults only. The approval was based on data from a one-year clinical study that compared the effects of orlistat (120 mg three times daily) vs placebo as combined with a reduced-calorie diet and exercise regimen in 539 obese adolescents. Results showed that orlistat therapy was associated with a significant decrease in body mass index (BMI; -0.55 kg/m2) compared with an increase of 0.31 kg/m2 in the placebo group. Almost twice as many adolescents treated with orlistat had a decrease of 5% or more in BMI (26.5% vs 15.7%) and body weight (19% vs 11.7%) relative to placebo. Patients who responded to orlistat therapy (weight loss of 5% or more at three months) had a mean reduction in body weight and BMI of 7.6 kg and 3.7 kg/m2 at one year, respectively. Orlistat therapy also resulted in a greater decrease in body fat at one year (mean, 2.4 vs 0.4 kg) and a decrease rather than an increase in waist circumference (-1.33 vs +0.12 cm) relative to placebo. Orlistat was well tolerated in adolescents, and adverse events were similar to those observed in adults. Orlistat was approved for use in adolescents aged 12 to 16 years by the U.S. Food and Drug Administration in December 2003.
BRANDS:-

ORLIS ORSILM XENICAL

FEROZSONS PHARMEVO ROCHE

www.youngpharmacists.com

Dosage and Method of Administration:The recommended dose of Xenical is one 120 mg capsule three times a day with each main meal (during or up to one hour after the meal). No dose adjustment is necessary for the geriatric patient

HOW SUPPLIED:Xenical 120mg blisters XENICAL is a dark-blue, hard-gelatin capsule containing pellets of powder.

CHEMICAL DATA;Formula Ml.wt.

C29H53NO5 495.735 g/mol

PHARMACOKINATIC DATA
Bioavailability Protein binding Metabolism Half life Excretion Routes Negligible >99% GI tract 1 to 2 hours Fecal

Oral

Pharmacology:Orlistat works by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.

www.youngpharmacists.com

Pharmacokinetic Properties:Based on faecal fat measurements, the effect of Xenical is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, faecal fat content usually returns to pretreatment levels, within 48 to 72 hours.

Absorption:In normal weight and obese volunteers, the systemic exposure to orlistat was minimal. Plasma concentrations of intact orlistat were nearly non-measurable (< 5 ng/mL) following a single oral administration of 360 mg orlistat. In general, after long-term treatment at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/mL or 0.02 M), without evidence of accumulation showing consistency with negligible absorption.

Distribution:The volume of distribution cannot be determined because orlistat is minimally absorbed. In vitro orlistat is > 99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Metabolism:Based on animal data, it is likely that the metabolism of orlistat occurs mainly presystemically. Two major metabolites (M1 and M3) accounted for approximately 42% of the total radioactivity in plasma resulting from the minute fraction of the dose that was absorbed systemically in obese patients.These two major metabolites have very weak lipase inhibitory activity (1000- and 2500-fold less than orlistat respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 ng/mL and 108 ng/mL respectively), these metabolites are pharmacologically inconsequential.

Elimination:Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed orlistat was the major route of elimination. Approximately 97% of the administered dose was excreted in faeces and 83% of that as unchanged orlistat.The cumulative renal excretion of total orlistat-related materials was < 2% of the given dose. The time to reach complete excretion (faecal plus urinary) was 3-5 days. The disposition of orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion

www.youngpharmacists.com

Pharmacodynamic Properties:Mechanism of action:Xenical is a potent, specific and reversible long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the serine residue of the active site of gastric and pancreatic lipases. The inactivated enzyme is thus unable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit has a positive effect on the weight control

Side effects: Head ach Sleep disorder Dizziness Anxiety Dry skin Rash Fatty/oily stool

Contraindications:

Malabsorption Hypersensitivity to Orlistat Reduced gallbladder function Pregnancy and breastfeeding Use caution with: obstructed bile duct, impaired liver function, and pancreatic disease

www.youngpharmacists.com

Adverse Effects:Gastrointestinal:The most common complaints are abdominal discomfort, liquid stools, soft stools, oily rectal spotting, flatulence and flatus with discharge, fecal urgency, fatty or oily stools, increased defecation, and fecal incontinence

Breast Cancer Risk:In pooled data from all clinical trials evaluating orlistat, 12 cases of breast cancer were found in orlistat-treated women, compared with 2 cases in those who received placebo

Fat-Soluble Vitamin Absorption:Orlistat inhibits pancreatic carboxylester lipase, the enzyme necessary for hydrolysis of vitamin esters and absorption of fat-soluble vitamins

Drug drug interactions:Drug-drug interaction studies indicate that XENICAL had no effect on pharmacokinetics and/or pharmacodynamics of alcohol, digoxin, glyburide, nifedipine (extended-release tablets), oral contraceptives, phenytoin, pravastatin, or warfarin. Alcohol did not affect the pharmacodynamics of orlistat. Absorption of fat-soluble vitamins and other fatsoluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitamins A, D, E, K, and beta-carotene should be taken once a day, at bedtime, when using orlistat.

