Anti-Obesity Medications

On the 19th century, thyroid hormone preparations were used as anti-obesity drugs.The mechanism of action of these preparations is by increasing both of basal metabolic rate (MBR) and energy expenditure. It had modest effect, however, it was stopped to beused as anti- obesity due to the side effects these side effectsinclude hyperthyroidism symptoms such as palpitations, difficulty sleeping, anxiety, insomnia and increase the risk of heart failure(24, 27,32).
In 1920, dinitrophenol was used as an anti-obesity drug by same mechanisms of the previously

used hormonal preparations (7).Dinitrophenol was withdrawn by FDA atthe end of 1938 due to its side effectssuch ascataract, neuropathy, sensation of warmth, sweating and increase risk of fatal hyperthermia in over dose (24,25,32).

Later, in ten years' time,a sympathomimetic amphetamines was introduced for the first time to be used as weight loss drug, after which phentermine was approved by FDA as appetite suppressant in 1959. However phentermine it was stopped due to its side effects (24, 26).amphetamines ware banned as anti-obesity in America by FDA and withdrawn from the European market in 1979 due to their adverse effects (24,27). Amphetamine elevate cardiac output and hypertensionwhich is dangerous in patients with hypertension, that may develop tolerance to drug, which leads to increasing the dose to achieve the same effect. In addition addiction, anxiety, dry mouth, nervousness, hypertension and tachycardia are other side effects associated with amphetamine (27,32).

In 1997, FDA approved sibutraminewhich is a nor-adrenaline and selective serotonin re-uptake inhibitor as a weight loss drug.Although, sibutraminewas a good anti-obesity drug, it was withdrawnon2010 due to its cardiovascular side effect (24, 29).In 1999, FDA approved orilistat as an anti-obesity drug. FDA did not approve any druguntil 2012, where Lorcaserin and Phentermine-toprimate (Qsymia)were approval by the administration (24).
Anti- obesity drugs mainly act on the appetite, however there are many other systems that can be targeted to decrease the weight, where drugs can be classified according to mechanism of actioninto; appetite suppressors, inhibitors of fat absorption, activators of energy consumption, and those involved in other mechanisms(25).
II.1 Appetite suppressors
II.1.1 Sympathomimetic Action
II.1.1.1 Phentermine
Phentermine is similar to amphetamine in having a sympathomimetic action(26). Phentermine is a member of The ??-phenethylamine family(26).In prolonged use, due to increase dependency and tolerance (27), phenterminewas approved by FDA in 1959 for short term ( up to 3 months)(26).Phentermine is noradrenergic drug that stimulate the release of noradrenaline and reduce food intake by acting on beta adrenergic receptors in hypothalamus(25, 29). It also increases heart rate and blood pressure(27).
Phentermine had been used in combination with fenfluramine or dexfenfluramine. Phentermine
was approved in 1959 and fenfluramine in 1973 by FDA. In September 1997, fenfluramine and

dexfenfluramine withdrawn from the market by FDA due to serious side effects
such as valvular heart disease, and pulmonary arterial hyper??tension.On the other hand FDA did not remove phentermine that still in use as anti-obesity alone or with
toprimate(26, 27).

Figure: Structure of phentermine. Adapted from (18).

II.1.1.2 Diethylepropion
Diethylpropion chemical formula is C13H19NO and its average weight 205.3 (33). Diethylepropion is amphetamine like analogue with minor sympathomimetic properties(26).It is
noradrenaline releaser but with feverstimulant. It was approved by FDA in 1959 for short term

use for reducing weight(25, 26).Side effecst like phentermine insomnia, tremor, increase blood

pressure and pulse rate, headache, palpitation, con??stipation. recently, it is approved for short term

weight management(26).

