Pharmacotherapy of IBS

“Spastic colon, irritable colon, mucous colitis, and spastic colitis”

Azza Baraka
Professor of Clinical Pharmacology
July 18, 2018 2
“IBS patients fight a battle that many do not understand”

July 18, 2018 3

July 18, 2018 4
 IBS puzzle

July 18, 2018 5

 Definition of IBS
• It is a chronic, often debilitating, and highly prevalent disorder of gut-brain
interaction (previously called functional gastrointestinal disorders) .
• In clinical practice, IBS is characterized by symptoms of recurrent abdominal
pain and disordered defecation .
• Patients with IBS should report symptoms of abdominal pain at least once weekly
(on average) in association with a change in stool frequency, a change in stool
form, and/or relief or worsening of abdominal pain related to defecation
• Although bloating is a commonly reported symptom, its presence is not
mandatory to accurately diagnose IBS.
• The Rome IV criteria is used to diagnose IBS .

April 12, 2022 NIDDK 6

 Rome IV diagnostic criteria for irritable bowel syndrome

July 18, 2018 7

 Clinicians should make a positive diagnosis of IBS based on
symptoms, in the absence of alarm symptoms or signs, and
abnormalities on simple blood and stool tests

July 18, 2018 8

July 18, 2018 9
 Pathophysiology of IBS
• Deranged brain-gut signaling, hypersensitivity of visceral sensory afferent fibers,
small intestinal bacterial overgrowth (SIBO), genetic alterations may play a role.
• For some patients with IBS, psychological comorbidity or distress may be a
consequence, rather than a cause, of the severity and frequency of symptoms
experienced.
• IBS is a disorder of altered bidirectional communication between the gut and
brain (via the gut-brain axis), and has a biopsychosocial aetiology. As a result, it
has been re-termed a disorder of gut-brain interaction.

April 12, 2022 NIDDK 10

 CLASSIFICATION OF IBS
• Patients are subgrouped according to their predominant stool pattern into
IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D), IBS with
mixed bowel habits (IBS-M) or IBS unclassified (IBS-U), to direct therapy.

April 12, 2022 NIDDK 11

 Tips during use of anti-IBS drugs
• A single mediator might have differing actions on GIT motility according to the
type of receptor upon which it acts.
• The presenting IBS symptom will determine the drug chosen.
• Avoid simultaneous administration of two drugs having the same mechanism of
action.
• Avoid simultaneous administration of two drugs having antagonistic actions.

April 12, 2022 NIDDK 12

The predominant site of action of the different classes of drugs

July 18, 2018 13

Treatment algorithm for IBS. *Review efficacy after 3 months of
treatment and discontinue if no response.
 First-line treatments
1. All patients with IBS should be advised to take regular exercise.
2. First-line dietary advice should be offered to all patients with IBS.
3. Soluble fibres, such as Psyllium hydrophilic mucilloid (ispaghula husk), are
effective treatment for global symptoms and abdominal pain in IBS,
but insoluble fibres (eg, wheat bran) should be avoided as it may
exacerbate symptoms. Soluble fibre should be started at a low dose
(3–4 g/day) and built up gradually to avoid bloating .

April 12, 2022 NIDDK 15

 First-line treatments
4. A diet low in fermentable oligosaccharides, disaccharides and monosaccharides
and polyols (FODMAP), as a second-line dietary therapy, is an effective
treatment for global symptoms and abdominal pain in IBS.
5. A gluten-free diet is NOT recommended in IBS .
6. Probiotics, as a group, may be an effective treatment for global symptoms and
abdominal pain in IBS. It is reasonable to advise patients wishing to try
probiotics to take them for up to 12 weeks, and to discontinue them if there is no
improvement in symptoms

April 12, 2022 NIDDK 16

 First-line treatments
7. Antispasmodics may be an effective treatment for global symptoms and
abdominal pain in IBS. Dry mouth, visual disturbance and dizziness are
common side effects
8. Peppermint oil may be an effective treatment for global symptoms and
abdominal pain in IBS. Gastro-oesophageal reflux is a common side effect
9. Loperamide may be an effective treatment for diarrhoea in IBS-D. However,
abdominal pain, bloating, nausea and constipation are common, and may limit
tolerability. Titrating the dose carefully may avoid this.
10. Polyethylene glycol may be an effective treatment for constipation in IBS-C.
Abdominal pain is a common side effect.

