Centrally Acting Anorectic Drugs

Appetite suppressing (anorectic) drugs affect fullness (when we stop taking meals after eating enough food), satiety (when hunger disappears due to meal intake), and hunger (a biological stimulus for food intake). By reinforcing the feeling of satiety and fullness and suppressing hunger, these medications help patients to reduce their calorie intake, improve control of food intake, and reduce the feeling of deprivation.

Anorectic drugs act in the CNS (central nervous system) at the level of the ventromedial and lateral nucleus of the hypothalamus. The regulation of appetite is ensured by the increase of three monoamines neural transmission: noradrenaline, serotonin (5-hydroxytryptamine) and, to a lesser extent, dopamine. Classic sympathomimetics act by either stimulating the release of noradrenaline or blocking its reuptake. Conversely, two serotonergic medications, which were prohibited in the USA in 1997, selectively stimulated the release of serotonin and blocked its reuptake. The third type of anorectic drugs (sibutramine) inhibits the reuptake of serotonin and noradrenaline (SNRIs).

All anorectic drugs recommended for obesity treatment, with the exception of sibutramine, are chemically and pharmacologically related to amphetamine. By making changes in either the aliphatic side chain or the aromatic ring, it became possible to reduce the severity of side effects on the central nervous system, excitation, euphoria, and the frequency of drug dependence. Over 200 short-term (1-3 months) controlled clinical trials have been conducted before the 1970s. They have shown that anorectic drugs reduce body weight (an average of 230 grams a week) to a greater extent than placebo. However, after drug discontinuation, patients quickly regained their initial body weight. This led to the mistaken conclusion about the ineffectiveness of drug therapy of obesity. Moreover, cases of improper use and the drug’s ability to cause drug dependence had made the Drug Enforcement Administration (DEA) place these substances in a Schedule of strong acting drugs. Accordingly, medical reference books started to recommend these old anorectic drugs as monotherapy for a short-term treatment of exogenous obesity only.

New concepts of drug therapy of obesity were obtained in the early 1980s in the studies by Dr. Weintraub and his colleagues. If we consider obesity within the chronic disease, like diabetes or arterial hypertension, it is necessary to take drugs for a long time in order to get stable weight loss. Dr. Weintraub made use of another concept – a combination of drugs – used for treating other diseases. By appointing two medications with different mechanisms of action, in smaller doses, it is possible to achieve equal or even greater effectiveness with fewer side effects. Based on these principles, a long-term prospective randomized double-blind clinical trial was carried out (with 121 obese participants). Patients were treated with a combination of adrenergic drug (phentermine) and selective serotonergic drug (fenfluramine). In the first 6 months weight loss due to the combination therapy was statistically significant compared with placebo (15.9% and 4.9% respectively). By the end of the clinical trial (3.5 years) body weight stabilized or slightly increased. This study was of key importance, because it has proven the effectiveness of a long-term drug therapy of obesity.

After Dr. Weintraub research, the effectiveness of the combined use of phentermine and fenfluramine (unofficially known as fen-phen) has been widely studied in the USA, directly from the manufacturer’s recommendations for its use. Dexfenfluramine, active fenfluramine’s d-isomer (started to be used in the USA in 1996), was the first medication used for obesity treatment since 1973. In 1994-1997 millions of overweight Americans took Redux along with fen-phen. In both cases, their body weight decreased by an average of 10-17% within one year. It was later discovered that the two serotonergic drugs, fenfluramine and dexfenfluramine, caused severe side effect – primary pulmonary hypertension (PPH). The PPH relationship and the use of anorectic drugs were researched in an international epidemiological PPH case-control study (International Primary Pulmonary Hypertension Study – IPPHS). It was discovered that the use of these medications for a period of 1-3 months increased the risk for developing PPH in patients compared to the risk for developing PPH in population by approximately 23 times. A huge number of PPH cases was discovered among patients who took these medications.

Valvular Heart Disease

The final rejection of fenfluramine and dexfenfluramine treatment occurred in September 1997. But it wasn’t due to the increased risk for developing PPH. It was the result of discovering another unexpected complication. 24 patients were described in Mayo Clinic in July 1997. They developed left-sided valvular heart disease during treatment. It was carcinoid syndrome, pathological heart valve lesions. This information prompted the US FDA to immediately collect and analyze echocardiography data from 5 studies of patients who took fen-phen or Redux. The valve lesion with moderate or more severe aortic insufficiency and/or moderate or more severe mitral insufficiency was detected in 30 and 38% of patients respectively. Based on preliminary research results and considering the fact that these drugs could be taken by millions of Americans, the US FDA requested firms-manufacturers to voluntarily withdraw from spreading fenfluramine and dexfenfluramine in the USA. All forms of these drugs were withdrawn from sale on September 15, 1997.

The reason for the increase in frequency of the mitral and aortic valve failure is unknown. But the results of numerous case-control studies have shown that the incidence of this compilation development is lower than it was previously thought (9-23%). It depends on the duration of treatment (> 3-4 months), and failure in the aortic valve develops more often than failure in the mitral valve. The guidelines published by the American College of Cardiology and the American Heart Association (“ACC/AHA Practical Guidelines”) recommend all patients, who took fenfluramine or dexfenfluramine, to go through clinical examinations (two-dimensional echocardiogram and Doppler ultrasound of the heart) with the specification of anamnesis, if clinical signs, noise or other signs of heart disease are present. Information on Phentermine-only treatment’s impact on the valvular heart disease is not convincing enough. This drug is still recommended for its use as anorectic medication, but each package includes information on phentermine’s possible connection with valvular heart disease.