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There are two main ways through which current anti-obesity drugs work, either by suppressing the patient's appetite or by preventing the absorption of food from the gastrointestinal (GI) tract. Anorectics function by suppressing the patient's appetite through acting on the Central Nervous system (CNS). Anorectics stimulate the sympathetic nervous system and alter the behaviour of their nerve terminals. Through this action of anorectics, the patient's calorie intake is significantly reduced hence he or she loses weight. On the other hand drugs such as Orlistat, interfere with fat absorption, and so assist these drug users in weight loss.
These new pharmaceutical interventions help to tackle obesity. It is important to reduce the proportion of people with this condition as obesity strongly correlates with a lower life expectancy and quality of life. The reasons for this is because later on this condition will eventually lead on to secondary associated diseases such as:Â cardiovascular diseases, cancer etc. Therefore, using this argument, anti-obesity drugs should be allowed for use since they increase the Quality-Adjusted Life Year (QUALY) of the patients.
On the contrary, the use of these pharmacological interventions inevitably comes with health and psychological disadvantages. The use of these drugs may be risky to one's health as they can have undesirable side-effects and in the past have known to cause death.
It is more cost-effective for the healthcare system to focus more on prevention rather than treatment. But due to the growing knowledge of these treatment options especially in More Economically Developed Countries (MEDCs), the fact that obesity has a cure may possibly deter people from taking care of themselves. Obesity is commonly referred to as a "disease of excess". However it is just as important to realise that genetic predisposition and ethnicity play roles in increasing one's susceptibility of becoming obese (Das et al, 2006). Â
Obesity is defined as having a Body Mass Index (BMI) of 30 or above.
Apart from drugs, bariatric surgery is another treatment option. Gastric banding and gastric bypass surgery are further examples of bariatric surgery. These operations are only carried out on dangerously-obese patients. The mortality rates of these operations tend to be low (O'Keefe et al, 2010).
This essay will concentrate on the pharmacological side of anti-obesity drugs. Presently administered pharmacological interventions have disadvantages to their usage and all have potential serious side-effects. In addition, this essay will assess, whether despite these risks should anti-obesity drugs still be utilized?
It is a widely known fact that obesity is a major contributing factor to many diseases and fatal conditions like cardiovascular problems and cancers. In fact obesity and weight gain account for approximately 20% of all cancer cases (Wolin et al, 2010).
We will now explore the mechanisms through which each of the currently available anti-obesity drugs work and review their drawbacks.
There are two categories of present anti-obesity drugs we will analyse: anorectics (appetite depressants) and absorption affecting drugs.
Current examples of anorectics are: Phendimetrazine, Amfepramone, Benzphetamine and Phentermine. They are all sympathomimetic amines which stimulate the Central Nervous System. These appetite depressants work at the satiety centres, in the hypothalamic region, of the brain (Aronson, 2006).
Phendimetrazine is actually an inactive prodrug which gets metabolised to active Phenmetrazine (Rothman et al, 2002). 'Rothman et al, 2002' explored the pharmacological effects of this anorectic. They showed that Phendimetrazine does not affect the dopamine, noradrenaline or 5HT (serotonin) transporters but in fact its active metabolites do.
In this same experiment, using a rat's brain, other active metabolites were also produced along with Phenmetrazine, which were:Â pseudophenmetrazine and its metabolites. Moreover, these products were involved in the activation of the sympathetic transporters. Not only did these increase the release of the neurotransmitters but also inhibited the uptake. The drug's metabolites increased the release of noradrenaline and inhibited the reuptake of dopamine (Rothman et al, 2002.)
Inhibition of reuptake of dopamine means that more of it is around, ready to affect the receptors at the post-synaptic axon. Dopamine is a transmitter which is involved in rewarding the brain after eating (Fulton, 2010). According to research food reinforcement is greater in the obese than the non-obese (Epstein et al, 2007). Even genetic factors for example the dopamine receptor genotype, like the DRD2 gene, of the individual, has an impact on the food intake (Epstein et al, 2007).
According to 'Rothman et al, 2002's' experiment, most of Phendimetrazine's metabolites hardly had an affect on the serotonin (5HT) transporters, but there was a slight increase in the serotonin levels.Â Serotonin is a neurotransmitter that gives the feeling of satiety.
Earlier this year a group of researchers from London were looking into the affectivity of a potential, prospective drug called Tesofensine (Sjödin et al, 2010). This drug works in a similar way to the anorectic Phendimetrazine. The makers claim that it produces twice the weight loss compared to present anti-obesity drugs (Sjödin et al, 2010). Tesofensine works by inhibiting the reuptake of noradrenaline, dopamine and serotonin through the presynaptic axon. By doing so there is an enhancement of neurotransmission by these three monoamines (Sjödin et al, 2010). Drugs which work via this mechanism are called: Serotonin-Noradrenaline-Dopamine Reuptake Inhibitors (SNDRI). Interestingly the main purpose of SNDRI drugs are the treatment of depression and affect similar pathways in the brain.
However there are disadvantages to the use of anorectics. Phenmetrazine can cause euphoria and can lead to addiction (Aronson, 2006). Amfepramone and Phentermine can also lead to slight euphoria (Aronson, 2006). There are also side-effects associated with the over-stimulation of the sympathetics and care must be taken when prescribing anorectics with antidepressants or with any blood pressure reducing drugs (Aronson, 2006).