April 12, 2022 NIDDK 17

 Second-line treatments
1. Tricyclic antidepressants used as gut-brain neuromodulators are an effective
second-line drug for global symptoms and abdominal pain in IBS. careful
explanation as to the rationale for their use is required, and patients should be
counseled about their side-effect profile. They should be started at a low dose
(eg, 10 mg amitriptyline once a day) and titrated slowly to a maximum of 30–
50 mg once a day.
2. Selective serotonin reuptake inhibitors used as gut-brain neuromodulators may
be an effective second-line drug for global symptoms in IBS. Careful
explanation as to the rationale for their use is required, and patients should be
counseled about their side-effect profile.

April 12, 2022 NIDDK 18

 Second-line treatments
3. The non-absorbable antibiotic rifaximin is an efficacious second-line drug for
IBS-D, with a limited effect on abdominal pain.
4. 5-Hydroxytryptamine 3 receptor antagonists are efficacious second-line drugs
for IBS-D. Ondansetron titrated from a dose of 4 mg once a day to a maximum
of 8 mg three times a day is a reasonable alternative. Constipation is the most
common side effect. This drug class is likely the most efficacious for IBS-D.

April 12, 2022 NIDDK 19

 Second-line treatments
5. Linaclotide, a guanylate cyclase-C agonist, is an efficacious second-line drug for
IBS-C in secondary care. It is likely to be the most efficacious secretagogue
available for IBS with constipation, although diarrhoea is a common side effect.
6. Lubiprostone, a chloride channel activator, is an efficacious second-line drug for
IBS-C in secondary care. This secretagogue is less likely to cause diarrhoea than
others. However, patients should be warned that nausea is a frequent side effect.
7. Tegaserod, a 5-Hydroxytryptamine 4 receptor agonist, is an efficacious second-
line drug for IBS-C. Diarrhoea is a common side effect

April 12, 2022 NIDDK 20

 I-For global symptoms

July 18, 2018 21

 1. LOW FODMAP DIET
FODMAP stands for fermentable oligosaccharides, disaccharides,
monosaccharides and polyols, which are short-chain carbohydrates (sugars) that
the small intestine absorbs poorly.
The elimination of dietary fermentable oligosaccharides, disaccharides,
monosaccharides, and polyols (FODMAPs) can be tried to treat IBS.
FODMAPs lead to increased GI water secretion and increased fermentation in
the colon, thus producing short-chain fatty acids and gases which can lead to
luminal distension and the triggering of meal-related symptoms .

4/12/2022 22
 LOW FODMAP DIET
High FODMAP foods that aggravate IBS include:
• Dairy-based milk, yogurt and ice cream
• Wheat-based products such as cereal, bread and crackers
• Beans and lentils
• Some vegetables, such as artichokes, asparagus, onions and garlic
• Some fruits, such as apples, cherries, pears and peaches

4/12/2022 23
 LOW FODMAP DIET
low FODMAP foods :
• Eggs and meat
• Certain cheeses such as cheddar and feta
• Almond milk
• Grains like rice, quinoa and oats
• Vegetables like eggplant, potatoes, tomatoes, cucumbers and zucchini
• Fruits such as grapes, oranges, strawberries, blueberries and pineapple

4/12/2022 24
 2. Fibers
• Soluble, but not insoluble, fibers are to be used to treat global IBS symptoms.
It is recommended to receive about 25–35 g of total fiber intake per day.
• Dietary fibers have diverse effects in the GI tract involving the gut
microbiome, metabolism, transit time, stool consistency.

