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332 Chapter 13 Disorders of the lower gastrointestinal tract
Oral rehydration solutions
Since its introduction and development, oral rehydration
therapy has prevented countless deaths due to
dehydration in diarrhoeal illness, particularly those of
children in developing countries (estimated to be up to a
million children every year). Oral rehydration solutions
(ORSs) are the best treatment for mild to moderate
diarrhoea in most adults and children. As noted above,
the transport of glucose and Na+ by the co-transporter
SGLT-1 is not aected by diarrhoea-inducing microbes.
Dehydration can therefore be prevented/treated by
products containing glucose and electrolytes at
concentrations designed to maximize water absorption
across the intestinal wall (see Box 13.1). Numerous
formulations and brands of oral rehydration solution are
available, two of which are compared in Table 13.1. e
presence of potassium prevents hypokalaemia, and is
particularly important in elderly patients. In the
treatment of mild to moderate diarrhoea, the target
consumption for adults is 2 litres in the rst 24 hours.
Inchildren, 30–50 ml/kg should be consumed over a
3–4hour period.
Antidiarrhoeal drugs
Short courses of drugs that reduce gut motility can be
given in acute diarrhoea. eir eect is to allow more time
for water to be reabsorbed from the small intestine. Such
drugs should be avoided in severe gastroenteritis or
dysentery, and are not suitable for young children.
Opiate derivatives
e use of analgesic opiates, such as morphine, is
commonly associated with troublesome constipation as a
Table 13.1 Comparison of two brands of oral rehydration
solution
Constituent World Health
Glucose (mmol/l) 75 90
Sodium (mmol/l) 75 60
Potassium (mmol/l) 20 20
Chloride (mmol/l) 65 60
Osmolarity
(mOsm/l)
*Oral rehydration solutions used in Western countries tend to have reduced
sodium levels (50–60 mmol/l) as patients tend to lose less sodium.
Organization
ORS
240 240
Gastrolyte®
ORS(sachet)
*
side eect (see Chapter 20, Section 20.3.1). is action is
taken advantage of in the treatment of diarrhoea with the
opiate derivatives diphenoxylate and loperamide. ese
compounds are analogues of the opiate drug pethidine;
the structures of all three are compared in Figure 13.1.
ereceptors targeted by these agonists are principally
opiate receptors, found on neurons of the enteric nervous
system (both submucosal and myenteric plexuses; see
Introduction to Part 4). ese neuronal pathways control
secretions and motility in the gastrointestinal tract. e
activation of the -opiate receptors inhibits the release of
acetylcholine (ACh) at the enteric nerve terminals,
bringing about decreased secretion of electrolytes and
uid. Opiates also mediate an increase in tone of sphincter
smooth muscles and reduced peristalsis; these eects
combine to delay transit of the gut contents, facilitating
reabsorption of water from the small intestine. e
receptors are Gi/Go coupled. eir stimulation leads to
decreased cyclic AMP levels, and to activation of K+
channels; this results in membrane hyperpolarization,
and a consequent decrease in Ca
sensitive Ca
2 +
channels, reducing muscle contractility.
2 +
entry through voltage-
Loperamide is the drug of rst choice for the treatment of
travellers’ diarrhoea. It has a relatively selective action on
the gastrointestinal tract; it does not readily cross the
blood–brain barrier, and so has few CNS eects.
In contrast, diphenoxylate is able to cross the blood–brain
barrier to act on opiate receptors in the brain. ere is
therefore a risk for developing dependency associated
with this drug, particularly when it is used over a
prolonged period or at high dose. To deter abuse, it is
administered in combination with a subtherapeutic dose
of atropine (co-phenotrope); antimuscarinic eects (e.g.
dry mouth, blurred vision, etc.) are not seen when the
drug is used at the recommended dosage, becoming
apparent only when the drug is abused. (Atropine itself
also has a slowing eect on gastrointestinal motility, but
its widespread eects elsewhere in the body preclude its
use as an antidiarrhoeal agent.) Codeine is also
sometimes used to treat diarrhoea but, like
diphenoxylate, it has the potential to be misused.
