Irritable Bowel Syndrome

Chinwon RimDepartment of Chemistry

Southern Methodist University

What is Irritable Bowel Syndrome(IBS)?

A group of functional bowel disorders Chronic abdominal complaints without a

structural or biochemical cause Constitutes a major health problem with

gastrointestinal (GI) symptoms The cause of IBS is unknown. Affects up to ~20 % adults in the industrialized

world The condition is more frequent in women. The direct medical costs of IBS are ~ $ US 8

billion in the US each year.

Symptoms of IBS

Abdominal discomfort and pain Bloating, mucous in stools, diarrhea, constipation,

or alternating diarrhea and constipation Depression, anxiety or stress IBS can be subdivided into

Diarrhea-predominant (IBS-D) Constipation-predominant (IBS-C) Alternating diarrhea and constipation

Subclassification of patients

Supportive symptoms of IBS1. Fewer than 3 bowel movements a week2. More than 3 bowel movements a day3. Hard or lumpy stools4. Loose or watery stools5. Urgency6. Feeling of incomplete bowel movement7. Passing mucus during a bowel movement8. Abdominal fullness, bloating or swelling

Diarrhea-predominant IBS (IBS-D) One or more of 2, 4 or 6 and none of 1, 3 or 5

Constipation-predominant IBS (IBS-C) One or more of 1, 3 or 5 and none of 2, 4 or 6

Serotonin is important in gut function

GI disorders may be related to an imbalance of serotonin in the gut an improper reaction of the digestive system to

serotonin a faulty communication network between serotonin in

the gut and the brain and spinal cord. Serotonin plays a major role in modulating

intestinal movement and perception of pain. Helps to soften stools by releasing water.

Serotonin (5-hydroxytryptamine, 5HT)

A monoamine neurotransmitter Found in cardiovascular tissue, the

peripheral nervous system, blood cells, and the CNS

95 % resides in the GI tract Serotonergic neurons secrete 5HT The function of serotonin is exerted

upon its interaction with specific receptors.

7 distinct families of 5HTreceptors; 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7

HO

NH

NH2

5HT3 receptors and its antagonists

5HT3 receptors A ligand-gated cation channel Present in the GI tract Control sensation, contraction of intestinal muscle Release of fluid into the intestines

5HT3 antagonists Slow intestinal transit Decrease intestinal secretions Decrease the water content of stool Diminish colonic pain

5HT4 receptors and its agonists

5HT4 receptors G-protein-coupled receptor Present in the GI tract Mediate both relaxation and contraction of circular

smooth-muscle strips Induces small bowel and to a lesser extent colonic

fluid secretion 5HT4 agonists

Accelerate gastric emptying Accelerate small and large bowel transit Increase stool water content

Alosetron in IBS-D

The first drug is approved for female patients by FDA

Brand name is Lotronex® by Glaxo Smith Kline A potent and selective antagonist of the 5HT3

receptors

Synthetic pathway of alosetron

N

NH

O

Me

N

N

O

Me

N

N

O

Me

N

NClH2C

MeCPh3

Na

NH

N

Me

+i

ii

Alosetron

(i) NaH, dimethoxyethane; (ii) HCl.

How does alosetron works?

The exact mechanism how alosetron relieves the symptoms of IBS-D is unknown.

Serotonin in the intestines controls how pain is felt, contraction of intestinal muscle, and release of fluid into the intestines. An excessive release of or an excessive response to serotonin causes a pain and diarrhea.

By blocking 5HT3 receptors, alosetron reduced pain and motor responses.

Alosetron-New Drug for IBS-D

Alosetron is rapidly absorbed and extensively metabolized.

Effective in relieving pain, normalizing bowel frequency, and reducing urgency

Constipation is the most common adverse effect Appears to provide a modest benefit to women Should be prescribed under the guidance of a

specialist Serious side effects and high-cost maintenance

problem

Tegaserod in IBS-C

The first selective serotonin 5HT4 receptor partial agonist approved by FDA for the treatment of abdominal pain and constipation predominent IBS patients

Brand name is ZelnormTM by Novartis Pharmceu. Corp.

Synthetic pathway of tegaserodOH

NO O

HN

O

HN

O

HN

O

O NNH

HNHN

i,ii iii

iv

Tegaserod

(i) K2CO3, RBr or ClCOX; (ii) t-BuOCH(NMe2)2 then H2, Pd/C; (iii) DMF, POCl3; and (v) N-pentyl-N’-aminoguanidine, MeOH/HCl.

How does tegaserod work?

The exact mechanism of tegaserod’s action is not yet understood completely.

Tegaserod binds with high affinity at 5HT4 receptors.

The activation of 5HT4 receptors in GI tract stimulates the peristaltic reflex and intestinal secretion. As a result, contractions increase and the increased contractions speed the transit of digesting food and reverse constipation.

Reduces the sensitivity of the intestinal pain-sensing nerves and reduces pain by inhibiting visceral sensitivity

Tegaserod –a Promising Option

Tegaserod is rapidly absorbed and metabolized. Effective in increasing the frequency of stools,

relieving abdominal pain and discomfort, and decreasing the sensations of bloating

Diarrhea is an occasional side effect. Is approved only for women Should be prescribed under the guidance of a

specialist

Conclusions

Alosetron, 5HT3 antagonists, appears to provide a modest benefit to women with IBS-D. Offers a new option for the treatment of IBS-D.

Tegaserod, 5HT4 agonists, appears to be a promising options in women with IBS-C not responding to increased dietary fiber or laxative therapy.

Both cases, need more researches on mechanism how drugs work and clinical studies for the treatment of men patients.

Need to discover new drugs for alternating diarrhea and constipation

References

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Kloppner, E.; Pfannkuche, H.-J.; Mattes, H. Journal of medicinal chemistry 1995, 38(13), 8.

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