Â The other major anti-obesity drug class interferes with the absorption of fat from the gastrointestinal tract. One well-known example of a drug from this category is Orlistat, which is sold "over-the-counter". Its trade name is "Alli" in the UK and is sold here without the need of a prescription.
There are four types of lipases that assist in digestion of fat and as mentioned in the 'Harp, 1998' article, these are: gastric lipase, pancreatic lipase, carboxylester lipase, and phospholipase A2. Orlistat works by inhibiting the action of two of these lipases in the gastrointestinal tract: gastric and pancreatic (Cruz-Hernandez et al, 2010).
Lipase is an enzyme required for the digestion of triacylglycerides (TAG). This drug forms a covalent bond with the active site of the lipase thus altering the enzyme's shape. This bonding, with the amino acid serine region of the active site, inactivates the enzyme (Ballinger and Peikin, 2002). Therefore the substrate can no longer bind to the inactive enzyme, as it is no longer complementary to the transitional state of lipase. So no digestion of the triacylglyceride molecule can take place. Because the triacylglycerides have not been digested, the body is unable to absorb the fat, as a consequence the patient loses weight.
According to a research review article written by 'Wilson et al, 2003' it has been shown that in comparison to the placebo group, Orlistat causes significant weight loss and better control of cardiovascular risk factors. The research study conducted by 'Romero-Corral et al, 2006' shows that patients with severe obesity, with a BMI greater or equal to 35, have the greatest risk of mortality caused by cardiovascular factors. To improve their health it is therefore necessary for these patients to lose weight.
On the contrary, research findings from trials conducted by 'Maahs Et al, 2006', strongly suggest that Orlistat does not work as efficiently for obese adolescents. During the first 6 months of this study there were no statistically significant differences between the BMI of a placebo-controlled group and the group of adolescents taking Orlistat. So Orlistat may not be so advantageous to the adolescent obese.
But it is important to realise that even drugs such as Orlistat that are sold over the counter may have drawbacks. The human body requires vitamins as part of his/her balanced diet. There are two categories of vitamins: fat-soluble and insoluble. Vitamins B and C are water soluble but Vitamins A, D, E and K are fat soluble. The decrease in fat absorption can result in a decrease in the absorption of these vital nutrients, thus can result a deficiency (Mingfang et al). 'Cruz-Hernandez et al, 2010', demonstrated that administration of Orlistat lowered the amount of incorporation of n-3 long-chain polyunsaturated fatty acids from eicosapentaenoic and docosahexaenoic acids in rats. This fatty acid is important for physiological body functions including the formation on eicosanoids eg. Prostaglandins, leukotrienes...etc. (Lands, 1992).
Additionally, it is important to realise that drugs like Orlistat do have side-effects and there is always the possibility of rare adverse effects. There is not enough long-term data to confirm that anti-obesity drugs definitely do decrease mortality from obesity-associated conditions (Snow et al, 2005).
According to 'Mingfand et al, 2009', Orlistat is known to cause side-effects which are related to unabsorbed fat left in the intestine, these are: diarrhoea, flatulence, bloating, abdominal pain and dyspepsia.
Another less well-known example of an absorption-affecting anti-obesity drug is Methylcellulose. Methylcellulose is the generic name for Celevac and it is derived from cellulose. Methylcellulose decreases the level of fat absorption in the intestines along with the overall TAG and High Density Lipoprotein (HDL)- cholesterol concentrations of the body (Bartley et al, 2010). Methylcellulose is a dietary fibre which is not absorbed by the body and adverse effects are not so common (Reppas et al, 2009).
According to a 4 week study trial, Methylcellulose is a bulk-forming appetite depressant that reduces appetite by 10% (Evans et al, 1975). Bulk-forming means that the methylcellulose makes it easier for the stools to pass through and out of the intestine.
In addition, current research suggests another reason of why methylcellulose is effective. A study in which hamsters were fed on a diet of methylcellulose for exactly a month began to express altered hepatic genes involved in lipid metabolism (Bartley et al, 2010).
Anti-obesity drugs work in a similar mechanism to the other drugs in the same class. We are still beginning to discover more mechanisms of how drugs such as methylcellulose work, even though it is already presently used in the market.
Orlistat works through altering the chemical shape of pancreatic and gastric lipases, through bonding to the serine amino acid of the enzyme. This bonding alters the behaviour of the enzyme and so its substrate is no complementary. Because the TAG is not digested, it is not absorbed through the lacteals of the intestine. Fat is left undigested in the intestine, this is also the reason for the uncomfortable side effects of Orlistat.
Anorectics mainly work in a similar way to amphetamines, in regard to how it increases dopamine concentrations in the synaptic cleft (Kuczenski et al, 1997). By increasing the levels of these neurotransmitters, the level of satiety in increased and dopamine promotes a "brain-rewarding" process. Overall appetite depressants function through stimulating the sympathetic nervous system part of the Central Nervous System. The disadvantage of anorectics is that many of its side-effects are due to over stimulation of the sympathetic nervous system.
Anti-obesity drugs need to be prescribed or taken with care and its side-effects should be taken into account. Weight loss decreases the chances of secondary diseases and so anti-obesity drugs are therefore advantageous in this respect.