This document discusses chronic constipation and provides information about linaclotide. It notes that approximately 28% of the global population suffers from chronic constipation. Linaclotide is presented as an effective treatment that works by activating guanylate cyclase-C receptors, increasing intestinal fluid secretion and reducing activation of pain neurons. Clinical trials showed that linaclotide significantly improved constipation symptoms, abdominal pain, and bloating compared to placebo. Linaclotide is recommended by guidelines as a novel and effective therapy for both constipation and IBS-C due to its ability to treat the full spectrum of symptoms with one drug and favorable side effect profile.
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Esomeprazole works by binding irreversibly to the H+/K+ ATPase in the proton pump.
Inhibition dramatically decrease the secretion of hydrochloric acid into the stomach
Peptic ulcers are open sores that develop on the inside lining of esophagus, stomach and/or the upper portion of small intestine. Peptic ulcer occur mainly due to imbalance between aggressive and defensive factors in the stomach.
This is the latest update on irritable bowel syndrome and gastroesophageal reflux by Associate Professor Reuben Wong from gutCARE. This is presented during the latest GP symposium
Esomeprazole works by binding irreversibly to the H+/K+ ATPase in the proton pump.
Inhibition dramatically decrease the secretion of hydrochloric acid into the stomach
Peptic ulcers are open sores that develop on the inside lining of esophagus, stomach and/or the upper portion of small intestine. Peptic ulcer occur mainly due to imbalance between aggressive and defensive factors in the stomach.
This is the latest update on irritable bowel syndrome and gastroesophageal reflux by Associate Professor Reuben Wong from gutCARE. This is presented during the latest GP symposium
Constipation is the symptom and is associated with primary & Secondary causes. Constipation is defined as occurrence of >3 episodes of bowel movements. the Rome III criteria defines the objective classification and bristol stool chart helps in assessing the type of stools passed. Management of constipation deals with early assess, treating the cause, adjuvant management, Pharmacological Management (laxatives, suppositories & enemas) and following constipation prevention bundle.
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an over view of IBS in the general population, talks about aetiology pathology clinical features and diagnosis with special reference to the ROME criteria and the differences between ROME II and III.
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation. Severe constipation includes obstipation (failure to pass stools or gas) and fecal impaction, which can progress to bowel obstruction and become life-threatening.
Constipation is a symptom with many causes. These causes are of two types: obstructed defecation and colonic slow transit (or hypo mobility). About 50 percent of people evaluated for constipation at tertiary referral hospitals have obstructed defecation. This type of constipation has mechanical and functional causes. Causes of colonic slow transit constipation include diet, hormonal disorders such as hypothyroidism, side effects of medications, and rarely heavy metal toxicity. Because constipation is a symptom, not a disease, effective treatment of constipation may require first determining the cause. Treatments include changes in dietary habits, laxatives, enemas, biofeedback, and in particular situations surgery may be required.
Constipation is common; in the general population rates of constipation varies from 2–30 percent. In elderly people living in care homes the rate of constipation is 50–75 percent.[4] In the United States expenditures on medications for constipation are greater than US$250 million per year.
The definition of constipation includes the following:
infrequent bowel movements (typically three times or fewer per week)
difficulty during defecation (straining during more than 25% of bowel movements or a subjective sensation of hard stools; straining in this context is a strong effort to push out stool often by holding one's breath and by pushing the respective muscles in the abdominal area hard), or
the sensation of incomplete bowel evacuation.
The Rome III criteria are widely used to diagnose chronic constipation, and are helpful in separating cases of chronic functional constipation from less-serious instances.
Another definition states that less than three bowel movements per week and straining on more than 75% of occasions represents constipation in clinical surveys.
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2. of global population suffers from
Chronic Constipation
28%
In Bangladesh, the prevalence is
11.8%
2-3 times more common
in women
Epidemiology
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114
3. 40%
35%
23%
2%
IBS-D
IBS-C
IBS-M
IBS-U
The Burden of CIC
Almost 85% of physician visit
for constipation results in a
prescription for laxative
Adults over the age of 35
years has a higher
prevalence(84%)
35% of IBS patients are
suffering from IBS-C subtype
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114
4. Definition of constipation
According to the Rome IV criteria for constipation-
A patient must have experienced at least two of the following
criteria over the preceding 3 months:
Fewer than three spontaneous bowel movements per week
Straining
Lumpy or hard stools
Sensation of anorectal obstruction or blockage
Sensation of incomplete defecation
Manual maneuvering required to defecate
For at least 25% of
defecation attempts
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114
6. Irritable bowel syndrome (IBS)
Irritable bowel syndrome (IBS) is a chronic, often debilitating, and highly
prevalent disorder of gut-brain interaction.
