Fenfluramine Anorectics

Finally, the actions of the so-called 5-HT releasing agent , if-fenfluramine, which is well known for its anorectic effects, should be mentioned here. This compound inhibits 5-HT uptake but its metabolite, if-norfenfluramine, increases 5-HT release as do high doses of (i-amphetamine. It is important to realise that this 5-HT release is independent of nerve impulses and the action of such compounds rests on their effects on the 5-HT transporters on the storage vesicles and terminal membrane. Once these drugs have been taken up into 5-HT neurons by the transporter, they cause 5-HT to leak out of its storage vesicles and, ultimately, to be extruded from the neuron by retrotransport (see below and Chapter 4 for further details). 

A link between 5-HT transmission and hypophagia is further reinforced by the pharmacology of drugs that reduce food intake ( anorectic agents), such as (7-fenfluramine or sibutramine. Both these compounds have actions that should lead to increased synaptic concentrations of 5-HT in the brain, albeit through different mechanisms (see below), but whether or not this actually explains the anorectic actions of (7-fenfluramine is controversial. 

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

In a summary of the human abuse literature on anorectic phenylethylamines, Griffiths et al. (1979) found there was a good correlation between the results of self-administration studies in animals and information about the subjective effects and abuse in man. Specifically, amphetamine, diethyl-propion, and phenmetrazine have been associated with numerous clinical case reports involving abuse, and these three compounds as well as benz-phetamine and /-ephedrine have shown similar subjective effects in drug abuser populations (Griffiths et al. 1979). In addition, fenfluramine was associated with low incidence of abuse in humans and did not maintain self-injection responding in animals. Chlorphentermine was similarly associated with low incidence of abuse in man, but did not maintain selfinjection uniformly in animals (Griffiths et al. 1979). 

The results of behavioral studies reviewed are summarized in table 3. It is clear that a neurotoxic regimen of METH produced tolerance to the effects of subsequent injections of METH on either conditioned or unconditioned behaviors. The regimen of METH produced long-lasting depletions of DA in each of these studies. Similarly, repeated administration of fenfluramine also produced decreases in 5-HT and tolerance to the anorectic effects of fenfluramine. Repeated administration of MDMA to rats performing a DRL schedule resulted in sensitization to the effects of MDMA. This latter finding is interpreted as being due to the effects, MDMA on DA release, in... 

Kleven. M.S. Schuster, C.R. and Seiden. L.S. The effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine. J Pharmacol Exp Ther 246 1-7, 1988. 

Anorectic A drug that reduces appetite and, thus, is sometimes used in the treatment of obesity. Many are amphetamines or amphetamine-like drugs (e.g., fenfluramine). 

Volmar, K.E. and Hutchins, G.M., Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents, Arch. Pathol. Lab. Med., 125, 1555-1561, 2001. 

An anorectic agent, (.S )-fenfluramine [(S)-5], as well as alcohols, (/ )-4 and (S)-4, were synthesized by using Sharpless asymmetric epoxidation.2 The asymmetric epoxidation of... 

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. 

Fuxe K, Famebo LO, Hamberger B, Ogren SO. On the in vivo and in vitro actions of fenfluramine and its derivatives on central monoamine neurons, especially 5-hydroxytryptamine neurons, and their relation to the anorectic activity of fenfluramine. Postgrad Med J 1975 51(Suppl 1) 35—45. 

Caccia S, Anelli M, Fracasso C et al. (1993) Anorectic effect and brain concentrations of D-fenfluramine in the marmoset relationship to the in vivo and in vitro effects on serotonergic mechanisms. Naunyn Schmiedeberg s Arch Pharmacol... 

Cooper SJ, Dourish CT, Barber DJ (1990b) Reversal of the anorectic effect of (+)-fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK-329. Br J Pharmacol 99 65-70... 

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. 

Amphetamines and other stimulatory anorectic agents, apart from fenfluramine, would be expected to impair the hypotensive effects of adrenergic neuron blocking drugs such as guanethidine. Not only do they release noradrenaline from stores in adrenergic neurons and block the reuptake of released noradrenaline into the neuron, but they also impair re-entry of the antihypertensive drugs (109). 

This section describes compounds developed as CNS agents for the treatment of obesity or depression for which independent hypoglycaemic activity has been observed. Whether or not this secondary effect is also centrally mediated is unclear. The first of these agents to be identified was fenfluramine (87), a serotonin agonist anorectic agent developed in the early 1960s. Its antidiabetic activity has been studied in animals and man and has been recently reviewed [384, 385]. 

Amphetamines and other stimulatory anorectic agents, apart from fenfluramine, would be expected to impair... 

Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety centre in the hypothalamus and also increase general physical activity (1). All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritabihty, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension (2). 

Anorectic drugs act mainly on the satiety centre in the hypothalamus (1). They also have metabohc effects involving fat and carbohydrate metaboUsm. Most of them are structurally related to amfetamine and increase physical activity. Their therapeutic effect tends to abate after some months, and part of this reduction in effect may be due to chemical alterations in the brain. Fenfluramine commonly produces drowsiness in normal doses, but has stimulaut effects in overdosage. Dexamfetamine, phenmetrazine, and benzfetamine all tend to cause euphoria, with a risk of addiction. Euphoria occasionally occurs with amfepramone (diethylpropion), phentermine, and chlorphentermine, but to a much lesser extent. Some adverse effects are due to sympathetic stimulation and gastrointestinal irritation these may necessitate withdrawal but are never serious. There are interactions with monoamine oxidase inhibitors and antihypertensive drugs. 

Restrictive cardiomyopathy due to endocardial fibrosis occurred in a 35-year-old woman 5 months after she had started to take fenfluramine 10 mg tds and phentermine 15 mg/day (7). The endocardial findings strongly resembled the valvular lesions associated with the use of fenfluramine-phentermine. Endocardial and valvular fibrosis associated with anorectic drugs is strikingly similar to the plaque material found in patients with carcinoid syndrome and those exposed to methysergide, and all possibly arise from a common mechanism. 

While tolerance to the anorectic effects of fenfluramine appears to set in after 6-12 months, tolerance to its adverse effects is much more rapid in onset (90). 

Anorectic drugs, appetite suppressants, are also found in diet pills such as fenfluramine (or fen-phen), phenter-mine, diethylproprion, and mazindol. Perhaps the most hazardous ingredient commonly found in diet pills until a few years ago was ephedrine. Ephedrine is more commonly known as one of the precursor chemicals needed to manufacture methamphetamine. 

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