Anorectics

GI diseases ulcerative coHtis and anorectal disorders Bacterial meningitis... 

Compounds available in the United States are Hsted in Table 1. Whereas they vary in degree, all of them share similar HabiUties of cardiovascular side effects, the potential for central nervous system (CNS) stimulation, the development of tolerance, and abuse potential. AH, with the exception of ma2indol, are derivatives of phenethylamine. The introduction of an oxygen atom on the -carbon of the side chain tends to reduce CNS stimulant properties without decreasing the anorectic activity. Following the Federal Controlled Dmg Act of 1970, dmgs were classified into one of five schedules according to medical utiUty and abuse potential. 

NT69L N Me-Arg-Lys-Pro-L-neo-Trp-f-Leu-Leu-OH Potent NT analog that crosses the blood-brain barrier Antipsychotic analgesic anorectic... 

A laxative is most often prescribed for the short-term relief or prevention of constipation. Certain stimulant, emollient, and saline laxatives are used to evacuate the colon for rectal and bowel examinations. Fecal softeners or mineral oil are used prophylactically in patients who should not strain during defecation, such as after anorectal surgery or a myocardial infarction. Psyllium may be used in patients with irritable bowel syndrome and diverticular disease. Fblycarbophil may be prescribed for constipation or diarrhea associated with irritable bowel syndrome and diverticulosis. Mineral oil is... 

Stimulants induce both tolerance and sensitization to their behavioral effects. Tolerance develops to the anorectic and euphoric effects of stimulants (Schuster 1981) however, chronic intermittent use of low doses of stimulants delays the development of tolerance. With the doses commonly used in clinical practice, patients treated for narcolepsy or for depressive or apathetic states find that the stimulant properties usually persist without development of tolerance however, the persistence of antidepressant effects remains a matter of controversy. Sensitization has been linked to the development of amphetamine-induced psychosis (Yui et al. 1999). Sensitization to the induction of psychosis is suggested because psychosis is induced by progressively lower doses and shorter periods of consumption of amphetamine following repeated use over time (Sato 1986). Sensitization for amphetamine-induced psychosis may persist despite long periods of abstinence. 

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). 

Until recently, d-fenfiuramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with if-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. 

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). 

Griffiths, RR. Brady, J.V. and Snell, J.D. Relationship between anorectic and reinforcing properties of appetite suppressant drugs Implieations for assessment of abuse liability. Biol Psychiatry 13 283-290, 1978. 

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. 

Functional constipation (constipation occurring in the absence of a demonstrated pathologic condition) involves the presence of at least two of the following symptoms straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction or blockage, need for manual maneuvers to facilitate defecation and/or, infrequent (fewer than three) bowel movements per week. 

As with phentermine, use of diethypropion should be avoided in patients concomitantly receiving or having received an MAOI within the preceding 14 days to prevent hypertensive crisis. Combination with other anorectic agents should be avoided.40... 

In addition to coffee and tea, the psychological effects of caffeine can be obtained from a number of other food sources. Chocolate is a popular and widely consumed source, but the drug is also found in considerable quantities in a number of medications, both prescription and over-the-counter (OTC). Caffeine tablets (e.g., No-Doz) are sold for those who use the drug to study, drive, or engage in other activities. Less obvious is the caffeine content in analgesics, cold preparations, and anorectants. 

Forman, J., Aizer, A. and Young, C. Myocardial infarction resulting from caffeine overdose in an anorectic woman, Ann Emerg Med 29(1), 178-180, 1997. 

A rather complex fused isoindoline (87) has been found to show good anorectic activity. This substance differs from other anorectic agents by not being a p-phenethylamine analogue. Preparation of this compound starts by reaction of a substituted benzoyl-benzoic acid (82) with ethylene diamine. The product (84) can be rationalized as being the aminal from the initially obtained monoamide 83. This is then subjected to reduction with lithium aluminum hydride... 

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). 

After 2 to 6 weeks, chickens were weak, anorectic, and lethargic 35% were anemic... 

---