April 12, 2022 NIDDK 25

 Fibers in IBS
• Dietary fibers are frequently recommended to improve symptoms in patients
with IBS, particularly when constipation is the predominant complaint.
• Different types of fibers can be distinguished on the basis of their solubility,
viscosity, and ability to resist fermentation in the colon.
• Soluble fibers are found in psyllium, oat bran, barley,.. Insoluble fibers are
found in wheat bran, whole grains, and some vegetables. Fibers that exert
laxative effects tend to increase stool water content and resist colonic
fermentation. Conversely, fibers that ferment in the colon will lose their water-
holding capacity and produce gas that could aggravate symptoms of bloating and
flatulence.

April 12, 2022 NIDDK 26

 Fibers in IBS
Therefore, Soluble, viscous, poorly fermentable fiber may provide benefits in
IBS. The apparent lack of significant side effects makes fiber a reasonable first
line therapy for IBS patients with symptoms.

April 12, 2022 NIDDK 27

 3. Probiotics
• Probiotics, as a group, may be an effective treatment for global symptoms and
abdominal pain in IBS, but it is not possible to recommend a specific species or
strain.
• It is reasonable to advise patients wishing to try probiotics to take them for up to
12 weeks, and to discontinue them if there is no improvement in symptoms.

28
 II- For IBS-D

July 18, 2018 29

 1. Loperamide (Imodium)
• Loperamide is a synthetic μ-opioid agonist that reduces myenteric plexus activity,
thereby increasing intestinal transit time and enhancing water reabsorption.
• It is effective for the treatment of diarrhea, reduction of stool frequency, and
improvement of stool consistency, but it is not effective for the relief of pain,
bloating, or global IBS symptoms.
• Abdominal pain, bloating, nausea and constipation are common side effects, and
may limit tolerability. Titrating the dose carefully may improve tolerability.

April 12, 2022 NIDDK 30

 Loperamide (Imodium)
• FDA Warns About Serious Life-Threatening Arrhythmias With High Doses of
Loperamide Including From Abuse and Misuse.
• The maximum recommended daily dose for adults is 8 mg per day for OTC use
and 16 mg per day for prescription use.
• It is noted that much higher than recommended doses of loperamide can result
in serious cardiac adverse events, including QT interval prolongation, torsade
de pointes or other ventricular arrhythmias.
• Patients with pre-existing cardiac conduction conditions may be at increased
risk. Also, patients should be advised that drug interactions with commonly
used medicines can also increase the risk of serious cardiac adverse events.
 Loperamide

• Contraindications of loperamide:
1. Infectious diarrhea.
2. Hepatic/renal dysfunction.
3. prolonged QT interval on ECG
4. paralysis of the intestines
5. bloody diarrhea
• It has many drug interactions

4/12/2022 32
 2. Racecadotril (Hidrasec)
• Racecadotril is an enkephalinase inhibitor. It functions by selective inhibition of
the enzyme neutral endopeptidase (also known as enkephalinase), a cell
membrane peptidase enzyme found on the epithelium of the small intestine and
functions to degrade endogenous enkephalins in the intestinal
mucosa. Enkephalins normally promotes antisecretory properties. Thus, the
hypersecretion of water and electrolytes is reduced without affecting intestinal
motility/transit.
• It is an antisecretory agent that can prevent fluid/electrolyte depletion from the
GIT WITHOUT affecting intestinal motility.

4/12/2022 33
 Racecadotril vs loperamide
• Unlike other opioid medications used to treat diarrhea, which reduce intestinal
motility, racecadotril has an antisecretory effect — it reduces the secretion of
water and electrolytes into the intestine.
• It has appropriate safety , it does not cause constipation or bloating or affection
of intestinal transit time like antimotility drugs.
• It is associated with less rebound constipation and less abdominal discomfort.
• Since, it does not affect intestinal transit time, thus bacterial enterocolitis is not
a contraindication for use of racecadotril, in contrast to loperamide
• No reported drug–drug interactions as (in contrast to loperamide) it does not
affect CYTP450 metabolic enzyme system.
4/12/2022 34
 Antimotility & COVID19
• Since these agents delay transit time, the clearance from the gut of (SARS-
CoV-2),the causative pathogen of COVID-19, may be delayed. Therefore, the
use of antimotility drugs could prolong the course of SARS-CoV-2 infection,
and subsequently leads to a more severe course of illness.

