How does orlistat affect the digestive system?
3. 3 Biochemistry For Medics 11/18/2012 Answer to case study C)-Orlistat inhibits gastric and pancreatic lipases, preventing the digestion and absorption of fats. The normal sequence of digestion is that triglycerides are emulsified by bile salts.
Why does the physician decide to start her on orlistat?
She is concerned that she does not have time to devote to exercise and wants to know if there is any pharmacologic treatment for her. The physician decides to start her on Orlistat which directly inhibits absorption of fats. Which of the following steps is directly inhibited by Orlistat ?
Can orlistat cause vitamin deficiency?
Over a period of time, orlistat therapy can induce deficiency of fat soluble vitamins. 4. 4 Biochemistry For Medics 11/18/2012 Case study A young man with normocytic anemia, jaundice, and splenomegaly was diagnosed as having RBC pyruvate kinase deficiency after a peripheral blood smear showed spiculated cells.
What is inhibited by orlistat?
Orlistat, a weight-loss agent with a novel mechanism of action, recently was approved by the Food and Drug Administration for the treatment of obesity. It inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat.
What is the mechanism of action for orlistat?
Mechanism of Action Orlistat acts by reversibly inhibiting the gastric and pancreatic lipases. These lipases have an important role in the digestion of dietary fat. They work by breaking down the triglycerides into absorbable free fatty acids and monoglycerides.
What type of inhibitor is orlistat?
Orlistat or tetrahydrolipstatin is a competitive inhibitor of pancreatic lipase (PL) with β lactone cycle incorporated into a carbon skeleton. This molecule is an irreversible inhibitor of human pancreatic lipase with an IC50 value of 0.14 mM.
Is orlistat an enzyme inhibitor?
Orlistat is a potent and selective inhibitor of various lipase enzymes responsible for the metabolism of fat. It acts in the gastrointestinal (GI) tract via covalent binding to the serine residues located on the active site of both gastric and pancreatic lipase.
How does orlistat reduce absorption of dietary fat quizlet?
The inactivate enzymes are unable to hydrolyze dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides. Therefore fewer calories are absorbs. 120mg three times a day, orlistat inhibits dietary fat absorption by about 30%.
What is the effect of orlistat to lipid digestion?
Orlistat binds to lipases in the gastrointestinal tract and thereby blocks the digestion of dietary triglycerides. This inhibition of fat digestion reduces micelle formation and, consequently, the absorption of long-chain fatty acids, cholesterol, and certain fat-soluble vitamins.
What happens if lipase is inhibited?
Lipase inhibitors bind to lipase enzymes in the intestine, thus preventing the hydrolysis of dietary triglycerides into monoglycerides and fatty acids. This then reduces the absorption of dietary fat.
How does a lipase inhibitor work?
Lipase inhibitors have been shown in numerous animal and clinical trials to improve lipid metabolism in obese individuals. By inhibiting the absorption of fatty acids and thereby reducing the accumulation of fatty acids in the body, meanwhile, reducing the level of LDL in the serum and increasing the level of HDL.
What inhibits pancreatic lipase?
A potent inhibitor of gastric and pancreatic lipase, orlistat (2) is a hydrogenated derivative of lipstatin, produced by Streptomyces toxytricini and acts by diminishing the absorption of dietary fat.
Does orlistat reduce triglycerides?
In conclusion, Orlistat treatment slightly reduces cholesterol and triglyceride levels, but not lipoprotein(a) levels. Total- and low-density lipoprotein cholesterol levels reductions are more consistent in patients with greater body weight reduction and shorter duration of orlistat treatment.
Does orlistat affect protein?
Although only a small amount of digested fat is required to elicit postprandial responses, literature has shown that orlistat has had an effect. Meals containing high amounts of protein and fiber have been shown to increase the postprandial gut hormone and satiety responses that orlistat may attenuate.
Does orlistat actually work?
Does orlistat work? Studies have shown that, on average, orlistat, plus a weight-reducing diet and exercise, causes more weight loss than a weight-reducing diet and exercise alone. Some people lose 10% or more of their body weight within six months with the help of orlistat. In others, it is less effective.
How long after taking orlistat does it work?
