The Orlistat (whose trade name is Xenical® de Roche), also well-known like tetrahidrolipostatina, is a drug to treat the obesity. [1] Its main function is to avoid the absorption of fats of the human diet, reducing therefore the ingestion of calories.

Active principle: Orlistat. Capsules with 120 mgs of Orlistat and excipientes.

Properties, effects.

Xenical is a powerful, specific inhibitor and of long gastrointestinal action of lipasas. Its effect exerts therapeutic it in the gastric cavity and the light of the thin intestine by means of the formation of a covalent bond with the active site of serina of lipasas gastric and pancreatic. The enzymatic inactivity prevents hydrolysis of fats, in the form of triglyceride, to absorbent free fatty acids and monoglicéridos. And since the triglyceride digested is not absorbed, the resulting caloric deficit has a positive effect for the control of the weight. Therefore, the systemic absorption of the drug is not necessary so that it carries out his activity.

Absorption:

The studies realised in volunteers of normal weight and obese have shown that the degree of absorption of the Orlistat in minimum. To the 8 hours of administered by oral route, the plasmatic intact drug concentration and to was not detectable (5 ng/mL.). After the administration of therapeutic doses, the plasmatic detection of intact Orlistat was, generally, sporadic and the concentration was extremely low (10 ng/mL.), without signs of compatible accumulation and with an insignificant absorption.

Distribution:

The volume of distribution of the Orlistat has not been able to determine, since it is absorbed in minimum amount and it does not have a defined systemic pharmacokinetics. Test-tube, the Orlistat is united in more of 99% to plasmatic proteins (mainly to lipoproteins and albumen). The amount of present Orlistat in erythrocytes is minimum.

Metabolism:

According to the data collected in animal, it mainly seems that the metaboliza Orlistat in the gastrointestinal wall. According to a study realised in obese patients, of the very small fraction of the absorbed dose systemically, two main metabolites, the M1 (hidrolizado ring of lactona of 4 links) and the m3 (M1 with fragmented the N-formil-leucina radical), approximately constitute 42% of total the plasmatic concentration. M1 and m3s have an open ring of b-lactona and its inhibiting activity of lipasas is extremely low (1000 and 2500 times smaller than the one of the Orlistat, respectively). In view of his reduced inhibiting activity and of the low plasmatic concentrations to dose (average: 26 ng/mL and 108 ng/mL, respectively), are considered that these metabolites lack pharmacological importance.

Elimination:

The taken studies I finish in individuals with a normal weight and in obese they have demonstrated that the main route of elimination is the faecal excretion of the drug, not absorbed. Approximately 97% of the administered dose are excreted with lees, being 83% of this inalterable Orlistat amount.

The accumulated renal excretion of all the compounds related to Orlistat was 2% of the administered dose. The time until the complete excretion (faecal but urinary) was of 3-5 days. The availability of the Orlistat seems to be similar in the volunteers with a normal weight and the obese ones. As much the Orlistat as the M1 and the m3 is excreted by biliary route.

Indications, way of use.

Xenical is indicated for the long term treatment, along with a moderate hypocaloric diet, of obese patients or with overweight, including which they present/display associated factors of risk to the obesity. Xenical allows a long term effective control of the weight (reduction, maintenance and prevention of the increase of weight). The treatment with Xenical leads to an improvement of the factors of risk and the upheavals associated to the obesity, like hipercolesterolemia, noninsulinodependiente diabetes miellitus, intolerance to the glucose, hiperinsulinemia and hypertension, as well as to a reduction of visceral fats.

Dosage and way of administration.

Adults:

The recommended dose of Xenical is of a capsule of 120 mgs with each main food (taken during the same or up to one hour later). If it is not taken or a food does not contain fat, the dose of Xenical can be omitted. The therapeutic benefits of Xenical (including the control of weight and the improvement of the risk factors) stay in the long term with the administration. The patient must follow nutritionally balanced and moderately hypocaloric a diet, with approximately 30% of the originating calories of fats. He recommends himself that the diet is rich in fruits and vegetables. The amount ingested daily of fats, carbohydrates and proteins must be distributed enters the three main meals. With dose superiors to 120 mgs three times to the day better results have not been obtained. In old it is not necessary to fit the dose.

In the determinations of the faecal fat, the effect of Xenical is observed 24-48 already hours of the administration. After the discontinuation of the therapy, the faecal fat content returns generally at the basal levels in the 48-72 space hours.

Hepatic or renal insufficiency: it is not precise to fit dose. Children and smaller adolescents of 18 years: the innocuity and to the effectiveness of Xenical in the children and the smaller adolescents of 18 years has not settled down.