4/12/2022 35
 3. Rifaximin (Gastrobiotic)
• Rifaximin is a nonabsorbed antibiotic which is FDA-approved for the treatment
of patients with IBS-D.
• Rifaximin treatment is based on the hypothesis that a portion of patients with
IBS-D have an abnormal microbiome. Some patients with IBS may have
underlying small intestinal bacterial overgrowth (SIBO).

April 12, 2022 NIDDK 36

 4. 5-HT-3 antagonists (Ondansetron/zofran)
• Serotonin is an important neurotransmitter in the brain and ENS.
• Patients with IBS-D have increased plasma 5-HT, while those with IBS-C have
reduced 5-HT levels. Drugs that act on the 5-HT3 receptor, such as ondansetron
are known to retard colonic tranist.
• 5-HT3 receptors are also important mediators of visceral pain .The 5-HT3R
antagonists alleviate specific IBS symptoms, such as frequent bowel movements,
feelings of urgency, and chronic abdominal pain and discomfort.
• The single dose of ondansetron should not exceed 8 mg and the daily dose
should not exceed 16 mg.

April 12, 2022 NIDDK 37

 5-HT-3 antagonists (Ondansetron/zofran)
• It is not recommended to take ondansetron in patients who take medications
that increase serotonin, such as SSRIs and SNRIs, as well as linezolid, as
taking ondansetron with these medications may lead to the occurrence of the
so-called serotonin syndrome and one of its symptoms is an increase heart
rate with high blood pressure, increased sweating, diarrhea.

April 12, 2022 NIDDK 38

 Please Avoid

July 18, 2018 39

 Antidiarrheals to be AVOIDED

Egyptian largely ineffective

pharmacies provide Streptoquin, an antibiotic combination that is

against diarrhoea, and which has been banned in many countries.

 Active ingredients of streptoquine

• Clioquinol,
• Homatropine Methylbromide,
• Phthalyl Sulfathiazole
• Streptomycin
 For IBS-C

July 18, 2018 42

1. Polyethylene glycol (PEG)(ClearLax, MiraLax, Macrogol)

• PEG is soluble in water and is not reabsorbed in GIT. PEG binds water
molecules. For this reason, it can prevent the reabsorption of water, which causes
water retention in the stool and increases the osmotic pressure. As a result, the
stool softens, and bowel movements occur more frequently.
• The average oral daily dose is 0.4 grams/kg/day . Maximum daily dose should
not exceed 17 grams/day. 17 g of PEG 3350 is mixed in 250 ml of liquid and
taken once daily.
• PEG may be associated with nausea, bloating, abdominal cramps, and vomiting.

4/12/2022 43
 PEG

• Due to the potential choking hazard, PEG is to be used with caution in those
patients prone to aspiration or regurgitation (e.g., gag reflex depression,
dysphagia, esophageal stricture, impaired mental status or dementia).
• PEG is contraindicated in patients with known or suspected bowel obstruction,
appendicitis, IBD, perforated bowel.

4/12/2022 44
 2. Intestinal Secretagogues
Chloride channel activators (Lubiprostone), GC-
agonists(Linaclotide)

July 18, 2018 45

 Lubiprostone (Amiprostone)
Lubiprostone has high affinity for type-2 chloride channels located in the apical
membranes of intestinal epithelial cells. Activation of these receptors increases
intestinal secretion and peristalsis .
lubiprostone may restore barrier function in individuals with increased intestinal
permeability . Lubiprostone is FDA-approved for the treatment of IBS-C at a
dosage of 8 μg twice daily. It also improves abdominal pain.
Diarrhea and nausea are the most frequently reported ADRs but less than
linaclotide. Nausea is dose-dependent, but may be reduced by consuming
lubiprostone with meals.