You can expect to see results in 1-3 months; aiming to lose 5% of your starting body weight in 3 months. Does Orlistat start working straight away? Orlistat will bind around 33% of the fat you consume in each meal where you take it with, or up to an hour after, food.
Is orlistat a CNS stimulant?
Orlistat is not a stimulant and does not affect the nervous system in the way that so many other weight loss drugs do. Instead it is what is known as a lipase-inhibitor - a drug that prevents the body from breaking down and absorbing fat.
What is the second level of obesity management?
Pharmacotherapy represents the second level of obesity management in patients at higher risk for overweight complications. The benefits of pharmacotherapy for weight control are, however, limited by side effects of different intensities, which reduce the compliance or may require discontinuation of treatment. Adverse effects induced by some categories of drugs have caused the withdrawal from the global or local markets of many agents, so there are few drugs nowadays approved for obesity control. The chapter focuses on characteristics mechanism of action, side effects and contraindications of each one.
What organ controls LDL?
The liver is the major regulator of the plasma low density lipoprotein cholesterol (LDL-C) concentration because it is not only the site of formation of very low density lipoproteins (VLDL), the precursors of most LDL in the circulation, but it is also the organ where the bulk of receptor-mediated clearance of LDL takes place. The liver also initially clears all the cholesterol that is absorbed from the small intestine. The absorption of excess cholesterol can potentially increase the amount of cholesterol stored in the liver. This, in turn, can result in increased VLDL secretion, and hence LDL formation, and also downregulation of hepatic LDL receptor activity. Such events will potentially increase plasma LDL-C levels. The converse situation occurs when cholesterol absorption is inhibited. Cholesterol enters the lumen of the small intestine principally from bile and diet. The major steps involved in the absorption process have been characterized. On average, about half of all cholesterol entering the intestine is absorbed, but the fractional absorption rate varies greatly among individuals. While the basis for this variability is not understood, it may partly explain why some patients respond poorly or not at all to statins and other classes of lipid-lowering drugs. There are few data relating to racial differences in cholesterol absorption. One study reported a significantly higher rate in African Americans compared with non-African Americans. Multiple lipid-lowering drugs that target pathways involving the absorption, synthesis, transport, storage, catabolism, and excretion of cholesterol are available. Ezetimibe selectively blocks cholesterol absorption and lowers plasma LDL-C levels by an average of 18%. When ezetimibe is coadministered with lower doses of statins, there is an additive reduction in LDL-C level, which equals the reduction achieved with maximal doses of statins alone. Dual inhibition of cholesterol synthesis and absorption is an effective new strategy for treating hypercholesterolemia.
How to reduce metabolic syndrome?
Weight reduction improves all components of the metabolic syndrome. This is seen with calorie-reduced diets as well as weight-loss Mediterranean-type diets. Exercise is also an effective strategy, but less so than diets usually because the weight loss is less. Sibutramine, xenical, and rimonabant are effective strategies to lower body weight and improve the metabolic syndrome. Surgery is more effective than the other strategies for reducing body weight and has significant effects on the components of the metabolic syndrome. Simply removing fat, however, is not enough to improve the features of the metabolic syndrome. Removal of subcutaneous fat by liposuction does not improve lipids or blood pressure, whereas removal of visceral fat by lipectomy does. Central adiposity can be attenuated independently of total body fat. Growth hormone, testosterone, cortisol, and dehydroepiandrosterone all have independent effects on visceral adipose tissue.
Is Orlistat good for weight loss?
It reduces the incidence of Type 2 diabetes in patients with impaired glucose tolerance and decreases LDL-C levels to a greater degree than expected from weight loss alone. Orlistat is a useful therapy in overweight and obese subjects with cardiovascular risk factors. The combination of orlistat with statins, fenofibrate and ezetimibe led to greater reductions of LDL-C levels compared with each monotherapy. The combination of orlistat with fenofibrate or ezetimibe also further decreased the concentration of atherogenic, small, dense LDL-C, as well as total plasma lipoprotein-associated phospholipase A2 activity, and improved several cardiovascular risk factors compared with monotherapy. However, studies investigating the combination of orlistat with other hypolipidemic drugs only included a small number of subjects with hyperlipidemia or the metabolic syndrome.
