Anti-obesity drugs


Qnexa image

Qnexa

by James J. Galligan,  Ph.D., Associate  Chair,
Department of Pharmacology and  Toxicology

The most recent blog discussed the Food and Drug Administration’s denial of an application for approval of a new weight loss drug, locanserin.

Well, an FDA advisory panel has recommended that an application for approval of another weight loss drug be denied.

The new drug, called Qnexa, is a combination of two drugs, phentermine and topiramate.  Phentermine is a component of the previously banned Fen-Phen weight loss drug that was removed from the market more than 10 years ago because it caused heart valve problems.

Phentermine is an amphetamine like drug that acts in the hypothalamus to control appetite.  Phentermine also stimulates the sympathetic nervous system and this caused an increase in heart rate in many patients taking Qnexa in the clinical trials.  Topiramate is an anti-seizure drug that is also used to treat bipolar disorders, obesity and binge eating.  Topiramate has multiple potential mechanisms effects on neurotransmission in the brain including blocking sodium channels and glutamate receptors and enhancing the actions of the inhibitory neurotransmitter, gamma amino-butyric acid (GABA).

While data from clinical trials of locanserin for weight loss showed marginal effects on body weight, the studies of the effectiveness of Qnexa on weight loss provide more impressive results.  Subjects taking Qnexa lost substantially more weight that subjects taking a placebo medication after 1 year.  Unfortunately, Qnexa also caused an increase in heart rate in many subjects and this raises the potential for heart arrhythmias in subjects that might be predisposed to this problem.  Most patients taking Qnexa would likely do just fine.  However, there are many people who are at risk for dangerous heart arrhythmias and who are unaware of this risk.  This raises the bar for approval of any medication that has even the slightest risk of heart-related side effects.

The FDA prefers to err on the side of patient safety in these cases.

Several months ago, I commented on a study that showed that there was an increased incidence of depression in patients taking a drug used to treat nicotine addition.  The study concluded that because nicotine and the endogenous neurotransmitter, acetylcholine, act to stimulate the brain’s own reward circuitry drugs which block this pathway would reduce the level of reward experienced by the subject during their normal life experiences.  Dopamine is an important neurotransmitter in the reward pathway and many activities that we enjoy activate this dopamine pathway.  One of these pleasurable and rewarding activities is eating. 

           

A recent study (http://www.sciencemag.org/cgi/content/full/322/5900/449) has further substantiated the role of dopamine in endogenous reward pathways and the results of this study suggest that deficiencies in the reward pathway might contribute to obesity.   The investigators used functional magnetic resonance imaging (fMRI) to measure blood flow in specific brain regions of human subjects.  Increases in blood flow indicate an increase in nerve activity in that area of the brain.  This study focused on the dorsal striatum which is a component of the endogenous reward pathway.  Dopamine is an important neurotransmitter in the dorsal striatum and dopamine stimulates D2 type dopamine receptors in this brain area.  The authors studied two groups of female subjects.  The first was a group of female college students while the second group was composed of adolescent females; the authors obtained genetic information about most of the women in the second group.  Body mass index (BMI) was calculated for all subjects in both groups. 

 

Subjects were shown pictures of a chocolate milkshake and then they were given a chocolate milkshake to drink.   During exposure to these stimuli fMRI scans of the ventral striatum were obtained.  The authors found that there was a negative correlation between BMI and activity in the ventral striatum when the subjects consumed the chocolate milkshake.  The authors interpreted these data to mean that the heavier subjects experienced less reward from consuming the chocolate milkshake compared to leaner subjects.  What was very interesting was that the subjects that experienced the least activation of the ventral striatum had a genetic polymorphism associated with low D2 receptor expression. 

 

Previous twin studies have shown that there is a genetic link for obesity.  This study suggests that at least in some subjects, reduced D2 dopamine receptor activity in the reward pathway may be associated with reduced levels of eating induced reward.  This would lead these individuals to consume more food in order to achieve some level of reward and this would predispose these subject to overeating.  Perhaps drugs which can activate the endogenous reward pathway, particularly the ventral striatum, might be useful in enhancing the reward associated with food intake and this might limit the size of meal needed to experience reward and therefore discourage overeating.    

The brain has nerve circuits that are part of the natural reward system for animals and humans.  Behaviors like sex or feeding activate these nerve circuits and therefore these behaviors feel good and are rewarding.  There are two types of chemical messenger molecules released from the nerves in these reward circuits: acetycholine and annandamide.  Acetylcholine released from nerve cells attaches to a “receptor” on target nerve cells; the receptor is called the nicotinic acetylcholine receptor.  This receptor gets its name from the fact that the active ingredient in tobacco, nicotine, also attaches to and activates the receptor.  This is one reason smoking cigarettes is pleasurable because nicotine activates the reward circuits. 

Annandamide is a molecule made by nerve cells that acts receptors called cannabinoid receptors (abbreviated CB receptors).  CB receptors are the same receptors activated by delta-9-THC, the active ingredient in marijuana smoke.  It is well known that delta-9-THC is an appetite stimulant (the “marijuana munchies”) and annandamide is the substance released from the brain that activates the reward circuits in response to feeding. 

A recent article on the newswire services summarizes new information that a drug used to treat nicotine addiction (Chantix) and an anti-obesity drug (Acomplia) may produce depression as an unwanted side effect because they disrupt the nerve circuits in the brain’s reward pathways.  Chantix is a drug that attaches to but does not activate the nicotinic acetylcholine receptor in the reward pathway.  Therefore, the receptor is blocked and can not respond to stimulation by the nicotine in cigarette smoke.  The individual taking Chantix as part of a nicotine cessation program, no longer experiences the rewarding effects of nicotine and this makes it easier to quit smoking.  The problem is that Chantix also blocks signals that come from other types of rewards and this might lead to depression. 

Acomplia is a drug that blocks CB receptors in reward pathways associated with feeding.  Patients taking Acomplia no longer find that eating is as pleasurable of rewarding and this will help obese patients lose wait.  However, CB receptors are also in the reward circuits and Acomplia may block pleasurable feelings associated with other kinds of rewarding behaviors.  Patients taking Acomplia may be at risk for developing depression. 

This new information highlights the challenges for modern pharmacologists interested in developing drugs for the treatment of disease.  Development of safe and effective drugs requires that scientists understand the complex functions of the human body and also understand the complex actions of drugs.  Pharmacologists have the specialized training to understand the complexity of the human body and to understand how drugs interact with the body.  This understanding helps to develop drugs that have beneficial effects without producing unwanted side effects. 

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