Morphine, in combination with the adsorbent agent
kaolin, is sometimes prescribed for treatment of acute
diarrhoea; it is not usually recommended, though,
because of a lack of evidence of ecacy.
Loperamide and diphenoxylate have similar ecacy.
Loperamide has a longer half-life (9–14 hours) compared
13.3 Constipation 333
N
N
Diphenoxylate
O
O
N
O
N
N
O
Pethidine
O
Loperamide
Figure 13.1 Similarities in the structures of diphenoxylate,
loperamide, and pethidine.
with diphenoxylate (~2.5 hours). Both are well tolerated,
with the main side eects being constipation resulting
from overuse, abdominal cramps, and dizziness. As
detailed above, antimuscarinic eects can arise from use
of the diphenoxylate–atropine combination in
susceptible individuals.
Enkephalinase inhibitors
Racecadotril is a pro-drug of thiorphan, an enkephalinase
inhibitor that prevents the breakdown of the endogenous
opioids, enkephalins. is drug reduces the hypersecretion
of electrolytes and water into the small intestine during
bouts of diarrhoea, but does not aect motility. It is used in
the symptomatic relief of acute diarrhoea in adults, and in
children as an adjunct to oral rehydration therapy. Its most
common side eect is headache.
OH
Cl
Other treatments for diarrhoea
Adsorbent agents including kaolin, pectin, and activated
charcoal are occasionally used in the treatment of
persistent diarrhoea. ese agents are believed to act by
adsorbing bacterial toxins in the gut, or by coating the
intestinal mucosa. ere is, however, limited evidence of
their ecacy. Such agents may also adsorb other drugs
and so reduce their eectiveness. For these reasons,
adsorbents are rarely recommended.
Antimicrobials
Antibiotics are not usually used for acute diarrhoea because
of the risk of encouraging bacterial resistance. In severe or
persistent cases, or for patients with dysentery, an antibiotic
such as ciprooxacin may be recommended. Metronidazole
is the rst-choice antibiotic for amoebic dysentery.
13.3 Constipation
Delayed transit of the gut contents through the large
intestine can result in constipation. is common
condition aects all age groups, but is most often seen in
elderly patients. Most people do not seek medical
attention for constipation. As noted above, bowel habits
vary widely between individuals; a diagnosis of
334 Chapter 13 Disorders of the lower gastrointestinal tract
constipation is made with reference to a person’s normal
bowel habits. It is important for patients to understand
that not having a bowel movement every day does not
indicate constipation, nor, by itself, is it potentially
harmful. Where there is a reduced frequency of bowel
movements, compared with the patient’s normal pattern,
accompanied by diculty passing hard faeces,
constipation may be diagnosed.
Constipation can cause signicant abdominal discomfort,
headache, loss of appetite, feeling of nausea, and/or
vomiting. Chronic constipation can lead to faecal
impaction, and straining to pass hard faeces can result in
anal ssures and haemorrhoids (‘piles’—swollen blood
vessels in the anal canal that can lead to bleeding and
itching, and if thrombosed, can cause discomfort and pain).
By far the most common cause of constipation in Western
populations is lack of bre in the diet. e recommended
bre intake for an adult is 20–35 g per day; most people
consume far less. e lack of bre leads to small hard
faeces; the problem is often compounded by insucient
water intake.
Constipation can arise from a number of other causes,
including:
• pathologies aecting the colon, e.g. cancer of the colon,
megacolon (an abnormally dilated colon, often
accompanied by paralysis of the peristaltic activity of
the bowel)
• as a symptom of a disease, e.g. Parkinson’s disease,
depression, and stroke
• delaying the emptying of bowels for psychological or
pathological reasons, e.g. painful anal ssures
• as a side eect of a large number of medicines, notably
ferrous sulfate (for iron-deciency anaemia),
aluminium-salt-based antacids, opiate analgesics,
tricyclic antidepressants, antimuscarinics (e.g.
hyoscine, procyclidine), and many others
• pregnancy.