figure (): structure of Diethylpropion. Adapted from (33).
II.1.2Combined norepinephrine and selective Serotonin Reuptake Inhibitor (SSRI)
II.1.2.1 Sibutramine
Chemically, Sibutramine is {1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}dimethylamine, its chemical formula is C17H26ClN and its average weight is 279.8(34).Sibutramine is centrally acting noradrenaline/serotonin reuptake inhibitor (26).Sibutramine acts by increasing post-prandial satiety and is usefulin the lack of satiety(29).Sibutramine was approved by FDA in 1997 to be used for weight reduction in conjunction with diet, and also approved by European Union in 1999 to be used with caution in patients hypertension or with history of coronary artery disease (CAD), stroke or arrythemia (26,27).However, the studies showed that 16% increasing the risk of serious, nonfatal myocardial infractions and stroke in people who taking sibutramine. So the drug withdrawn from the market in Europe in Augest 2010. Two month later, in October 2010 Sibutramine was removed from U.S and Canada(26,27).

figure: structure of Sibutramine. Adapted from (34)
II.1.3 Cannabinoid-1 receptorsantagonist:
In 2006, Rimonabant was approved by European Medicines Agency (EMA) as anti-

Obesitydrug(24), however, was not approved by FDA and thus it was available in 56 countries

and not in US and until its withdrawal in 2009 (26).Rimonabant acts by blocking cannabinoid -1

receptors (CB1) that are found in the nervous system and in peripheral tissues such as adipose

tissue, gastrointestinal tract, liver and muscle, which are all involved in lipid and glucose

metabolismthat control in the food intake with a significant role in appetite control (27, 28, 29).

The drugs was not approved by FDA due to the fact thatits benefits less than its side effects like psychiatric disorders-anxiety, depressive symptoms and suicidal thoughts (24,27,28).

Figure : structure of Rimonabant. Adapted from (35)

II.1.4Selective 5HT2C receptor agonist:
Chemically,lorcaserin belongs to 3-benzazepines family.The IUPAC name of locaserin is1(R)-8-Chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (3).Lorcaserinewas approved by FDA in June 2012 as anti-obesity rug (24, 28).Lorcaserine is selective serotonin 2C agonist to reduce the weight by decrease t food intak(26).The selectivity to 2c decreases the main side effects(26).

Figure : Structure of lorcaserin. Adapted from (10).
II.1.5Noradrenaline, dopamine and serotonin reuptake inhibitor
II.1.5.1 Tesofensine
Tesofensine inhibits noradrenaline, dopamine, and serotonin reuptake and indirectly stimulates the cholinergic system and sympathomimetic(26). It is not approved by FDA (24).

Figure: structure of Tesofensine. Adapted from ( 36)
II.2 Inhibitors of fat absorption
II.2.1 Orlistate
Orlistate was approved in 1998 by FDA (24,26). Orlistate mechanism depends on preventing dietary fat absorption by 30 % by inhibitingpancreatic and gastric lipase(26, 30). When administered with fat-containing foods, it partially inhibits the hydrolysis of triglycerides, thus reducing the subsequent absorption of monoglycerides and free fatty acids, leading to a reduced fat absorption(29).Orlistate is the only approved antiobesity drug for long term. It is available as over the counter drug in several countries (26).

Figure: structure of Orlistate. Adapted from (37)
II.3 Activators of energy consumption
II.3.1 Ephedrine and caffeine
Ephedrine and caffeine can be added to health supplement, so they are not needed to take approval from FDA like other drug. They are used to increased energy expenditure and thermogenesis (25).Clinical trialsapproved that the combination of ephedrine and caffeine reduce the body weight(7).The effectiveness and safety of ephedrine and caffeine when used for weight loss are not as well documented as other anti-obesity agents (25).

Figure : structure of Ephedrine. Adapted from (38)

Figure : structure of caffeine. Adapted from (39)

II.4 Drugs involved in other mechanism
II.4.1Toprimate:( Anticonvulsant)

Toprimate is an antiepileptic drug that blocks voltage-dependent sodium channels, glutamate

receptors, and carbonic anhydrase, and augments the activity of ??-aminobutyrate . Combination with

phentermine was approved by FDA as anti-obesity drug (25).Toprimate side effects arediarrhea,

possible harm to fetus, increased heart rate, dizziness, altered taste, fatigue, memory im??pairment,

somnolence, an??orexia and abdominal pain (25, 26). It was recently approved (26).

Figure : structure of Topiramate. Adapted from (19).

