Fenfluramine mechanism

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. 

In view of the apparent pleasurable effects of MDMA, it becomes of considerable interest to understand the mechanism of action of substances with a similar effect. Major efforts have been directed toward the study of agents that have an effect on serotonin pathways, since that is the neurotransmitter system that seems most implicated in the mechanism of action of MDMA. This hypothesis is further reinforced by the observation that MDMA substitutes for fenfluramine (Schechter 1986). and fenfluramine substitutes for MBDB (Oberlender and Nichols, unpublished). The substitution data for (+)-amphetamine and cocaine in (-t-)-MBDB-trained rats are also similar to the data for substitution of these agents in fenfluramine-trained rats (White and Appel 1981). 

Steranka, L.R., and Sanders-Bush, E. Long-term effects of fenfluramine on central serotonergic mechanisms. Neuropharmacology 18 895-903, 1979. 

The behavioral effects of amphetamine, methamphetamine, MDMA, MDA, p-chloroamphetamine, and fenfluramine are not identical. Except for the last drug, all can cause some degree of behavioral stimulation, but exact behavioral effects differ markedly. More complete definition of their behavioral differences is a prerequisite to a better understanding of the mechanism(s) of these drugs. 

Further investigation of the possibility that inhibitors of the serotonin uptake carrier protect against serotonin depletion by /r-chloroamphetamine, fenfluramine, MDMA, MDA, and methamphetamine because they prevent the accumulation of those drugs within serotonin nerve terminals is warranted, but at present compelling evidence for this mechanism does not exist. 

Berger, U.V., Gu, X.F., Azmitia, E.C. The substituted amphetamines 3,4-methylenedioxymethamphet-amine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur. J. Pharmacol. 215 153, 1992. 

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. 

Harrison-Read PE Evidence from behavioural reactions to fenfluramine, 5-hydroxyptryptophan, and 5-methoxy-N,N-dimethyltryptamine for differential effects of short-term and long-term lithium on indoleaminergic mechanisms in rats. Br J Pharmacol 66 144-145, 1979... 

Furthermore, long-term treatment with fenfluramine has been shown to reduce plasma 5-HT levels (67-70). These findings negated the role of increased plasma 5-HT in fenfluramine-associated VHD. Thus, investigators began searching for other mechanisms underlying fenfluramine s cardiopulmonary side effects. 

Garattini S, Buczko W, Jori A, Samanin R. The mechanism of action of fenfluramine. Postgrad Med J 1975 51(Suppl l) 27-35. 

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... 

False neurotransmitters. A number of substances, in some cases structurally related to the biogenic amines, are considered to act as false neurotransmitters and GC-MS methods have been applied to their detection. Thus, p-hydroxynorephedrine, a metabolite of (-l-)-amphetamine, can apparently replace noradrenaline and be taken up and released by a similar mechanism to that involved for the catecholamine. A quantitative SIM assay for this metabolite (as the pentafluoropropionyl derivative) has been used in studies of its formation and localisation in brain regions of the rat [473]. Similar methods have been applied to the detection in neural tissue of the N-dealkylated metabolites of methamphetamine, which depletes brain noradrenaline and fenfluramine which depletes serotonin [474]. 

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. 

The mechanism of fenfluramine-associated pulmonary hypertension has been reviewed (SEDA-21, 3). Since only a minority of patients exposed to fenfluramines develop pulmonary hypertension, it has been postulated that a subset may be genetically susceptible. Whether there is a related genetic abnormality in the familial PPH gene located on chromosome 2q (67) or an abnormality of the angiotensin-converting enzyme gene (68) has yet to be explored. 

Fenfluramine (No. 13) is unique among amphetamine-type anorexiants. In spite of its amphetamine structure and the presence of the highly lipophilic m-CF3 group, this compound possesses a sedative rather than CNS stimulatory effect. The drug has been shown to cause serotonin depletion. Serotonin (and NE) are involved in sleep regulatory mechanisms. Thus a relationship seems possible. 

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