Rome IV diagnostic criteria for irritable bowel syndrome-
• Recurrent abdominal pain on average at least 1 day/week in the last 3
months, associated with 2 or more of the following criteria-
• Related to defecation.
• Associated with a change in the frequency of stool.
• Associated with a change in the form (appearance) of stool.
These criteria should be fulfilled for the last 3 months with symptoms onset at
least 6 months before diagnosis.
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114
7. Type I-II
is constipation predominant
stool.
But , for Asian countries Type III
is also considered constipation
defining stool.
8. Difference between CIC & IBS-C
Traits CIC IBS-C
Cause Idiopathic or
secondary causes
Altered GI motility,
GI hypersensitivity,
Psychosocial factors.
Primary symptom Constipation Abdominal pain
Secondary symptom Abdominal pain,
bloating, itching,
bleeding
Constipation,
bloating
9. Overlapping of CIC And IBS-C
• According to Rome IV definition, IBS-C patients are more likely to
predominantly have abdominal pain in comparison with CIC patients.
• But in (real-world) clinical practice was found that approximately 90% of
patients with IBS-C also met criteria for CC and 44% of the CC patients
also met criteria for IBS-C.
• In approximately 1/3rd of patients, symptoms shift over time between FC
and IBS-C.
• So, sometimes it is difficult to distinguish between IBS-C & CIC and
determine the appropriate therapy.
11. History
Taking
Alarm
features
ROME IV criteria
Stool consistency(
Bristol Stool form scale)
H/O Laxative use
Secondary causes
Change in stool caliber
Heme-positive stool
Iron-deficiency anemia
Obstructive symptoms
Patients > 50 years with no
previous colon cancer
screening
Recent onset of constipation
Rectal bleeding
Rectal prolapse
Weight loss
12. Physical
examinations
Investigations
Gastrointestinal mass &
lymphadenopathy
Anorectal inspection by
DRE
- Fecal impaction
- Rectal mass
- Stricture
- Prolapse
- Rectocele
Blood tests
Colonoscopy & sigmoidoscopy
Anorectal Manometry
Balloon expulsion test
Colonic transit study
Defecography
13. Treatment options for Constipation
Bulk forming
laxative
Osmotic
Laxative
Stimulant
Laxative
Lubricants/Stool
softeners
Increasing the
"bulk" or weight of
stool, which in
turn stimulates
your bowel.
Osmotic laxatives
draw water from
the rest of the
body into bowel to
soften stool and
make it easier to
pass.
stimulate the gut
muscles helping
the stool to pass.
Works by reducing
surface tension
between lipid and
water
interface.(check the
language)
Ex- Psyllium Ex- Lactulose,
polyethylene glycol
Ex- Bisacodyl ,
senna ,
sodium picosulfate
Docusate
Laxatives
14. CLC-2 agonist GC-C agonist 5HT4-agonist
Activation of CLC-2
channel increases
intestinal secretion and
peristalsis.
Activation of GC-C
receptors, increases
intestinal fluid
secretion & peristalsis,
reduces activation
of
visceral pain
sensitive neurons.
Increases secretion of
fluid in intestines and
speed up the rate at
which food passes
through the colon.
Lubiprostone Linaclotide Prucalopride
Non- Laxatives/
15. Challenges in treatment of Constipation
Association of multiple
pathophysiology
makes the treatment
approach difficult.
Requires Multiple
drugs to alleviate
individual symptom.
Altered
GUT
Motility
Altered
GUT
Sensitivity
Altered brain
gut axis
Multiple
symptoms
Constipation
Abdominal pain
Bloating
Distension
Repeated & long-term
use of Laxatives
causes adverse effects
& makes the intestine
insensitive
Lack of patient
compliances &
hampers the
quality of life.
16. Linaclotide
A novel therapy for constipation
A single intervention to treat-
Constipation
Abdominal pain
Bloating/Distension
Reduces disease burden,
Improves quality of life
17. Linaclotide binds to guanylate cyclase-C (GC-C) act
locally on the luminal surface of the intestinal
epithelium(Luminally acting agent)
Both intracellular and extracellular concentrations
of cyclic guanosine monophosphate (cGMP) rises
Elevation in intracellular cGMP stimulates secretion
of chloride and bicarbonate into the intestinal
lumen, resulting in increased intestinal fluid and
accelerated transit.
Linaclotide has been also shown to reduces
activation of visceral nociceptive neurons and
reduce intestinal pain.
Mechanism
of
action
18. Linaclotide was also evaluated in 3 CIC clinical trials of more
than 2400 patients.
Results: Patients had increased no of CSBMs, greater improvements
in stool consistency & straining over the treatment period.
