Stipsi: terapia medica
(su basi razionali o empiriche?)
Corrado Blandizzi
Divisione di Farmacologia e Chemioterapia
Dipartimento di Medicina Clinica e Sperimentale
Università di Pisa
XV CONGRESSO NAZIONALE GISMAD
Firenze, 19 aprile 2013
Constipation is more than just infrequent passage
of stool
P
a
ti
e
n
t
s
[
%
]
Sandler RS et al.,
., Dig Dis Sci 32, 841, 1987
Chronic idiopathic constipation: pathophysiological bases
SLOW TRANSIT
14%
8%
26%
OUTLET
OBSTRUCTION
52%
NORMAL TRANSIT
Lembo A & Camilleri M, New Engl J Med, 349, 1960,
2003
Evaluation of the clinical efficacy of
prokinetics: a challenging issue
A problem with developing
prokinetic drugs is represented
by the poor correlation between
symptoms and altered motility
patterns, which may lead to
failure of not appropriately
designed clinical trials
Drugs for the management of chronic constipation
FIRST LINE LAXATIVES
Macrogol
Osmotic laxation
Lactulose
Osmotic laxation
SECOND LINE LAXATIVES
Bisacodyl
Stimulation of motility-secretion-absorption
Sodium picosulphate
Stimulation of motility-secretion-absorption
PROKINETICS WITH PREDOMINANT ACTION ON INTESTINAL MOTILITY
Prucalopride
Stimulation of 5HT4 receptors
COLONIC SECRETAGOGUES WITH INDIRECT MOTOR ACTIVITY
Linaclotide
Stimulation of type C guanylate cyclase
Lubiprostone
Stimulation of type 2 chloride channel
FIRST LINE LAXATIVES
macrogol
lactulose
Macrogol: pharmacodynamics
!
!
!
!
Soluble, non absorbable, non metabolized, electrically
neutral compound
Formation of hydrogen bonds with water molecules in
the gut lumen
Water retention in the bowel lumen: high osmotic
pressure opposes bound water
Some formulations include electrolytes to ensure
negligible net absorption/elimination of sodium,
potassium and bicarbonate
Macrogol increases stool weight and the proportion of
dilution water in stool, without marked variations of
intestinal transit
Chaussade S,, Ital J Gastroenterol Hepatol 31 ((Suppl.. 3), S242,
242, 1999
Macrogol is more effective than lactulose in
accelerating colonic transit in healthy volunteers
Comparative tolerability of low dose macrogol-electrolyte solution
and lactulose in the treatment of constipation
70
Patients with a median daily score >1 [%]
PEG
60
Lactulose
50
40
*
30
*
*
20
*
10
0
Liquid stools
Bloating
Abdominal pain
Attar A et al.,
., Gut 44, 226, 1999
Rambling
Flatus
SECOND LINE LAXATIVES
bisacodyl
sodium picosulfate
Bisacodyl: The first randomozed controlled trial after almost
60 years of use
Effects of bisacodyl on ascending colon emptying and overall
colonic transit in healthy volunteers
Bisacodyl accelerated transit in the ascending colon, but
had no effect on the overall colonic transit
Manabe N et al.,
., Aliment Pharmacol Ther 20, 930, 2009
High-amplitude peristaltic contractions after intracolonic
infusion of bisacodyl in a healthy volunteer
De Schryver et al.,
., Dig Dis Sci 48, 1206, 2003
Bisacodyl stimulated the occurrence of highamplitude propagated contractions in all
patients evaluated in this study
PROKINETICS WITH A PREDOMINANT
ACTION ON INTESTINAL MOTILITY
prucalopride
Prucalopride: pharmacodynamics
Selective
stimulation of 55HT44 receptors on
smooth muscle and
intrinsic neurons
Colon
Triggering of
peristaltic reflex
and colonic
mass movement
Significant
acceleration of
overall colonic transit
and proximal colonic
emptying
Rectum
Grider et al.,
., Gastroenterology 115, 370,
1998
Bouras et al.,
., Gut 44, 682,1999
Prins et al.,
., Br J Pharmacol 131, 927, 2000
Briejer et al.,
., Eur J Pharmacol 423, 71, 2001
Gastrointestinal effects of prucalopride in healthy
volunteers
!