Efficacy:The amount of weight loss achieved with orlistat varies. In one-year clinical trials, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body mass. After orlistat was stopped, a significant number of subjects regained weightup to 35% of the weight they had lost.

Clinical trials:OBJECTIVES: This paper describes the methodology of a multicentre study designed to assess the efficacy and tolerability of orlistat 120 mg tid as therapy for inducing weight loss in excess of that achieved with a moderately calorie-restricted diet alone. The results from a single centre are presented to illustrate the nature of the response.

www.youngpharmacists.com
DESIGN: This was a double-blind, randomized, parallel-group, placebo-controlled multicentre study. A four-week, single-blind, placebo run-in period preceded a 52 week double-blind treatment period during which patients received either orlistat or placebo three times a day. At the start of the run-in period, all patients were placed on a diet containing approximately 30% of calories as fat and designed to cause an energy deficit of approximately 600 kcal/d. SUBJECTS: Patients of either sex, more than 18 y of age, with a body mass index (BMI) between 30 and 43 kg/m2 were eligible for enrolment. MEASUREMENTS: Efficacy assessments included: measurements of body weight; anthropometry; quality of life; blood pressure; serum lipids; fasting serum glucose and insulin. Safety assessments included: adverse events; vital signs; ECG; renal and gallbladder ultrasound; haematology; serum biochemistry. OUTCOME: In the single centre there was a reduction in body weight of 5.5 +/- 4.5 (s.d.) kg (5.7% reduction) in the placebo group and 8.6 +/- 5.4kg in the orlistat-treated group (8.4% reduction) by six months. Thereafter, the placebo group tended to relapse whereas the orlistat group maintained their loss (2.6% vs 8.4% reduction from initial value at 52 weeks). Total and LDL cholesterol fell by 0.05 mmol/l (1.6%) and 0.14 mmol/l (4.2%), respectively, in orlistat treated patients. The drop-out rate was 48% in the placebo group and 39% in the orlistat group. Intestinal symptoms related to orlistat were significantly increased compared to placebo but were well tolerated. Fat soluble vitamin levels remained within the normal range in the treatment group; the reduction seen in alphatocopherol levels in patients receiving orlistat was normalized by the decrease in plasma cholesterol concentrations. Beta-carotene and vitamin D concentrations also decreased in orlistat-treated patients. CONCLUSIONS: This preliminary analysis suggests that orlistat, when used with a health-promoting low-fat and moderately energy-restricted diet, confers advantages in the long-term management of obesity.

RESEARCH PAPAR:Orlistat - the only non-controlled anti-obesity prescription drug approved by FDA:Obesity refers to an excessive amount of body fat. Most health care professionals agree that men with more than 25 percent body fat and women with more than 30 percent body fat are obese. Most available weight-loss medications approved by the Food and Drug Administration (FDA) are appetite-suppressant medications. However, Orlistat is one drug that works in a different way. Orlistat works by reducing the body's ability to absorb dietary fat by about one third. It does this by blocking the enzyme lipase, which is responsible for breaking down dietary fat. When fat is not broken down, the body cannot absorb it, so fewer calories are taken in. Prescription weight-loss medications should be used only by patients who are at increased medical risk because of their weight. They should not be used for "cosmetic"

www.youngpharmacists.com
weight loss. Prescription weight loss drugs are approved only for those with a body mass index (BMI) of 30 and above, or 27 and above if they have obesity-related conditions, such as high blood pressure, dyslipidemia (abnormal amounts of fat in the blood), or type 2 diabetes. BMI is a measure of weight in relation to height. A BMI of 18.5 to 24.9 is considered healthy. Approved for long-term use

Only 2 medications have been approved for long term use by the United States Food and Drug Administration (FDA). Orlistat is one of them. Obesity is a chronic disease that affects many people and often requires long-term treatment to promote and sustain weight loss. Non-Controlled Substances

When considering long-term weight-loss medication treatment for obesity, one of the concerns is the potential for abuse and dependence. Currently, all prescription medications to treat obesity except orlistat are controlled substances, meaning doctors need to follow certain restrictions when prescribing them. Weight-loss medication for children and teens

Orlistat is currently approved for use in teens age 12 or above. Other weight-loss medications are not approved for use in children under the age of 16, although studies in children and teens are ongoing.

Side

Effects

Some side effects of orlistat include cramping, intestinal discomfort, passing gas, diarrhea, and leakage of oily stool. These side effects are generally mild and temporary, but may be worsened by eating foods that are high in fat. Also, because orlistat reduces the absorption of some vitamins, patients should take a multivitamin (Vitamin D,E,A and beta-carotene) at least 2 hours before or after taking orlistat.

By Published: 11/4/2006

Julian

Chee