13.3.1 Treatment of constipation
In many cases of mild constipation changes to diet and
exercise regimes adequately manage symptoms, and
treatment with drugs is not necessary. Increasing dietary
bre and uid intake should be trialled for a month. Fibre
intake should be increased gradually, so as to reduce
problems of atulence, bloating, and distension of the gut
due to the increased activity of gut ora. High bre foods
include brown rice, wholemeal bread, and fruit and
vegetables with edible skins. Exercise is believed to
promote transit of ingested material through the gut, and
should also be encouraged.
Laxatives
Drug treatment for constipation involves laxatives. ese
can be grouped into several classes according to their
action; the comparative eectiveness of the various types
is unclear.
Faecal softeners (emollient laxatives)
ese are the most gentle laxatives available. Docusate
and poloxamer are surfactants which reduce the surface
tension around the faeces, allowing uid to penetrate
more easily. Both are also very weak stimulant laxatives
(see below). When taken orally, they have a very slow
onset of action (taking 3 or 4 days to work), and are
therefore generally only used prophylactically when
constipation is anticipated, for instance due to medication.
Rectal administration leads to a fast onset of action, but
should be avoided where the patient has haemorrhoids
oranal ssures. ey have virtually no side eects and
can be given safely to children; both are available in
liquidform.
Liquid paran has been used traditionally as a lubricant
to ease the passage of faeces. Its use is associated with a
number of potential risks, such as lipoid pneumonia
(following accidental inhalation of the fatty liquid), and
impairment of the absorption of fat-soluble vitamins. For
these reasons, combined with a lack of evidence of
ecacy, it is now seldom used.
Bulk-forming laxatives
Bulk-forming laxatives are polysaccharide polymers (i.e.
bre). ese agents remain undigested in the gut and
retain fluid, increasing faecal mass and improving
consistency. is larger volume then stimulates peristalsis,
promoting defecation. e bre also provides a substrate
for colonic bacteria which proliferate, further improving
faecal bulk and softness. Bulk-forming laxatives largely
come from natural sources, and include the husks of
seeds, including ispaghula and sterculia.
Bulk-forming laxatives are slow acting, normally taking
24–48 hours before an eect is seen. ey are of value only
if the diet is decient in bre. ese agents are very well
tolerated. e main side eects are the result of the
increased activity of colonic bacteria, giving rise to gases
13.3 Constipation 335
HO
which lead to bloating and atulence; these eects
generally improve after the rst few days of treatment.
Patients should be encouraged to drink plenty of uids,
toprevent obstruction of the digestive tract.
Osmotic laxatives
Osmotic laxatives are poorly absorbed solutes that create
an osmotic load in the intestinal lumen. is has the
eect of retaining water to maintain faecal bulk, which in
turn stimulates peristalsis, and leads to softer faeces.
ere are two main groups.
1. Saline osmotic agents include preparations of sodium
phosphate, magnesium sulfate (Epsom salts), and
magnesium hydroxide (milk of magnesia). ey can be
given orally and act within 2–5 hours. When a faster
onset is required (e.g. before surgery or examination),
these agents can be given as rectal preparations that
act within 30 minutes.
HO
HO
OH
H
H
2. e most widely used non-saline agents are lactulose
and polyethylene glycol (PEG, or macrogol).
Lactulose is a poorly absorbed semi-synthetic
disaccharide of fructose and galactose. Some of its
benecial action derives from metabolism by colonic
bacteria (Figure13.2), which convert lactulose to a
range of organic acids. ese lower the pH of the gut
lumen, and soften the stool. e acids also trap
ammonia from the blood in the lumen by converting
it from un-ionized ammonia (NH3) to cationic
ammonium (NH
+
), whichcannot pass back into the
4
blood. is property of lactulose is used in the
treatment of hepatic encephalopathy (brain
dysfunction arising from liver failure). In this situation,
the failing liver is unable to convert ammonia into
urea, and so plasma ammonia levels rise; there is,
however, limited evidence of the ecacy of lactulose
in treating this condition.