April 12, 2022 NIDDK 46

 Linaclotide (Linzess)
• Linaclotide is a guanylate cyclase-C (GC-C) agonist that targets GC-C receptors
residing in the apical membranes of intestinal epithelial cells.
• This increases intra-cellular (cGMP), secretion of chloride and bicarbonate into
the intestinal lumen, and sodium and water secretion. The increase in cGMP may
also have effects on sensory afferent neurons, leading to pain inhibition.
• It is effective for relieving symptoms of IBS-C. Responses develop quickly and
are maintained over time. Diarrhea is the most common ADR.

April 12, 2022 NIDDK 47

 3. 5 HT-4 receptor agonists

July 18, 2018 48

 Mosapride(Fluxopride), Itopride (Ganaton), Sulpride(Dogmatil/
Colona) , Prucalopride (Resolor), Tegaserod (Zelmac),
• 5-HT4 receptors in the GI tract are found on enteric neurons and smooth muscle
cells. Stimulation of 5-HT4 receptors leads to acetylcholine release and prokinetic
effects, and causes reduction in visceral hypersensitivity .
• Stimulation of the 5-HT4 stimulates giant migratory contractions; the
contractions that traverse the length of the colon and initiate the urge to defecate.
• 5-HT4 agonists are used to treat IBS-C symptoms in women younger than 65
years with ≤1 cardiovascular risk factors who have not adequately responded to
secretagogues.
• Adverse effects are diarrhea, cramping, and cardiovascular AEs.

April 12, 2022 NIDDK 49

• Prucalopride is not metabolized and is excreted largely unchanged and
predominantly in the urine. Consequently, clearance is significantly reduced
in patients with severe renal impairment and a halving of the usual adult
dose (2 mg daily) is thus recommended.
• Prucalopride has no adverse cardiac events.

April 12, 2022 NIDDK 50

 Tips for good therapy of constipation

• Investigate about intake of drugs that might lead to constipation including

anticholinergic drugs ( atropine , first generation antihistaminics, TCAs),
calcium and vitamin D ( large doses).

4/12/2022 51
 For IBS (pain)

July 18, 2018 52

 1. Antispasmodics
They are among the most frequently used OTC treatments for IBS, and can be
divided, broadly, into
1. Antimuscarinics:
• dicycloverine (Spasmodigestin),
• propantheline,
• Tiemonium ( Visceralgin)
• otilonium bromide
• hyoscine butylbromide (Buscopan)
2. Smooth muscle relaxants ; mebeverine (coloverin).

April 12, 2022 NIDDK 53

 Antispasmodics
Antimuscarinics should not be used in:
1. Closed angle glaucoma
2. children under six years of age.
3. fructose intolerance, glucose-galactose malabsorption (Buscopan tablets contain
sucrose).
Antimuscarinics should be used with caution in elderly and in patients with :
1. heart problems
2. hyperthyroidism
3. enlarged prostate gland
4. Constipation
 Antispasmodics
Drug interactions with other drugs having atropine-like action:
1. antihistamines, eg promethazine, brompheniramine, chlorphenamine, diphenhydramine,
2. antimuscarinic medicines for Parkinson's symptoms, eg trihexiphenidyl
3. antimuscarinic medicines for urinary incontinence, eg oxybutynin, trospium, tolterodine
4. antipsychotics, eg chlorpromazine, clozapine, thioridazine
5. Anti-motionsickness medicines, eg meclozine, cyclizine,
6. other antispasmodics, eg atropine, propantheline, dicycloverine
7. tricyclic antidepressants, eg amitriptyline, clomipramine.
8. If taken with domperidone (primperan) or metoclopramide (motilium) the actions of the
medicines may cancel each other out. This is because metoclopramide and domperidone
increase the motility of the gut, whereas antimuscarinincs reduce it.
• If a patient is receiving a first generation antihistaminic and requires an
antispasmodic then mebeverine ( coloverin/colona) is preferred over buscopan.
• Since mebeverine's action is not mediated by blocking the parasympathetic
nervous system, the usual anticholinergic side effects of buscopan may be
absent.
• Mebeverine is thus also suitable for patients with prostatic hypertrophy and
glaucoma.