Metformin is 1-carbamimidamido-N,N-dimethylmethanimidamide, its chemical formula C4H11N5 and its average weight is 129.1 (40).Metformine is anti-diabetic drug that used for long time to prevent development of diabetes and inhibit hepatic synthesis of glucose with a decrease in peripheralinsulin resistance(29). Metformin is not approved to treatment of obesity, however, it consider as first linefor treatment of obesity in obese type 2 diabetes(29).

Figure (): structure of Metformin. Adapted from (40)
Many drugs were developed over years to manage obesity; each one has its own mechanism of action and works on specific site or receptor in the body. Examples include orilstatwhich acts on lipase enzyme and sibutramine which is a serotonin (5-HT) and norepinephrine reuptake inhibitor (3). It was proved that serotonin plays a great role in regulation of appetite and metabolism there are different subtypes of serotonin receptor with different affinities. 5-HT2Breceptor is found mainly in hypothalamus and regulatesappetite. Fenfluramine was panned from used recently due to its hazard on the heart; this drug acts basically on 5-HT2c receptor (6).
Earlier antiobesity agents, such as dexfenfluramine, were withdrawn from the market because of
an association with valvular heart disease thought to be caused by agonism at the 5-HT2B
receptor(4). Because the stimulation of 5HT2B may cause cardiomyopathy and endocardial
fibrosis of cardiac valves(3

V. Lorcaserin and phentermine-topiramate, two recently approved drugs by FDA
The FDA has not approved a prescription obesity drug science 1999.However 13 years later

(2012), Lorcaserinand phentermine-topiramatewere approved(1).Lorcaserine (Belviq) is now available in the market since June 2013.
Will be sorted out later and delete figures
V.1 Lorcaserin
In September 2006, phas III was initiated on Lorcaserine , the 1st clinical trial was called BLOOM (Behavioural Modification and Lorcaserin for Overweight and Obesity Management), 3200 subject were treated for more than 2 years with Lorcaserine. Behavioural Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM)-the 2nd trial- was designed to evaluate efficacy of 10mg and 20mg daily doses of Lorcaserine over the placebo. BLOOM in Diabetes Mellitus (BLOOM DM)-the 3rd trial was designed to evaluate efficacy of 10mg and 20mg daily doses of Lorcaserine over the placebo in obese patients with type 2 diabetes over 1 year treatment. The 2nd and 3rd trial were initiated in December 2007 . On 6 June 2009 Lorcaseine company announced positive results of Phase III trials(35).
In December 2009, the company of Lorcaserine submitted new drug application ( NDA )for Lorcaserine in FDA. In February 2010, the submission was accepted by FDA, however, in October 2010, FDA rejected Lorcaserine application because the preclinical study revealed correlation between Lorcaserine and occurrence of cancer and also the efficacy of the drug on non diabetic obese subjects was marginal. On 10 May 2012, after a new round of studies submitted by Lorcaserine company, an FDA panel voted to recommend lorcaserin with certain restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes(36). On may 2013, it was classified as a Schedule IV drug under the control substance(36).
V.1.1 Physico-chemical properties
Chemically, lorcaserin belongs to 3-benzazepines family. The IUPAC name of locaserin is1(R)-8-Chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (3)(figure ). Locaserin has a molecular formula of C11H15Cl2N and a molecular weight of 232.1495(10). Lorcaserin is a crystalline solid which has a solubilityin water of greater than 400 mg/ml (11). It is also soluble in ethanol (30mg/ml), DMSO (Dimethyl sulfoxide) (25mg/ml) and dimethyl formamide(25mg/ml)(8). Lorcaserin stability is for more than 2 years and at -20??C (8).