OH
O
HO
H
H
H
O
O
H
H
OH
Lactulose
OH
H
Colonic bacteria
Draws in water
O
C
OH
H
Formic acid
Soften stools
Figure 13.2 Action of lactulose.
Lactulose is a synthetic disaccharide that is unabsorbed from the intestines and acts as an
osmotic laxative, drawing water into the gut and retaining it there. It is metabolized by
bacteria in the colon to generate organic acids which also soften the stool. These acids
trap ammonia, converting it to ammonium ions which cannot then pass into the plasma.
O
OH
OH
H
HC
C
H
Acetic acidLactic acid
Traps NH
O
+
4
HO
336 Chapter 13 Disorders of the lower gastrointestinal tract
HO
HO
Polyethylene glycols, or macrogols, are inert polymers
of ethylene oxide with large molecular weights (e.g.
macrogol 3350; the number indicates the average
molecular weight in daltons). eir large size prevents
absorption from the gut lumen. Some preparations
contain electrolytes, such as sodium chloride and
potassium chloride, or additional saline osmotic
agents, such as sodium sulphate.
Both lactulose and macrogols can take up to 48 hours
to have an eect.
While these agents are generally well tolerated, they can
lead to uid and electrolyte disturbances, which can be
particularly problematic in the elderly. e risk of this is
greatest with the saline osmotic agents, and is
exacerbated if the patient fails to drink sucient uid.
Stimulant laxatives
ese agents are believed to act through direct
stimulation of myenteric plexus nerves to increase
peristalsis, and so decrease the transit time of the gut
contents. ey also increase secretion of electrolytes, and
therefore water, by the colonic mucosal cells. Agents in
use come from both natural (e.g. senna) and synthetic
(e.g. bisacodyl) origins.
Sennosides, or senna glycosides, are anthroquinones
from the leaves and seed pods of the owering plant
Senna alexandrina. Sennosides are natural pro-drugs,
which are degraded to the active compound, rhein
anthrone, through the action of bacteria in the lower
gastrointestinal tract. A number of alternative stimulant
laxatives are derived from other plants, including Aloe,
Cascara, and Frangula. Preparations combining senna
and the bulk-forming laxative ispaghula are available.
Bisacodyl can be taken orally, but is often given in
suppository form to stimulate the rectal mucosa and
rapidly induce defecation. Glycerol suppositories act in a
similar way.
Stimulant laxatives have a rapid onset of action, working
in 6–12 hours when given orally, and within minutes
when suppositories are used. Side eects include
cramping and abdominal pain, which are commonly
experienced. Overuse of any laxative may lead to an
atonic colon (‘lazy bowel’), where eective peristaltic
movement is reduced.
Treatment of opiate-induced constipation
e use of analgesic opiate drugs, such as morphine and
codeine, is associated with constipation through the
activation of -opiate receptors on enteric neurons, which
regulate secretion and motility in the gut (see Section 13.2).
is provides the rationale for the treatment of diarrhoea
with opiate derivatives. Where other laxatives have failed to
relieve opiate-induced constipation, it can be treated with
methylnaltrexone, an opiate receptor antagonist. Unlike
the parent compound naltrexone, methylnaltrexone has
poor lipid solubility, and is unable to cross the blood–brain
barrier; it therefore has only peripheral eects, promoting
bowel activity without interfering with the analgesic eects
of opiates. (Naltrexone is used to block the eects of
opiatesin opiate toxicity, and in the treatment of opiate
dependency; see Chapter 20.) e structures of
methylnaltrexone and naltrexone are shown in Figure 13.3.
O
H
O
Naltrexone
Figure 13.3 Comparison of the structures of naltrexone and methylnaltrexone.
N
H
OH
O
H
OH
O
Methylnaltrexone
+
N
H
13.4 Irritable bowel syndrome 337
Alvimopan also antagonizes peripheral -opiate
receptors. It does not cross the blood–brain barrier to
interfere with the central analgesic eects of opiates. e
use of this drug, though, is limited to hospitalized patients
at risk of obstruction of the ileum following bowel
resection surgery.