Contraindications.

Xenical is contraindicated in patients with the chronic syndrome of malabsorption, as well as in which they present/display hypersensitivity known the Orlistat or some other component the capsule.

Precautions.

In the ample clinical tests in the long term realised (3300 patients dealt with Xenical up to 2 years) adverse effects or risks for the health have to date not been registered serious related to the use of Xenical (to see indirect effect). One is due to advise to the patients who follow with the dietetic directives (to see dosage). It can increase the probability of reactions gastrointestinal (to see indirect effect) if day is taken Xenical with a rich fat diet (for example in a diet from 2000 calories/; 30% of the calories of greasy origin equivalent to 67 fat g. The daily fat ingestion must be distributed enters the three main meals. If Xenical is taken with a very rich fat diet, can rise the probability of gastrointestinal reactions.

Pregnancy and lactancia: the innocuity of Xenical in the pregnant women has not settled down. In the reproduction studies animal embriotóxicos nor teratógenos effects have not been observed associated Xenical. However, since the animal studies not always are predictive of the answer in humans, Xenical during in the pregnancy is not due to use, unless the awaited benefit surpasses the possible risks. Since she does not know herself if Xenical is excreted by maternal milk, the nursing women do not have to take it, unless the awaited benefit is major that the possible risks.

Indirect effect.

Most of the adverse reactions to Xenical are gastrointestinal and are related to their pharmacological effect to prevent the ingested fat absorption (to see pharmacokinetics). The habitually observed reactions are oily spots, increase of the defecation and faecal incontinence. The incidence of these reactions grows as it increases the fat content of the diet and, therefore of lees. The patients must receive advice about the possibility that gastrointestinal indirect effect appear and on the best form to come, for example of reinforcing the diet, coverall in the percentage of contained fats. The consumption of a low fat diet diminishes the probability of gastrointestinal reactions, which can help the patients to watch and to regulate its fat ingestion. In the clinical tests, these pharmacological effects did not consider an impediment to continue Generally with the therapy, these adverse reactions are slight and fleeting. The gastrointestinal reactions appear in the beginning of the treatment (in the 3 first months), and the majority of the patients undergoes only an episode. Only 3% have suffered more than two episodes of anyone of the adverse reactions.

Interactions.

Interactions with drugs of frequent use like digoxina, fenitoína, oral warfarina, contraceptives, nifedipino GITS, nifedipino retard, gliburida, furosemida, captopril and atenolol do not take place, nor with alcohol. Nevertheless, the Orlistat increases the bioavailability of the pravastatina (increase of the plasmatic concentrations in approximately a 30%), as well as its hipolipemiante effect. In the clinical tests very diverse medecines have been used concomitantly, without adverse interactions were observed clinically significant. In the studies of interactions pharmacokinetics, the Orlistat inhibited the absorption of the oral supplements of some liposoluble nutrients, like the betacaroteno (around a third) and vitamin acetate E (around half), but not those of vitamin acetate To, and it did not reduce the ingested vitamin concentrations either K with foods. In the clinical tests, the concentrations of some liposoluble and analogous vitamins fell. In the immense majority of the patients who followed the treatment up to 2 years, the vitamin concentrations remained within the normal energy levels, without clinical sequels were detected. In the diabetic patients, lost by weight induced by Xenical it is accompanied by an improvement of the metabolic control, which can allow or require a diminution of the doses of oral hipoglucemiante (for example sulfonilureas).

Sobredosificación.

The overdose of Xenical has still not settled down. Unique doses of 800 mgs of Xenical and multiple doses of up to 400 mgs three times to the day have studied during 15 days in individuals with normal weight and obese, without there were significant adverse findings. In addition, three times to the day have been administered to dose of 240 mgs during 6 months to obese patients. The doses superiors to recommended of the 120 mgs three times to the day have not improved appreciably the effectiveness, but they can increase the gastrointestinal reactions. In case of important overdose of Xenical it is recommended to observe the patient during 24 hours. According to the studies realised in humans and animal, any systemic effect attributable to the properties of Orlistat to inhibit lipasas would have quickly to be reversible.

Conservation.

This medicine will only be able to be used to date of lapsing, indicated with EXP in the package. Strips to blister: they are conserved less than to 25ºC and they are protected of the humidity. Glass bottles with desiccant: they are conserved less than to 30ºC.

Presentation.

Capsules of 120 mgs strips to blister 50, 100 capsules.

Silvia Andrea Mateluna Aldayuz. Student of Chemistry and Pharmacy (5º year). University of Chile.