Figure : Structure of lorcaserin. Adapted from (10).
V.1.2 Mechanism of action
Lorcaserin is a selective agonist for 5-HT2C receptors, where it was found that it is 14 and 61 times more selective for serotonin receptor 5-HT2C than receptors 5-HT2A and 5-HT2B (7, 2). Lorcaserin stimulates 5-HT2c receptors in the hypothalamus which activates the production of pro-opiomelanocortin (POMC), a polypeptide precursor of alpha-melanocyte-stimulating hormone (??-MSH), Adrenocorticotrophin (ACTH) and ??-Endorphin(14). The produced ??-MSH will act on the melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus and ultimately effects satiety and reduced food intake throughout this mechanism (2) (figure).Replace this figure with original for simplicity

Paraventricular nucleus, hypothalamus

Figure : Mechanism of action of lorcaserin. Lorcaserinstnulates 5-HT2c agonist leading to production of POMC by mRNA. POMC cleaved to ??-MSH which acts on the melanocortin 4 receptor in the paraventricular nucleus of the hypothalamus to suppress appetite and increase satiety. POMC: pro-opiomelanocortin; ??-MSH: alpha-melanocyte-stimulating hormone
ACTH: Adrenocorticotrophin; MC4R: melanocortin 4 receptor. Adapted from (2).

V.1.3 Therapeutic effects
Drugs targeting the 5-HT system have a long history in the management of obesity(3).Agonism

to 5HT2c receptors is to reduce food intake and increase satiety leading to weight

loss(2,3). Lorcaserin, reduced-calorie diet and regular exercise is suggested for treating obese patients with a BMI of 30kg/m2in presence of one or more comorbid conditions, including hypertension, type 2 diabetes, or dyslipidemia(2,3,5).

In a phase III study of lorcaserin, three trials were carried out. In one trial, there was at least 5% of loss in body weight in patients aged 18-65 with BMI of 30-45. In the second trial, lorcaserin was given for two years, where there was a significant difference in more than 10 % of body weight between each of lorcaserin and placebo groups. In the last trial, either metformin or sulphonyl urea was given to obese patients having diabetes mellitus, where beside weight reduction, there was improvements in both of glycosylated hemoglobin A1c which identifies average plasma glucose level over a long period of time, as well as fasting glucose values (4).

V.1.4 Pharmacokinetics
Loracserin has high bioavailability even though it has 75% plasma protein binding after which almost 90% of the dose absorbed. Recommended daily dose is 10 mg two times for adults aged 18 years and older. After oral administration (twice daily [b.i.d.]), more than 90% of rapidly absorbed. Time to reach maximum plasma concentration is approximately 1.5 to 2 hours, and its half-life (t1/2) is about 11 hours. The volume of distribution in the body is 252 L in a 92.5 kg subject(3).Lorcaserin is mainly metabolized in the liver and excreted by the kidney.Lorcaserin is metabolized in the liver by multiple enzymatic pathways. The major circulating metabolite is lorcaserinsulfamate (M1), and the major urinary metabolite is N-carbamoylglucuronide (M5)(3).

In patients with renal impairment, lorcaserin and its metabolites increases by approximately 1.7-

to 6-fold and cannot be removed from the circulation by hemodialysis. SoLorcaserin should be

used with caution in patients with moderate renal impairment and not recommended in

patients with severe renal impairment or end stage renal disease (5). No dose adjustment is required for patients with mild to moderate hepatic impairment, but in patients with severe hepatic impairment and should be used with caution in such patients (5).

V.1.5 Adverse effects
The most common adverse effects were headache, dizziness, fatigue, nausea, dry mouth,

constipation, back pain, cough, anxiety ,bladder pain, bloody or cloudy urine, blurred vision,
body aches or pain chills, cold sweats, coma, confusion cool, pale skin, depression, sore throat
and slow or fast heartbeat (1,13).

Clinical trials of lorcaserin indicated that it could result in headache, upper respiratory tract infections, nausea and dizziness (4). Lorcaserin is a mild to moderate inhibitor of CYP2D6; thus, interaction potential with drugs such as dextromethorphan and desipramine should be noted during drug combinations, since both drugs are metabolized by CYP2D6 (figure ) (3, 9).