4/12/2022 56
 2. Peppermint oil

• The major constituent of peppermint oil is menthol, which has

antispasmodic properties. Menthol inhibits smooth muscle contractility
in the GI tract by blocking calcium influx.
• Menthol-induced analgesia is mediated by activation of the ion channel,
TRPM8 expressed by nociceptive visceral afferents, where TRPM8 has
anti-nociceptive properties.
• Peppermint oil can worsen GERD symptoms and lead to heartburn and
belching.

April 12, 2022 NIDDK 57

 3. Trimebutin(Gastreg)
• The actions of trimebutine are mediated via an agonist effect on peripheral mu,
kappa and delta opiate receptors and a modulation of GIT peptides release.
• The final motor effects on the gut are : acceleration of the gastric emptying, an
induction of the migrating motor complex in the small intestine and a
modulation of the contractile activity of the colon. Also, it decrease reflexes
induced by distension of the gut lumen and it may therefore modulate visceral
sensitivity.
• It functions at various levels, from motility to pain control, makes this drug
unique and its spectrum of action can be used for the treatment of both
hypermotility and hypomotility disorders

4/12/2022 58
 4. Gut brain neuromodulators
Antidepressants
Rational behind use of antidepressants in IBS:
• Depression modifies the brain’s response to painful stimuli,
• Antidepressants have beneficial effects in chronic painful disorders
• Antidepressants affect GI motility, with (TCAs) prolonging gut transit
times, and (SSRIs) decreasing orocecal transit time. It would therefore
seem sensible to use TCAs in IBS-D, and SSRIs in IBS-C.

April 12, 2022 NIDDK 59

 TCAs
• TCAs are a class of agents, now commonly referred to as neuromodulators, which include
amitriptyline, nortriptyline, imipramine, and desipramine.
• TCAs improve visceral pain and central pain by acting on norepinephrine, and dopaminergic
receptors, thus making them attractive candidates for the treatment of IBS-related abdominal
pain .
• TCAs may also improve abdominal pain because of their anticholinergic effects and, at higher
doses, can also slow GI transit, thereby improving symptoms of diarrhea in some patients .
• Coexisting psychological distress may also improve because of the effects on
dopaminergic and norepinephrine receptors. Patients should be started on a low dose
(e.g., 10-mg amitriptyline or 10 mg of desipramine) with gradual dose titration upward
to achieve therapeutic relief of symptoms while minimizing side effects .

April 12, 2022 NIDDK 60

 5. GABAergic agents
• Activation of the central BZD receptors affects GABA interaction with
central GABA-A receptors and may influence the ANS, dorsal vagal nuclei,
and the ENS.
• They reduce the release of several excitatory neurotransmitters, which are
involved in pain mechanisms.

April 12, 2022 NIDDK 61

 Chlordiazepoxide/Clidinium (Librax)
• Clidinium bromide is an anticholinergic/antispasmodic agent, and
chlordiazepoxide hydrochloride is a benzodiazepine/anxiolytic drug. The FDA
approved the use of this combination, clidinium/chlordiazepoxide, as an adjunct
therapy for the treatment of IBS.
• ADRs: sedative effect

April 12, 2022 NIDDK 62

 Chlordiazepoxide/Mebeverine (Coloverin A)

April 12, 2022 NIDDK 63

 For bloating/distension
• Wheat-fiber withdrawal, limitation of fat intake, avoiding carbonated
drinks, and excluding artificial sweeteners.
• Simethicone, an antisurfactant , Activated charcoal are frequently
recommended for gas-related complaints.
• Rifaximin, which is a nonabsorbable antibiotic, has been shown to reduce
gas production, flatus events, and abdominal distension, although,
paradoxically, no improvement in bloating was reported in this study.

April 12, 2022 NIDDK 64

 IBS-C PEG, 5HT-4 agonists, Racecadotril

Loperamide, Racecadotril, Rifaximin, 5HT-3

IBS-D
antagonists

IBS Fibers, Probiotics, FODMAP

Antispasmodics, Peppermint, TRIMEBUTIN, GBA

IBS-pain NEUROMODULATORS, GABAergic, 5HT-3
antagonists, 5HT-4 agonists

IBS-bloating Simethicone, activated charcol, rifaximin