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Pharmacological Management of the Patient with Obesity
Published in James M. Rippe, Lifestyle Medicine, 2019
Magdalena Pasarica, Nikhil V. Dhurandhar
Benzphetamine is a sympathomimetic amine approved in 1960 for short-term (few weeks) treatment of weight loss in addition to caloric restriction in patients with a BMI at or above 30 kg/m2 who have not responded to a lifestyle management of obesity. A systematic review of clinical trials shows reports that benzphetamine produces on average 3.3 kg of weight loss over 16 to 17 weeks of treatment compared to a placebo.28 It shouldn’t be used with other anorectic drugs. Even though no cases of valvulopathy have been reported with benzphetamine use alone, it is recommended to carefully assess the benefits of weight loss vs. the potential risks for serious side effects such as valvular heart disease and pulmonary hypertension (https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012427s026lbl.pdf). It is rarely used to treat obesity with only 4% of total weight loss prescriptions reported between 2008 and 2011 when only six drugs were approved for weight loss.15 This may be due to the drug being Schedule III, with abuse potential higher than the more favored and low-risk Schedule IV drugs. Due to the similarity between the structures of benzphetamine and amphetamines, it is recommended not to discontinue abruptly in order to avoid extreme fatigue and mental depression. Serious side effects include psychosis, HTN, dependency/abuse, cardiomyopathy, and cardiac ischemia. Common side effects include palpitations, tachycardia, insomnia, tremor, and elevated blood pressure (https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012427s026lbl.pdf).
Acetylenes: cytochrome P450 oxidation and mechanism-based enzyme inactivation
Published in Drug Metabolism Reviews, 2019
The well-characterized inactivation of CYP2B4 by 4-tert-butylphenylacetylene offers a particularly clear insight into cytochrome P450 inactivation via protein modification. This particular inactivation reaction is highly efficient in that every oxidation of the inhibitor results in covalent modification of the protein, that is, every ketene molecule that is formed binds to the protein, inhibiting the enzyme (Zhang et al. 2009, 2011). Quantitative analysis indicates that in each protein one molecule of the inhibitor is bound to Thr302, causing a 5-nm shift of the Soret band. The addition of benzphetamine, a normal substrate, to the inactivated protein fails to cause either the normal spin shift or the greatly enhanced reduction of the protein normally observed on binding of benzphetamine. The conclusion that covalent attachment of the inhibitor to Thr302 sterically interferes with productive substrate binding is supported by a resonance Raman studies (Mak et al. 2010). An even more precise view of this steric interference is provided by a crystal structure of the inactivated protein, which shows the oxidatively activated 4-tert-butylphenylacetylene molecule attached via an ester link to the oxygen of Thr302 (Gay et al. 2011). This is the adduct expected from reaction of the threonine hydroxyl with the ketene formed from the acetylene group. A second crystal structure shows that 9-ethynylphenanthrene also inactivates CYP2B4 by binding covalently through an ester bond to Thr302 (Zhang et al. 2013).
Treating obesity in patients with cardiovascular disease: the pharmacotherapeutic options
Published in Expert Opinion on Pharmacotherapy, 2019
Caroline A. Andrew, Katherine H. Saunders, Alpana P. Shukla, Louis J. Aronne
The five medications that are currently FDA-approved for long-term weight management are phentermine/topiramate, bupropion/naltrexone, orlistat, lorcaserin and liraglutide. Phentermine, and the less commonly prescribed diethylpropion, benzphetamine and phendimetrizine, are approved for short-term weight management (up to 3 months). In 2015, the Endocrine Society published clinical practice guidelines for the pharmacological management of obesity. For patients with uncontrolled hypertension or a history of heart disease, the guidelines recommend that sympathomimetic agents, such as phentermine, be avoided. Furthermore, medications such as lorcaserin, orlistat and liraglutide, which are not sympathomimetic, are considered medically appropriate options for patients with CVD according to these guidelines [15]. Additionally, for patients with type 2 diabetes, the guidelines recommend the use of weight-loss-promoting or weight-neutral medications, such as glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose cotransporter-2 (SGLT-2) inhibitors as first- and second-line treatment after metformin. This article will review currently approved anti-obesity medications and their use in patients with CVD.
The safety of pharmacologic treatment for pediatric obesity
Published in Expert Opinion on Drug Safety, 2018
Ariana M. Chao, Thomas A. Wadden, Robert I. Berkowitz
Several medications have been approved by the FDA for the short-term (≤12 weeks) management of obesity, as an adjunct to a reduced-calorie diet and increased physical activity, in adults with a BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with obesity-related comorbidities. These drugs are noradrenergic sympathomimetic agents that decrease appetite and include phentermine, benzphetamine, diethylpropion, and phendimetrazine. Their effectiveness in youth has not been established, though there have been some small trials of phentermine conducted for pediatric obesity [30]. Side effects of these medications include increased pulse rate, blood pressure, dry mouth, insomnia, and constipation. There is a risk of abuse and dependence. Benzphetamine and phendimetrazine have been classified as Schedule III and diethylpropion and phentermine are Schedule IV controlled substances in the US [31]. Rare but serious side effects have also been reported among patients taking a combination of phentermine and fenfluramine or dexflenfluramine, including primary pulmonary hypertension and valvular heart disease. Fenfluramine and dexfenfluramine are no longer on the market because of their association with valvulopathy. As pediatric obesity is a chronic condition and requires long-term management, use of phentermine as monotherapy in pediatric patients is not recommended, as there are no short- or long-term efficacy and safety data available in youth.