Fenfluramine Appetite suppressants

Figure 4.1 The chemical structure of amphetamine and fenfluramine are illustrated here. Fenfluramine (bottom) is a diet pill that is very similar in structure to amphetamine (top). Fenfluramine is an appetite suppressant, like amphetamine, but it does not have stimulant effects. Fenfluramine was proposed as a safer alternative to amphetamine and was very effective in causing weight loss, especially when used in combination with phentermine. Unfortunately, fenfluramine eventually led to devastating side effects, which led to its being withdrawn from the U.S. market.

Fenfluramine hydrochloride Pondimin Wyeth-Ayerst Appetite suppressant 6/14/1973 9/15/1997 23.25 years Valvular heart disease Not available... 

The newest appetite suppressant, sibutramine (Meridia), works by blocking the reuptake of both serotonin and norepinephrine. It does not stimulate nerve cells to release serotonin, as do fenfluramine and dexfenfluramine. Administered at 20 mg/ day, sibutramine effectively reduces weight in obese patients, but its use has not been assessed in eating disorder patients. The most common side effects of this medication are insomnia, dry mouth, and constipation. It has not been associated with the more serious heart and lung complications observed with fenfluramine and dexfenfluramine. Because sibutramine acts in part through modulation of norepinephrine, there is no rational basis for coadministering phentermine, which acts via this same mechanism. 

Qosely related chemically to amphetamine are the so-called appetite suppressants or anorexiants, such as fenfluramine, mazindole, and sibutra-mine. These may also cause dependence and their therapeutic value and safety are questionable. 

Until approximately 10 years ago, the most popular and successful appetite suppressants were the nonselective 5-HT2 agonists fenfluramine and dexfenfluramine. Combined with phentermine as Fen-Phen and Dex-Phen, they... 

The amphetamines were replaced by amphetamine analogs—substances somewhat less potent than amphetamines. Fen-Phen, the combination of fenfluramine and phentermine, was a popular appetite suppressant in the 1990s, but was associated with severe health problems such as pulmonary hypertension, heart valve dysfunction, and nerve damage. As a result, both drugs were withdrawn from the market. 

The diet pills developed to replace amphetamines became known as anorectics or appetite suppressants and are central nervous system stimulants. The FDA approved phentermine in 1959, fenfluramine in 1973, and dexfenfluramine in 1996. 

Another amphetamine derivative, phentermine, has been in use as an appetite suppressant since its approval by the FDA in 1959. However, there are fewer clinical studies of phentermine s effectiveness in weight loss programs. Munro and colleagues (31) studied the effectiveness of phentermine during a 36-wk trial and reported a 13% reduction in initial body weight, compared to a 5.2% reduction for the placebo. The weight loss induced by phentermine over and above caloric restriction is comparable to that attained with fenfluramine. 

The amphetamine analogue fenfluramine, whose synthesis you designed while you were reading Chapter 31, used to be marketed as an anorectic (appetite-suppressant)—it stimulates the production of the hormone serotonin and makes the body feel satisfied—until it became clear that some undesirable side-effects could be avoided by administering it solely as the (S)-enantiomer. Fenfluramine relaunched as the enantiomerically pure dexfenfluramine, and was reputedly a turning point for your overweight patients —was available in the USA as a component of the slimming pill Redux. 

Fenfluramine (approved in 1973, withdrawn in 1997) and phentermine (appetite suppressant approved in 1959 and still available). Wyeth-Ayerst Laboratories, a subsidiary of American Home Products Corp. of Madison, New Jersey, manufactured and marketed fenfluramine under the brand name Pondimin. Wyeth-Ayerst also marketed Redux (dexfenfluramine), which was manufactured for Interneuron Pharmaceuticals. See http //www.fda.gov/cder/news/phen/fenphenpr81597.htm... 

ProbiGm 5.15 Draw both enantiomers of fenfluramine, one component of the appetite suppressant Fen-Phen. 

The noradrenergic drugs fenfluramine, dexfen-fluramine and phenteramine were formerly prescribed as appetite suppressants but were withdrawn when their use was associated with cardiac valve disease and pulmonary hjrpertension. 

Although it resembles amfetamine structurally, the appetite suppressant fenfluramine does not produce central nervous system stimulation in therapeutic doses. 

The above study was based on information derived from the General Practice Research Database in the UK. Subjects who had been given at least one prescription for dexfenfluramine, fenfluramine, or phentermine after 1 January 1988, and who were 70 years or younger at the time of their first prescription were included. Subjects were considered to have a new cardiac abnormality if they had no history, on the basis of clinical records, of cardiac valvular abnormahties and if there was evidence of a new valvular disorder on the basis of echocardiography or chnical examination after exposure to appetite suppressants. All the data had been recorded before the pubhcation of recent reports of an association between appetite suppressants and cardiac valve disorders (25,27,30-32) or primary pulmonary hjq)ertension (14). Hence, it was possible to exclude the possibihty that enhanced awareness of possible serious adverse effects of appetite suppressants had led to closer surveillance of patients who were taking these drugs. Nevertheless, the study did not provide information on the frequency of idiopathic cardiac valve disorders that are asymptomatic or otherwise not chnicaUy diagnosed. 

A 44-year-old woman who had previously taken appetite suppressants, developed valvular disease consistent with the effects of fen-phen. She had an identical twin who, despite having been treated with the same medication, remained symptom-free and without abnormal echocardiography. Both the patient and her sister took fen-phen for 2 years. However, the patient took a daily dose of fenfluramine of 60-120 mg (and often as much as 240 mg) and phentermine 90 mg (at times 180 mg), whereas her twin sister adhered to the daily amount prescribed (fenfluramine 60 mg and phentermine 24 mg). 

Despite the withdrawal of the fenfluramines, the appetite suppressants phendimetrazine and phentermine have remained in widespread use for the treatment of obesity. 

Following the withdrawal of the fenfluramines, alternative combinations have been explored as appetite suppressants. In an open study of a combination of phentermine + fluoxetine in 16 obese patients with... 

New pharmacological treatments have been developed for the treatment of obesity. These include the combination of phentermine and fenfluramine (phen-fen) and, alternatively, dexfenfluramine (Redux). Phentermine (Fastin, lonamin) is a stimulant and fenfluramine (Pondimin) is a serotonin agonist. In combination they have persistent appetite suppression and weight loss effects. These medications can cause anxiety and insomnia and must be used with extreme caution if taken with antidepressants, especially SSRIs. Dexfenfluramine works similarly, but avoids the side effect of increased anxiety, and instead tends to cause diarrhea, dry mouth, and somnolence. There have also been reports of pulmonary hypertension, a potentially fatal condition, especially when taken for longer than three months. Some researchers (Ricuarte et al. 1991 McCann et al. 1994) have expressed concern because rats given these medications showed evidence of neuronal toxicity. Thus, they are effective medications, but must be used with caution. 

Despite its mechanistic complexity, the Hofmann rearrangement often gives high yields of both aryl- and alkylamines. For example, the appetite-suppressant drug phentermine is prepared commercially by Hofmann rearrangement of a primary amide. Commonly known by the name /cn-phen, the combination of phentermine with another appetite-suppressant, fenfluramine, is suspected of causing heart damage. 

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