Methylnaltrexone is given as a subcutaneous injection
every second day, whereas alvimopan is given orally once
daily. Both are well tolerated, with the main side eects
being abdominal pain, diarrhoea, nausea, and atulence.
Both drugs are signicantly more expensive than the
older osmotic and stimulant laxatives, and their place in
therapy is yet to be established.
Other laxatives
Prucalopride is a selective agonist at serotonin 5-HT4
receptors. ese Gs-coupled receptors are located on
colonic smooth muscle cells, as well as presynaptically on
cholinergic neurons of the enteric nervous system;
activation promotes the release of ACh. Stimulation of
5-HT4 receptors by prucalopride increases mucosal
secretions, and promotes colonic motility and mass
movement, providing the propulsive force for defecation.
(See Chapter 12, Section 12.5.1, for more information on
the role of serotonin in the digestive tract.)
Prucalopride is generally given only when other laxatives
have not provided relief from constipation. It is taken
orally, and has good bioavailability. e drug’s half-life is
between 24 and 30 hours. It is largely excreted without
hepatic metabolism, and therefore has a low potential for
interactions. In the elderly, or those with reduced renal
function or severe hepatic impairment, the dose should
be reduced. e most commonly experienced side eects
of prucalopride are headache, nausea, abdominal pain,
and diarrhoea.
Lubiprostone is derived from prostaglandin E1. It
activates chloride channels on the apical membrane of
the enterocytes lining the gastrointestinal tract, increasing
chloride-rich secretions into the lumen. ese secretions
soften the faeces, and increase gut transit time. Lubiprostone
is given orally twice a day. It has poor oral bioavailability,
being rapidly metabolized in the stomach and duodenum,
meaning that it lacks drug interactions.
13.4 Irritable bowel syndrome
Irritable bowel syndrome (IBS) is a common functional
abnormality in gastrointestinal function, which aects
upto 20% of the population; its underlying cause is not
understood. A diagnosis of IBS is usually made when
other causes for presenting symptoms have been excluded.
Dysfunctional gut motility is a prominent feature of IBS,
and it is a chronic, often lifelong, condition characterized
by abdominal pain and discomfort, which may be
associated with defecation and/or with an alteration
tobowel habits. Onset is usually in young adulthood,
andcan follow an infection or a traumatic event. e
condition affects twice as many women as men. IBS
should not be confused with inammatory bowel disease
(IBD), where there is chronic inammation in the
gastrointestinal tract.
IBS patients often have a heightened sensitivity to pain
from internal organs (visceral hyperalgesia), and may
sense normal gut movements or the presence of gases in
the gut as painful.
ere is a close, albeit unexplained, correlation between
IBS and a number of psychiatric disorders including
anxiety and depression.
IBS is often classied according to the dominant
symptom, which then guides the choice of therapy:
diarrhoea dominant (IBS-D), constipation dominant
(IBS-C), mixed diarrhoea and constipation (IBS-M), and
alternating diarrhoea and constipation (IBS-A).
Frequently, though, patients switch between subtypes.
13.4.1 Role of serotonin in IBS
As discussed in Chapter 12, Section 12.5.1, serotonin
(5-HT) plays a pivotal role in regulating gastrointestinal
function. For example, 5-HT4 receptors augment
peristalsis and promote release of neurotransmitters,
including acetylcholine, which have a direct eect on gut
motility and secretions. Peripheral 5-HT4 receptors may
also be involved in normalizing pain sensitivity in the
colon. It is perhaps not surprising then that disturbance
of serotonin signalling is implicated in the symptoms of
IBS. Consistent with this, decreased expression of the
serotonin transporter (SERT) has been noted in intestinal
mucosal cells of IBS patients. By terminating the action of
serotonin, SERT regulates the extracellular availability of
serotonin, and hence its activity. A decrease in SERT
338 Chapter 13 Disorders of the lower gastrointestinal tract
expression will therefore augment the local eects of
serotonin and provides the rationale for the use of 5-HT
receptor antagonists in IBS. Decreased expression of
SERT seen in IBS patients may correspond to
polymorphism in the gene encoding SERT; certain
genotypes are associated with lower expression of the
functional SERT protein.