No effect on gastric emptying
!
No effect on small bowel transit
!
Acceleration of ascending colonic
emptying
!
Acceleration of overall colonic transit
!
No effect on anorectal sensory-motor
functions
Bouras EP et al.,
., Gut 44, 682, 1999
Poen AC et al.,
., Aliment Pharmacol Ther 13, 1493, 1999
Gastrointestinal effects of prucalopride in patients with
chronic constipation
!
!
!
!
!
!
Acceleration of gastric emptying
Acceleration of small bowel transit
Acceleration of oro-cecal transit
Acceleration of ascending colonic emptying
Acceleration of overall colonic transit
Effect on anorectal sensory-motor functions
(conflicting finding!)
Bouras EP et al.,
., Gastroenterology 120, 354, 2001
Emmanuel AV et al.,
., Aliment Pharmacol Ther 16, 1347, 2002
Sloots CEJ et al.,
., Aliment Pharmacol Ther 16,759, 2002
Prucalopride accelerates colonic transit in patients with
constipation without rectal evacuation disorders
Placebo
GC4 =
1.0
GC24 =
2.1
GC4 =
1.5
GC24 =
4.1
Prucalopride
4 mg os
Bouras EP et al., Gastroenterology 120, 354, 2001
PROKINETICS WITH A PREDOMINANT
ACTION ON INTESTINAL SECRETION
linaclotide
lubiprostone
Relationship between water and ion movements and
transit in the intestine
Norma
l
Physiological balance
Net fluid accumulation
(Diarrhea)
Laxative
s
Decrease of Na+,Cl- and H20
absorption
Opioid
s
Net fluid absorption
(Constipation)
Courtesy of Prof. Carmelo Scarpignato (Parma, Italy)
Linaclotide: pharmacodynamics
GUANYLINE
UROGUANYLINE
SSSS
ENTEROTOXINS
TYPE C GUANYLATE CYCLASE
Luminal surface of the vintestinal epithelium
LINACLOTIDE
CYCLIC GUANOSINEvMONOPHOSPHATE
ACTIVATION OF CYSTIC FIBROSIS TRANSMEMBRANE
CONDUCTANCE REGULATOR
SECRETION OF CHLORIDE AND BICARBONATE
INTO THE INTESTINAL LUMEN
ACCUMULATION OF FLUIDS IN THE INTESTINAL
LUMEN AND ACCELERATION OF INTESTINAL
TRANSIT
Carter NJ & Scott LJ, Drugs 69, 1229, 2009
Lubiprostone: pharmacodynamics
LUBIPROSTONE
ACTIVATION OF TYPE 2 CHLORIDE CHANNEL
SECRETION OF CHLORIDE AND BICARBONATE
INTO THE INTESTINAL LUMEN
ACCUMULATION OF FLUIDS IN THE INTESTINAL
LUMEN AND ACCELERATION OF INTESTINAL
TRANSIT
Andresen V et al., Gastroenterology 133, 761, 2007
Acceleration of large bowel transit by colonic segretagogues,
lubiprostone or linaclotide, in humans
5
GC 24
GC 48
GC 48
4
4
Baselin
e
PostTx
3
3
2
2
1
1
0
0
Placeb Lu
o
b
Placeb Lu
o
b
Placeb
o
Linaclotid Linaclotid
e
e
100 g
1000 g
Camilleri M et al., Am J Physiol Gastrointest Liver Physiol 290, G942, 2006
Andresen V et al., Gastroenterology 133, 761, 2007
Overall…
…knowledge on the pathophysiology and pharmacology of
constipation needs to be expanded, since:
!
Most of current drugs are targeted mainly on the
stimulation of propulsive colonic motility
!
Current drugs lack effects on anorectal sensorymotor functions
!
Healthy volunteers may not be suitable for
predicting the gastrointestinal effects of drugs in
patients with chronic functional constipation
… and the scenario appears to be even more complicated
and confusing if we look at studies showing that…
2013
... Macrogol was as effective and generally
better tolerated than prucalopride, when
administered
to
patients
with
chronic
constipation in whom laxatives had previously
failed to provide adequate relief!!