Drug Treatment of ,2
Total Page：16
File Type：pdf, Size：1020Kb
Drug treatment of ,2 George A Bray ABSTRACT The currently available drugs for treatment of with amphetamine, methamphetamine, ephedrine, and phen- obesity act on two pharmacologic systems in the central nervous rnetrazine but is minimal or absent with the others. Moreover, system: the noradrenergic system and the serotonergic system. weight loss may actually lower blood pressure. 3) Metabolic ef- There are clear and convincing clinical data that these drugs are fects expressed as a rise in the concentration of free fatty acids effective and safe. However, several types of barriers exist to and/or glycerol in plasma have been observed after administra- their proper and effective use, including public perceptions that tion of amphetamine, rnetharnphetarnine, and phenmetrazine. obesity is a disease resulting from lack ofwillpower, professional Methamphetamine has been found to antagonize the lipolytic expectations that anorexiant drugs should cure obesity, hindrance effects ofnorepinephrine in vitro but has no direct lipolytic effect by state licensing agencies, regulatory rigidity, limited research itself. Mazindol has been reported to increase the uptake of glu- funding, and legislative inaction. In spite of these limitations, cose after intraarterial administration in humans. Fenfluramine Downloaded from several new and potentially valuable drugs are under develop- reduces blood glucose through non-insulin-dependent mecha- ment, and given an appropriate clinical and therapeutic envi- nisms (4). ronment, the future is bright for treatment of obesity. Am The peak blood concentration of anorexiant medications J Clin Nuir l992;55:538S-44S. usually occurs shortly after oral administration. However, the half-life ofthe drugs in the serum varies considerably; benzphet- KEY WORDS Anorexiant drugs, noradrenergic drugs, se- amine and amphetamine have 2-5-h half-lives compared with www.ajcn.org rotonergic drugs, stigmatization, thermogenic drugs much longer ones for phentermine, fenflurarnine, and fluoxetine (a serotonergic antidepressant that has been reported to produce weight loss but has not been approved for that indication, see Introduction below). There are important pharmacologic differences among Drugs for the treatment of obesity can be classified by using the stereoisomers of these compounds. The dextro isomer of by on April 30, 2010 a feedback model to understand alterations in nutrient balance amphetamine, for example, is four times more potent than the (1). A feedback model consists of a control system of nutrient levo isomer. The d-isorner of fenfluramine appears to contain intake, digestion, absorption, storage, and oxidation, which sends most, ifnot all, ofthe appetite-suppressing effects ofthe racemic afferent messages of a hormonal, neural, or nutrient type to a (d, I) mixture with the /-isomer being ineffective in this regard. central controller in the brain, which in turn sends efferent signals Urinary excretion of several drugs is dependent upon urine pH to regulate digestion and metabolism offood and the partitioning and may increase in acidic urine (4). of nutrients between fat, protein, and energy utilization. A clas- Clinical use of noradrenergic appetite-suppressing drugs. In sification of treatments for obesity by use of this approach is evaluating the clinical usefulness of appetite suppressants, two shown in Table 1 (2). questions need to be answered: Are they effective? And are they safe? The Food and Drug Administration has provided one of the Drugs acting on the central nervous system largest reviews ofeffectiveness for noradrenergic drugs (5). They analyzed 105 new drug applications containing data on 4543 Drugs acting on noradrenergic neurotransmitters placebo-treated and 3 182 patients treated with active drugs. In Most appetite-suppressing drugs currently marketed for the studies comparing placebo and active drug, the dropout rate treatment of obesity are derivatives of phenethylamine (3, 4). after 4 wk of therapy was 18.5% for subjects on placebo and The exception is mazindol, which is an imidazoisoindole. The 24.3% for those receiving active drug. At the end of the study currently available drugs are listed in Table 2 according to the periods, lasting 3, 4, 8, or more weeks, equal percentages of Drug Enforcement Agency (DEA) Schedule. patients receiving placebo and active drugs remained in treat- Pharmacologic effects. The pharmacologic effects of appetite ment (49% for the placebo group vs 47.9% for the active-drugs suppressants can be divided into three categories. 