13.4.2 Management of IBS
Dietary modication, including reducing intake of fat,
caeine, alcohol, and spicy foods, is often suggested for
patients with IBS, although the direct evidence for its
ecacy is lacking. Cognitive behavioural therapy (CBT)
and hypnotherapy have also been assessed in clinical
trials, and can be helpful to some patients with and
without obvious psychological pathologies.
As the cause of IBS is not understood, pharmacological
treatment is aimed at dominant symptoms. is involves
the agents described above for treating diarrhoea and
constipation. In addition, there are a number of drugs
specically for this indication.
Treatment of constipation-dominant IBS (IBS-C)
Where laxative treatment has proved unsuccessful,
linaclotide may be considered. is drug, a complex
cyclic peptide of 14 amino acids, stimulates the guanylyl
cyclase-C receptor on the cell surface of intestinal
enterocytes. e resulting increase in intracellular
concentration of the second messenger cyclic guanosine
monophosphate (cyclic GMP) leads to enhanced
secretions from the cells into the intestinal lumen. is
eect is mediated by protein kinase G, which
phosphorylates and activates chloride channels,
increasing the secretion of chloride and bicarbonate ions;
the result is increased gastrointestinal motility and
decreased transit time. Linaclotide may possess
additional benecial analgesic properties.
Linaclotide has almost no oral bioavailability. It is
metabolized in the gut, rst to an active metabolite which
also stimulates cyclic GMP production, which is then
proteolytically degraded. It is taken orally. Side eects
include bloating, abdominal pain, diarrhoea, and
dizziness.
Treatment of diarrhoea-dominant IBS (IBS-D)
Opiate derivatives for the management of diarrhoea, as
described in Section 13.2.1, are used for exacerbations of
diarrhoea in IBS. Loperamide is the agent of choice, as it
has fewer side eects compared with diphenoxylate, and
reduced dependence potential compared with codeine.
In the treatment of IBS-D, loperamide is dosed regularly.
Alosetron is a 5-HT3 receptor antagonist which has been
used to treat IBS-D in women. rough inhibition of 5-HT3
receptors on intestinal smooth muscle, this drug slows
colonic transit time, enhancing fluid and sodium
absorption. It also reduces abdominal pain and discomfort,
although its mechanism of action is not understood.
e use of alosetron is very limited, largely because of its
association with severe constipation-related complications
and with ischaemic colitis (reduced blood supply to
thecolon).
Antispasmodics
A number of drugs that inhibit gastrointestinal smooth
muscle spasm can provide relief from abdominal pain in
IBS, and may reduce diarrhoea in IBS-D. Antimuscarinic
agents including hysoscine butylbromide, propantheline,
and dicycloverine (also called dicyclomine) antagonize
the cholinergic input to the gut, thereby decreasing
motility. ese drugs are charged quaternary ammonium
compounds; they do not readily cross the blood–brain
barrier and hence lack central eects. Dicycloverine is a
weak muscarinic antagonist, which is believed to have an
additional direct relaxant eect on gastrointestinal
smooth muscle.
Mebeverine and alverine are direct-acting smooth
muscle relaxants. Mebeverine inhibits sodium channels
on the smooth muscle cells. is leads to a decrease in
Ca2+ inux through voltage-gated calcium channels, and
therefore reduced muscle contraction. Alverine likewise
inhibits Ca2+ uptake, although its full mechanism of action
remains unclear. Side eects of either drug are few;
allergic reactions (rash, urticaria), dizziness, headache,
and nausea are possible.
Peppermint oil may provide relief from abdominal pain
in IBS; it is a major constituent in a number of over-thecounter remedies. e active antispasmodic ingredient is
-menthol which acts as a calcium channel antagonist to
relax smooth muscle. It has additional actions, including
anti-inammatory properties and 5-HT3 receptor
antagonism, which may also be benecial in IBS.
e main side eect of peppermint oil results from its
relaxant action on the lower oesophageal sphincter,
13.4 Irritable bowel syndrome 339
causing gastro-oesophageal reux disease (see Section
12.3.1); this can be avoided with gastro-resistant capsules,
delivering the peppermint oil to the small intestine for
sustained release.