Linaclotide Placebo
Therapeutic efficacy Trials of Linaclotide in CIC
19. Therapeutic efficacy Trials of Linaclotide in
IBS-C
Linaclotide was evaluated in 2 IBS-C clinical trials of more than 1600 patients. Trials evaluated
abdominal pain responders, CSBM(Complete spontaneous bowel movements) responders, and
combined responders.
Study population
Linaclotide
group
Placebo
Group
Trial 1 405 395
Trial 2 401 403
21. Abdominal pain responders
0
5
10
15
20
25
30
35
40
45
Trial 1 Trial 2
6 out of 12 weeks
Linaclotide Placebo
34.3%
38.9%
27.1%
19.6%
0
10
20
30
40
50
60
Trial 1 Trial 2
9 out of 12 weeks
Linaclotide Placebo
50.1%
48.9%
37.9%
34.5%
Patients had significant improvement in both abdominal pain and frequency of
CSBMs.
Reference:
1.LINZESS (linaclotide) [prescribing information]. Madison, NJ: AbbVie Inc.; 2018.
2.Data on file. Forest Laboratories, LLC.
22. Combined responders
0
2
4
6
8
10
12
14
Trial 1 Trial 2
6 out of 12 weeks
Linaclotide Placebo
12.1%
12.7%
5.1%
3%
0
5
10
15
20
25
30
35
40
Trial 1 Trial 2
9 out of 12 weeks
Linaclotide Placebo
33.6%
33.7%
21%
13.9%
Significant responder rates in abdominal pain and in CSBMs vs placebo.
Reference:
1.LINZESS (linaclotide) [prescribing information]. Madison, NJ: AbbVie Inc.; 2018.
2.Data on file. Forest Laboratories, LLC.
23. Mean abdominal pain score & percent reduction
0
1
2
3
4
5
6
Trial 1 Trial 2
Baseline
Linaclotide Placebo
5.7%
5.6%
3.2%
3.9%
0
1
2
3
4
5
6
Trial 1 Trial 2
At week 12
Linaclotide Placebo
5.6
%
5.5%
3%
4%
Relief from abdominal pain was maintained in Linaclotide group over the
treatment period.
-44% -30% -46% -27%
24. Improvement in overall abdominal symptoms was observed
at Week 1 and continued to improve through 12 weeks
34% of patients in the
Linaclotide arm experienced
a clinically meaningful
reduction in overall
abdominal symptoms vs
18.5% in the placebo arm.
25. Comparison between laxatives & Linaclotide
in the treatment of Constipation
Traits Laxatives Linaclotide
Benefit Relieves only constipation. Relieves the entire symptoms complex
as constipation, abdominal pain,
bloating etc.
Role in IBS-C Low efficacy, so not
recommended except for
bulk forming agents( soluble
fibers)
High efficacy, so strongly
recommended by all the renowned
guidelines.
Effect on visceral
hypersensitivity
Poor, so no effect on pain
relief.
Reduce visceral hypersensitivity, thus
relieves abdominal pain and bloating.
Adverse effects Long term uses result in
dehydration, electrolyte
imbalance, persistent
bloating & abdominal
cramps, colonic insensitivity.
Insignificant systemic absorption (
<1%). So, less chances of adverse
effects. Occasional diarrhea is the
commonest adverse effects.
26. Traits Linaclotide Lubiprostone
Therapeutic group Guanylate cyclase
activators
Chloride channel
activators
Mechanism of action Activation of GC-C
receptors, increases
intestinal fluid secretion
& peristalsis, reduces
activation of
visceral nociceptive
neurons.
Activation of CLC-2
channel increases
intestinal secretion and
peristalsis.
Therapeutic response Quick & sustained Delayed & improves
over time.
Dosing Once daily Twice daily
Most common AE Diarrhea(discontinuation
rate is very low)
Nausea(dose
dependent)
Quality of evidence
In favor
High Moderate
Recommendation quality Strongly recommended
by all the guidelines.
Recommended/
suggested
Therapeutic
benefits of Linaclotide
over Lubiprostone
27. Adverse Effects
Linaclotide may cause diarrhea as its most frequent side effect, but has a very low risk of
major systemic adverse responses due to its local action in the intestinal lumen and low
bioavailability(less than 1%).
28. Most of the renowned guidelines has recommended Linaclotide as a novel
& effective therapy for CIC and IBS-C with quotation of strong quality of
evidences .
29. In clinical practice, Chronic Idiopathic Constipation(CIC) and IBS- C
symptoms may overlap and require individual drugs for individual
symptom.
But in both cases the entire symptom complex can be treated by a single
solution.
It has high efficacy and excellent tolerability.
The ultimate therapy for constipation
Linaclotide
CONCLUSION