1) Most of these medications can stimulate the central nervous system, but the degree is highly variable; and two ofthem, phenylpropanol- amine and fenfluramine, appear almost devoid of this effect. I From the Pennington Biomedical Research Center, Baton Rouge, 2) Some appetite-suppressing drugs have cardiovascular effects, LA. which include a rise in heart rate and blood pressure, but most 2 Address reprint requests to GA Bray, Pennington Biomedical Re- do not. A rise in heart rate and blood pressure has been observed search Center, 6400 Perkins Road, Baton Rouge, LA 70808. 538S Am J C/in Nuir l992;55:538S-445. Printed in USA. © 1992 American Society for Clinical Nutrition DRUG TREATMENT OF OBESITY 539S TABLE 1 A nutrient balance approach to treatment of obesity Component Mechanism Example Agents acting on controlled system Decrease nutrient density of food High-carbohydrate, low-fat diet Fiber Simplesse Olestra Reduce digestibility Tetrahydrolipstatin Olestra Disaccharidase Inhibitors Disrupt micelle formation Cholestyramine Increase energy expenditure Cold exposure Exercise Exercise Vasodilation Prazosin Calorigenic drugs Thyroid Growth hormone -3 Adrenergic agonists Ephedrine Caffeine Change nutrient partitioning fi-3 Adrenergic agonists Growth hormone Downloaded from Corticosteroids Androgens Estrogens Agents acting on afferent system Palatability Sweeteners Saccharin Aspartame Topical anesthetic Benzocaine www.ajcn.org Taste altering drugs Capsaicin Gastric distention Gastric balloon Gastrointestinal peptides Aconitase Cholecystokinin Procolipase signal peptide by on April 30, 2010 Bombesin Nutrients 3-Hydroxybutyrate Lactate l-Butene-4-olide 3,4-Dihydroxybutyrate Agents acting on controller GABAergic antagonists (GABA-A receptors) Picrotoxin Adrenergic agonists (a-I, $-3) Phenethylamine derivatives Serotonergic agonists Fenfluramine Fluoxetine Sertraline Histaminergic (H-l) agonists Peptides Cholecystokinin agonists Opioid antagonists (Naloxone; Nalfemene; Kappa-receptor antagonists) NPY antagonists CRH-agonists Agents acting on efferent mechanisms Thermogenic drugs i-3 Agonists Jaw-wiring Steroid removal Adrenalectomy RU-486 blockade of steroid receptors Inhibit prolactin release Dopamine agonists group). Drug-treated patients lost on average 0.25 kg/wk (0.56 of 1.4 kg/wk, achieved by 2% of those on active drugs com- lb/wk) more than subjects receiving placebos. pared with 1% ofthose on placebo. An examination ofthe weight The effectiveness of weight loss by anorexiant medications loss results after 4 wk of treatment shows 68% of patients on can also be evaluated in terms ofthe proportion ofsubjects who the active drugs lost 0.45 kg/wk compared with 46% patients lost given amounts of weight per week. A weight loss of 0.45 on placebo and 10% ofthe drug-treated subjects vs 4% of those kg/wk was almost twice as common in patients receiving active receiving placebo lost 1.4 kg/wk. In clinically effective doses drugs (44%) as in those on placebo (26%), as was a weight loss there was no basis on which to choose between these drugs in 540S BRAY TABLE 2 Appetite-suppressing drugs Excreted Peak blood unchanged Genetic and proprietary Common trade concentration Half-life in acidic names names Dosage Administration (h after po dose) in blood urine mg mg h % Over-the-counter Phenylpropanolamine Dexatrim 25, 75 25 tid, 75 in morning Schedule IV Diethylpropion Tenuate, propion 25, 75 25 before meals (tid), 1-2 8-13 24 (Noradrenergic) 75 in morning Fenfluramine Pondimin 20 20-40 before meals I 20 20 (Serotonergic) Mazindol Sanorex, mazanor 1, 2 1 before meals, 2 13 22 (Noradrenergic) 2 in morning Phentermine Ionamin 15, 30 15 tid, 30 in morning Free 7-8 75 (Noradrenergic) Fastin 1 20-24 Schedule 111* Phendimetrazine Plegine, obalan 35 35 before meals - 4 7? (Noradrenergic) Downloaded from Benzphetamine Didrex 25, 50 25-50 before meals 1-2 - 7? (Noradrenergic) Schedule II Amphetamine Dexedrine 5, 10, 15 5-10 before meals (tid) 1-2 5 55 (Noradrenergic) Methamphetamine Desoxyn 5, 10, 15 2.5 or S before meals (tid), 1-2 13 45 www.ajcn.org (Noradrenergic) 10 or 15 in morning Phenmetrazine Preludin 25, 50, 75 25 (bid or tid) - - 19 * The Federal Controlled Substances Act of 1970 places the prescription anorexiants into five schedule categories. Appetite suppressants in schedule II are most likely to be abused whereas those in schedule IV have little or no risk of abuse. by on April 30, 2010 terms of their rates of weight loss or the duration over which including food intake. Drugs modulating serotonin metabolism this weight loss occurred (5). The data from one 20-wk trial are influence body weight (4). Food intake is reduced by the ad- shown in Figure 1. ministration of tryptophan or 5-hydroxytryptophan, two pre- Additional data are available from trials lasting from 6 to 52 cursors that are converted to serotonin after entering the brain. wk (4). Weight loss continued at a decelerating rate for the du- Similarly, drugs that release serotonin