Tricyclic antidepressants (TCAs), such as amitriptyline
and imipramine (see Chapter 19, Section 19.2.3), can be
used for the relief of abdominal pain or discomfort in
patients with IBS who have not responded to laxatives,
loperamide and antispasmodics. e mechanism behind
their analgesic eects is not fully clear, but is thought to
be separated from that underlying their antidepressant
action, occurring more rapidly and at much lower doses.
eories behind the analgesic action of TCAs in IBS
patients include reduced peripheral pain sensations, as
Key references and suggested reading
Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G,
Higgins CS, et al. Pharmacologic properties, metabolism, and
disposition of linaclotide, a novel therapeutic peptide
approved for the treatment of irritable bowel syndrome with
constipation and chronic idiopathic constipation.
J Pharmacol Exp er 2013; 344(1): 196–206.
Eluxadoline for irritable bowel syndrome (diarrhoea-
predominant)—rst line. Horizon Scanning Research &
Intelligence Centre. National Institute of Health Research.
ID: 6758. http://www.hsric.nihr.ac.uk/topics/eluxadolinefor-irritable-bowel-syndrome-diarrhoea-predominant-rstline/.
Ginzburg R, Ambizas EM. Clinical pharmacology of
lubiprostone, a chloride channel activator in defecation
disorders. Expert Opin Drug Metab Toxicol 2008; 4(8): 1091–7.
Kraft MD. Emerging pharmacologic options for treating
postoperative ileus. Am J Health-System Pharm 2007;
64:S13–20.
well as modication of central pain perceptions in the
anterior cingulate cortex, an area of the brain responsible
for processing pain and emotions. TCAs also have
antimuscarinic properties which may be helpful in IBS-D
through a slowing of gut motility.
Given the important role of serotonin in the gut, the
selective serotonin reuptake inhibitors (SSRI; see Chapter
19, Section 19.2.2) have also been investigated in the
treatment of the symptoms of IBS. Like TCAs, their
mechanism of action is uncertain, but appears unrelated
to their antidepressant action. SSRIs have been shown to
reduce gastrointestinal pain associated with IBS, but lack
antimuscarinic eects and hence do not reduce gut
motility.
Mawe GM, Coates MD, Moses PL. Intestinal serotonin
signalling in irritable bowel syndrome. Aliment Pharmacol
erapeut 2006; 23: 1067–76.
Rome III Diagnostic Criteria for Functional Gastrointestinal
Disorders. Rome Foundation. http://www.romecriteria.org/
edproducts/romeiii.cfm.
Schiller LRMD. Clinical pharmacology and use of laxatives and
lavage solutions. J Clin Gastroenterol 1999; 28: 11–18.
Sentongo TA. e use of oral rehydration solutions in children
and adults. Curr Gastroenterol Rep 2004; 6: 307–13.
Wong BS, Manabe N, Camilleri M. Role of prucalopride, a
serotonin (5-HT4) receptor agonist, for the treatment of
chronic constipation. Clin Exp Gastroenterol 2010; 3: 49–56.