Figure (): structure of Dextromethorphanstructure. Adpated from (16)

Figure (): structure of Desipramine structure. Adapted from (15)

Figure : Structure of lorcaserin. Adapted from (10).
V.2: phentermine-topiramate.
phentermine-topiramate was approved by FDA in July 2012 for the treatment of obesity. It is available in the U.S since September 2012 (Qsymia)(20). Phentermine is noradrenergic drug, available since 1959 used in treatment of obesity. Toprimate is a fructose derivative .In 1996, toprimate was approved for seizure treatment, and in 2004, it was approved for migraine treatment. Weight loss has been observed in patient taking toprimate for seizures or migraine (20).
V.2.1 Physico-chemical properties.
Chemically, Phentermine is ??,??,-Dimethylphenethylamine hydrochloride , it has a molecular
formula of C10H15N.HCLand a molecular weight 185.7(figure).The drug is white, odorless and hygroscopic crystalline powder. It is soluble in water, methanol and ethanol, slightly soluble in chloroform and insoluble in ether(17,18).Phentermine is stable up to 5 years at 25??C /60% RH (Relative Humidity) and for up to 6 months at 40??C /75% RH(Relative Humidity) (10).

Figure : Structure of phentermine. Adapted from (18).

Topiramate is 2,3:4,5??-Di-O-isopropylidene-D-fructopyranosesulfamate with a molecular formula of C12H21NO8S, its molecular weight 339.36. (Figure). Topiramate is white powder which has a bitter taste (22). It is non-hygroscopic and slightly soluble in water (9.8 mg/ml) and alkaline solution with pH of 9-10 (17). It has high solubility in aceton, chloroform and ethanol(17,19). Topiramate is stable up to 12 month at 25??C /60% RH and for up to 6 months at 40??C /75% RH(17).

Figure : structure of Topiramate. Adapted from (19).
V.2.2 Mechanism of action.
Phentermine reduces the body weight by decreasing the caloric intake. Phentermine stimulates the release of norepinephrine centrally in the hypothalamus and inhibits norepinephrine reuptake, that increasescatecholamines. In turn this causes an increase in blood leptin level, hormone that is made by fat tissues as to act on the brain to regulate food intake and body weight. Thus,appetite is suppressed and satiety is enhanced (20). Figure?

V.2.3 Therapeutic effects:
Similar to lorcaserin, phentermine-topiramate is indicated to reduce the body weight and to maintain weight loss in patients with BMI greater than 30 kg/m2 and also having obesity related disease such as diabetes(type 2), hypertension or hyperlipidemia conjunction with reduced calorie diet and physical activity(20,21,22).
V.2.4 Pharmacokinetics.
Phentermine-topiramate is once daily combination designed to morning release of phentermine and evening delayed release of toprimate(20)can you explain briefly here.Recommended daily dose is 3.75 mg/23 mg for 14 days and then up to 7.5 mg / 46 mg (22). The dose can be increased up to 15 mg / 92 mg for additional 12 weeks (13). In patients with renal impairment or hepatic impairment, the daily dose should not exceed (7.5 mg/46 mg)(22).
After oral administration, time to reach to maximum plasma concentration (Tmax) is 6 hours for phentermine and 10 hours for toprimate (21,22), where the half-life (t1/2) for phentermine is 65 hours and 20 hours for toprimate (21). The volume of distribution is 348 L for phentermine, while for toprimate, the volume in the central and peripheral compartment are 50.8 L and 13.1L, respectively (22).
Phentermine is metabolized by two pathways; p-hydroxylation on the aromatic ring and N-oxidation on the side chain, while toprimate metabolized via hydroxylation, hydrolysis,andglucuronidation(22)figure. Phentermine and toprimate mainly excreted through the urinary excretion(17).

V.2.5 Adverse effects.
Adverse effects of phentermine-toprimate are dry mouth, constipation, nausea, diarrhea, dyspepsia (GIT ) nervousness, insomnia, anxiety, headache, dizziness, paraesthesia, fatigue, rash, back pain, palpitation, muscle spasm, cough, nasal congestion, eye pain and eye dryness(22). More common side effects are constipation, change or loss of taste, memory problems, runny nose, ear congestion and eye pain (23).
Reference :
10., 8/3/2014
11., 16-3-2014.
12., March 13, 2014
13. (14-3-2014)
15. (25-3-2014)
16- (25-3-2014)
18- ( (21-3-2014)
19- ( ) (21-3-2014).
23-( (22-3-2014).
(33) (26-4-14)
(34) (26-4-14)
(35) (26-4-2014)
(36) (26-4-2014)
(37) (26-4-14)
(38) (26-4-14)
(39) (26-4-14)
(40) (26-4-14)

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