M

(+) Pseudoephedrine (-) Pseudoephedrine

Figure 6 Structure of caffeine.

6.18.6.3 Antiobesity Drugs that Act through Peripheral Mechanisms

6.18.6.3.1 Orlistat 6.18.6.3.1.1 Mechanism of action

Orlistat (Xenical: Figure 7) has a unique mechanism of action among agents approved for the treatment of obesity and was approved in the US in 1999 and in the European Union in 2003. Most dietary fat is in the form of triglycerides, i.e., three fatty acids covalently bound to a glycerol backbone. To be absorbed into the body the triglycerides are broken down into monoglycerides and free fatty acids by intestinal lipases (Figure 8). Orlistat is a reversible inhibitor of these lipases, and the unmetabolized triglycerides are passed on through the bowel and eliminated. About 30% of dietary fat absorption is inhibited by a dose of 120 mg given three times daily.

6.18.6.3.1.2 Approved indications

Orlistat is indicated for obesity management, including weight loss and weight maintenance when used in conjuction with a reduced-calorie diet. It is also indicated to reduce the risk of weight regain after prior weight loss. Orlistat is indicated for obese patients with an initial BMI of >30 or >27 kg m_ 2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia).

6.18.6.3.1.3 Side effects, warnings, and contraindications

Since orlistat is poorly absorbed from the gastrointestinal tract, systemic exposure is minimal. Thus, side effects are primarily confined to actions in the gut, and are primarily related to the mechanism of action, i.e., prevention of absorption of fats so that they are passed out of the body through the intestine. The nature, frequency, and extent of these side effects may be influenced by the fat content of the patient's diet. The commonly observed side effects seen with orlistat include oily spotting from the rectum, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence.

6.18.6.4 Concluding Remarks Regarding Currently Available Pharmacotherapies for Obesity

The overall performance of the currently approved medicines for treating obesity is much less than desired, both from side-effect profiles and efficacy measures.5'13 Because of the side-effect issues, only two agents are currently approved by the FDA for long-term treatment. Sibutramine's use is limited because of patient, physician, and regulatory

Figure 7 The chemical orlistat.

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