SUMMARY OF DRUGS USED FOR DIARRHOEA AND CONSTIPATION
340 Chapter 13 Disorders of the lower gastrointestinal tract
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse
drug reactions
Opiate derivatives Diphenoxylate
Enkephalinase inhibitor Racecadotril Inhibit breakdown of enkephalins
Faecal softeners
(emollient laxatives)
Bulk-forming Psyllium (ispaghula)
Osmotic Saline-based:
Stimulants Sennosides
-opiate receptor
antagonist
Loperamide
Codeine
Docusate
Poloxymer
husks
Sterculia
Methylcellulose
Bran
e.g. Magnesium
sulfate
Sodium phosphate
Non-saline:
e.g. Lactulose
Polyethylene glycol
Cascara
Phenolphthalein
Bisacodyl
Castor oil
Methylnaltrexone
Alvimopan
-opiate receptor agonists
Reduce intestinal secretions and motility
to favour reabsorption of fluids and
electrolytes
(endogenous opioids)
Anti-secretory action
Detergent action allows penetration of
water
Remain undigested in gut, retaining
water and increasing faecal mass which
stimulates peristalsis
Increase osmotic load in gut lumen,
retaining water in faeces and stimulating
peristalsis
Act on myenteric plexus to exert direct
effect on the intestinal mucosa,
increasing peristalsis
Stimulate secretion of electrolytes and
water by colonic mucosal cells into the
gut lumen
Antagonist at -opiate receptor
Acute diarrhoea
Acute diarrhoea Used as an adjunct to oral
Constipation 3–4 days for effect, so best used
Constipation Requires 24–48 hours to take effect
Constipation Rectal administration of saline
Constipation Effect within 4–6 h following oral
Opiate-induced constipation Cannot penetrate blood–brain barrier,
Not recommended for children <12
years
Loperamide does not cross
blood–brain barrier, fewer central side
effects
Diphenoxylate combined with
subtherapeutic atropine
(co-phenotrope) to deter abuse
rehydration in children
prophylactically
Take with plenty of water to avoid
intestinal obstruction
laxatives gives fast effect (within
30 min)—useful for bowel evacuation
before examination or surgery
Take with plenty of water
administration, and within minutes
following rectal administration
so only exerts peripheral effect in gut,
and does not interfere with analgesic
effect of opiates
Dizziness Flatulence
Headache
Constipation
Nausea
Antimuscarinic effects
(diphenoxylate/atropine
combination)
Nausea
Vomiting
Drowsiness
Respiratory depression
Headache
Rash
Virtually none!
Bloating
Flatulence
Abdominal discomfort
Flatulence
Nausea
Vomiting
Fluid and electrolyte
disturbances
Cramps
Abdominal pain
‘Lazy bowel’ (lacking
peristaltic movement due
to overstimulation)
Abdominal pain
Diarrhoea
Nausea
Flatulence
13.4 Irritable bowel syndrome 341
Other laxatives Prucalopride Selective 5-HT4 agonist Chronic constipation Evidence to date based largely on
Lubiprostone Activates chloride channels on the apical
membrane of colonic enterocytes
Chronic constipation Third-line use where other laxatives
treatment of women
have failed
Abdominal pain
Nausea
Diarrhoea
Abdominal pain
Diarrhoea
Dizziness
Dyspepsia
SUMMARY OF DRUGS USED FOR IRRITABLE BOWEL SYNDROME
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse
Direct guanylyl
cyclase-C receptor
agonist
Antispasmodics Mebeverine
Tricyclic
antidepressants
Selective serotonin
reuptake inhibitors
Linaclotide Increases cyclic GMP levels in
Alverine
Antimuscarinics:
Hyoscine
butylbromide
Dicycloverine
Propantheline
Peppermint oil Direct-acting smooth muscle relaxant
Amitriptyline
Imipramine
Citalopram
Paroxetine
enterocytes, stimulating chloride and
bicarbonate secretions, increasing gut
motility
Direct relaxant action on intestinal
smooth muscle
Antagonize ACh-mediated gut motility
and secretions
Reduces GI motility and spasm
Mechanism unclear
May reduce peripheral and central pain
perception
IBS-C May also have analgesic effects Bloating
Abdominal pain associated
with IBS
Abdominal pain associated
with IBS
Commonly used
May also reduce diarrhoea in IBS-D
Dicycloverine has additional direct
relaxant action on gut smooth muscle
Given as enteric-coated preparation
to deliver peppermint oil to small
intestine
Effect independent of antidepressant
action
SSRIs only considered for patients
who do not respond to TCAs
drug reactions
Abdominal pain
Diarrhoea
Dizziness
Allergic reactions
Rash Dizziness
Headache
Constipation
Blurred vision
Dry mouth
Facial flushing
Allergic reactions
Bradycardia
Headache
Heartburn
See Chapter 19
See Chapter 19