**2. Drugs used in weight LOcSS**

#### **2.1. Sympathomiometic agents**

#### *2.1.1. Diethylpropion hydrochloride (Tenuate®; Tenuate® Dospan®; Durad®)*

Diethylpropion HCl (amfepramone, Figure 1a) is a sympathomimetic aminoketone agent with some similarity both chemically and pharmacologically to amphetamines and other related stimulant drugs. Similarly to amphetamine, diethylpropion stimulates release while inhibiting reuptake of dopamine, norepinephrine, and 5-hydroxytryptamine [20, 21]. The increase in norepinephrine and dopamine levels along with inhibition of their reuptake is proposed as the mechanism of diethylpropion anorectic effects [22]. Diethylpropion is indicated for short term management of obesity in patients with a body mass index (BMI) of > 30 kg/m2 who have not responded to diet and exercise alone [23]. Because of its similarity to amphetamine, some patients become psychologically dependent on diethylpropion with an increased risk of selfmedicating at higher dosages, increasing potential for drug interactions.

Diethylpropion is a monoamine and therefore can interact with monoamine oxidase inhibitors (MAOI), resulting in hypertension [23]. The manufacturer recommends avoiding use of diethylpropion during or within 14 days of discontinuation of MAOI administration. There is also one reported case of diethylpropion -induced psychosis in a 26 year old female patient taking phenelzine [24]. The authors hypothesized that chronic diethylpropion use led to an increased sensitivity to MAOI psychosis-inducing effects. Although the additive effects of diethylpropion in combination with other anorectic agents has not been studied, combined use of these agents is contraindicated due to the potential increased risk of cardiovascular issues [23]. In an early study of diethylpropion in 32 obese hypertensive patients, a drop in blood pressure was observed [25]. However, it was unclear if the drop in blood pressure in these subjects was due to weight loss or the additive effect of additional hypertensive agents that the patients were taking. The manufacturer also recommends potential modification of insulin dosing, although no strong evidence to support this statement can be found. In one study done in the rat, it was determined that anorectic drugs acting via the dopaminergic system antagonize hyperphagia induced by 2-deoxy-D-glucose, although the authors did not find any modifications to insulin-induced hypoglycemia [26]. There are no reported cases of drug-herb interactions with diethylpropion. However, theoretically herbal products with CNS stimulant properties (e.g. ephedra, caffeine, bitter orange), potential for interaction with sympathomimetic agents (e.g. Indian snakeroot), or MAOI activity (e.g. yohimbe) should be avoided due to an increased risk of hypertension, cardiovascular effects, and changes in blood pressure [27].

**Figure 1.** Molecular structures of anorectic drugs.

efficacy of herbal products is often unknown, especially given the presence of multiple chemical compounds, lack of known active constituents or lack of standardization of known compounds [16-19].This chapter presents a review of the chemistry and pharmacology of approved anti-obesity drug products, the proposed mechanism of action for common dietary supplements used in the management of weight loss, and potential drug-drug or herb-drug

Diethylpropion HCl (amfepramone, Figure 1a) is a sympathomimetic aminoketone agent with some similarity both chemically and pharmacologically to amphetamines and other related stimulant drugs. Similarly to amphetamine, diethylpropion stimulates release while inhibiting reuptake of dopamine, norepinephrine, and 5-hydroxytryptamine [20, 21]. The increase in norepinephrine and dopamine levels along with inhibition of their reuptake is proposed as the mechanism of diethylpropion anorectic effects [22]. Diethylpropion is indicated for short

not responded to diet and exercise alone [23]. Because of its similarity to amphetamine, some patients become psychologically dependent on diethylpropion with an increased risk of self-

Diethylpropion is a monoamine and therefore can interact with monoamine oxidase inhibitors (MAOI), resulting in hypertension [23]. The manufacturer recommends avoiding use of diethylpropion during or within 14 days of discontinuation of MAOI administration. There is also one reported case of diethylpropion -induced psychosis in a 26 year old female patient taking phenelzine [24]. The authors hypothesized that chronic diethylpropion use led to an increased sensitivity to MAOI psychosis-inducing effects. Although the additive effects of diethylpropion in combination with other anorectic agents has not been studied, combined use of these agents is contraindicated due to the potential increased risk of cardiovascular issues [23]. In an early study of diethylpropion in 32 obese hypertensive patients, a drop in blood pressure was observed [25]. However, it was unclear if the drop in blood pressure in these subjects was due to weight loss or the additive effect of additional hypertensive agents that the patients were taking. The manufacturer also recommends potential modification of insulin dosing, although no strong evidence to support this statement can be found. In one study done in the rat, it was determined that anorectic drugs acting via the dopaminergic system antagonize hyperphagia induced by 2-deoxy-D-glucose, although the authors did not find any modifications to insulin-induced hypoglycemia [26]. There are no reported cases of drug-herb interactions with diethylpropion. However, theoretically herbal products with CNS stimulant properties (e.g. ephedra, caffeine, bitter orange), potential for interaction with sympathomimetic agents (e.g. Indian snakeroot), or MAOI activity (e.g. yohimbe) should be

who have

term management of obesity in patients with a body mass index (BMI) of > 30 kg/m2

medicating at higher dosages, increasing potential for drug interactions.

interactions.