Does orlistat help with fatty liver?
... It also helps in the reductions in total cholesterol, triglycerides, LDL, and small dense LDL particles than lipid-lowering agent independent of weight loss. [11] Another systematic review and meta-analysis study that evaluated the efficacy and safety of orlistat in the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) concluded that orlistat may reduce the damage to hepatocytes by decreasing the fat accumulation in liver and thereby decrease the level of ALT, AST and GGT compared to baseline in patients with NAFLD, however there were no significant difference in NASH patients; however, it does not show any significant differences in patients with NASH. These findings demonstrate that orlistat could serve as a therapeutic drug to improve biochemical indicators of liver damage, but not as a first choice drug for the management of NAFLD or NASH; thus, suggesting a novel palliative drug only for the treatment of NAFLD. ...
Does orlistat affect lipase activity?
It was reported that, improvement in concentrations of cholesterol resulted from therapy with orlistat is a result of its effect on the body's ability to absorb dietary fats; orlistat is known to be associated with an increased incidence of gastrointestinal events in its users, in addition to, its positive decreasing effect on pancreatic lipase activity (Pi et al., 1996). It alters energy balance by reducing the absorption of triglyceride and cholesterol from the gastrointestinal tract (Mittendorfer et al., 2001). Reduction of the enzymatic activity is mediated through the covalent binding of orlistat to the serine residue of the lipase active site (Asler et al., 2007, Guerciolini andR., 1997). ...
Does orlistat affect cholesterol?
Orlistat decreases the absorption of dietary triglycerides by inhibiting intestinal lipases. Orlistat therapy is associated with a greater decline in plasma low-density lipoprotein-cholesterol concentrations than that expected from weight loss alone. Therefore, we evaluated the effect of orlistat treatment on dietary cholesterol absorption as a possible mechanism for the independent effect of orlistat on plasma cholesterol concentration. Cholesterol absorption from a standardized meal, containing 72 mg of cholesterol, was determined in 18 subjects with class II abdominal obesity (BMI, 35.0 to 39.9 kg/m (2)) by simultaneous administration of intravenous ( [ (2)H (6)] cholesterol) and oral ( [ (2)H (5)] cholesterol) cholesterol tracers. In protocol 1 (n = 9), cholesterol absorption was determined on two different occasions, 10 to 20 days apart, to assess the reproducibility of the tracer method. In protocol 2 (n = 9), cholesterol absorption was determined with and without orlistat therapy in a prospective, randomized, crossover design to assess the effect of orlistat on cholesterol absorption. In protocol 1, cholesterol absorption from the test meal was the same on both occasions (53 +/- 5% and 51 +/- 5%). In protocol 2, orlistat treatment caused a 25% reduction in cholesterol absorption, from 59 +/- 6% to 44 +/- 5% (p < 0.01). These data demonstrate that orlistat inhibits dietary cholesterol absorption, which may have beneficial effects on lipoprotein metabolism in obese subjects that are independent of weight loss itself.
Abstract
The transfer of radiolabelled orlistat ( [ 14 C]orlistat), a potent gastrointestinal lipase inhibitor, through an oil–water interface from a single oil droplet to an aqueous phase was investigated, using an oil drop tensiometer.
1. Introduction
Orlistat (tetrahydrolipstatin, (THL)), a hydrogenated analogue of lipstatin isolated from streptomyces toxytricini, is a potent inhibitor of gastrointestinal lipases ( Hogan et al., 1987, Borgström, 1988, Hadvàry et al., 1988, Gargouri et al., 1991, Ransac et al., 1991 ).
4. Conclusions
The availability of orlistat at the surface of lipid emulsion droplets, the main site of action of lipases ( Sarda and Desnuelle, 1958, Verger, 1997 ), is of prime importance for efficient lipase inhibition. Orlistat molecules present in the core of the droplets act as a reservoir continuously supplying the surface with orlistat.
Acknowledgements
We would like to thank F. Carrière and J. de Caro at the Laboratoire de Lipolyse Enzymatique (LLE-CNRS, Marseille) for their generous gift of purified human pancreatic lipase and porcine pancreatic colipase, respectively. The doctoral fellowship of A.