108 Drug Discovery

**2. Drugs used in weight LOcSS**

*2.1.1. Diethylpropion hydrochloride (Tenuate®; Tenuate® Dospan®; Durad®)*

**2.1. Sympathomiometic agents**

#### *2.1.2. Phentermine / Phentermine hydrochloride (Fastin®, Ionamin®, Adipex-P®, Suprenza®)*

Phentermine (Figure 1b), a member of the β-phenylethylamine family of compounds, exerts anorectic activity centrally through appetite suppression and is indicated in the short term treatment of obesity in patients with a BMI ≥ 30 kg/m2 [28]. A meta-analysis of six randomized controlled trials of phentermine cumulatively show an added 3.6 kg weight loss over 2 to 24 weeks compared to control groups [29]. Phentermine acts by increasing the release of and inhibiting the reuptake of norepinephrine or dopamine [22]. Although one of the oldest approved anti-obesity drugs, the safety of monotherapy of phentermine is relatively scarce due to the long history of combination products, most notably phentermine/fenfluramine (Phen-Fen), which was removed from the market due to serious and potentially fatal cardio‐ vascular effects [30, 31]. More recently a combination product containing phentermine and topiramate has been investigated (see *Topiramate* below) and is currently under review by the US Food and Drug Administration (FDA).

anhydrase inhibitors should be monitored due to the potential additive effects when coadmi‐ nistered with topiramate [51-55]. High doses of topiramate (600 mg/day) can increase systemic exposure to lithium. However, since topiramate dosage proposed to anorectic effects is low, this interaction may not be a significant concern when used as anti-obesity treatment [56]. No clinical studies or case studies are available for interactions with CNS depressants (e.g alcohol), although combined use is contraindicated by the manufacturer due to combined CNS depression [35]. No data supporting herb-drug interactions are available specifically related

Interactions with Drugs and Dietary Supplements Used For Weight Loss

http://dx.doi.org/10.5772/51145

111

Zonisamide (Figure 1d), a methanesulfonamide, is an antiepileptic agent which has broad spectrum activity and has proven to be useful in patients not responding to other antiepileptic treatments [57]. The drug blocks sustained and repetitive neuronal firing by blocking voltage sensitive sodium channels and decreasing voltage sensitive T-type calcium channels [58, 59]. Additionally, it was found that zonisamide has dopaminergic and serotonergic activity, which contributes to the anorectic effects of the drug [60, 61]. In one randomized placebo-controlled trial, 30 subjects were administered zonisamide 100 mg daily along with a low calorie diet (500 kcal/day) for a period of 16 weeks. Dosage was increased to up to 600 mg/day for patients not losing >5% of their initial body weight within the first 12 weeks. The zonisamide group lost significantly more body weight at the end of the trial compared to the placebo group (approx.

Zonisamide is metabolized by the cytochrome P450 3A4 system and therefore can potentially interact with other drugs metabolized via this route. In one study, the half-life of zonisamide (t½ = 60 h) was decreased in patients receiving both zonisamide and phenytoin (t½ = 27 h), carbamazepine (t½ = 38 h, and sodium valproate (t½ = 46 h) [57, 63]. Another study in the dog demonstrated decreased plasma levels of zonisamide during administration of phenobarbital [64]. However, any associated decrease in levels of other antiepileptic drugs was not found to be clinically significant [65, 66]. Cigarette smoking may alter the pharmacokinetics of zonisa‐ mide. Coadministration of carbonic anhydrase inhibitors may increase risk of metabolic acidosis and kidney stone formation, therefore monitoring is recommended in this patient population [66]. One study on the effects of cigarette smoke on zonisamide concentrations in rats suggests that cigarette smoke may decrease plasma levels of the drug due to decreased oral absorption [67]. Brain, but not plasma levels of zonisamide may be affected by chronic ethanol consumption. In one study inbred EL mice were administered zonisamide 75 mg/kg for 1 – 4 weeks along with 10% ethanol *ad libidum*. In groups with 4 week coadministration, representing chronic use of alcohol, a decrease in zonisamide brain concentrations, but not

Orlistat (Figure 1e) is a gastrointestinal lipase inhibitor approved both as a prescription (Xenical®) and over-the-counter (Alli®) weight loss aid in the long term treatment of obesity [69]. The drug exhibits antiobesity activity by inhibiting the absorption of dietary fat from the

to use of topiramate at low doses as an anorectic agent [27].

*2.2.2. Zonisamide (Zonegran®)*

6% loss vs. 1% loss) [62].

serum concentration were observed [68].

**2.3. Orlistat (Xenical®, Alli®)**

Because of the similarity in activity and mechanism of action, drug interactions with phenter‐ mine are similar to those for diethylpropion (see *Diethylpropion* above) including avoidance of alcohol, potential changes to antidiabetic agent therapy, and avoidance of coadministration of MAOIs [28]. There is one case report of a female patient experiencing two penropative hypertensive crises, which were attributed to an interaction between phentermine and anesthetic agents [32].
