Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5353_Библиотеки_им_академика_М_И_Перельмана.pdf
312 Chapter 12 Upper gastrointestinal tract disorders
Lifestyle changes such as weight loss and stopping
smoking may improve symptoms in some people. A
number of drugs that mediate smooth muscle relaxation,
such as calcium channel blockers and nitrates (see
Chapter 5), can reduce the contractile state (tone) of the
lower oesophageal sphincter, and therefore potentially
exacerbate gastro-oesophageal reux.
12.3.2 Peptic ulcer disease
Peptic ulcers are lesions in the mucosal lining of the stomach
or duodenum caused by the digestive actions of the gastric
juices. ey range from small supercial erosions causing
few symptoms, to large ulcers which perforate the stomach
or duodenal wall, leading to bleeding. ere are two main
causes of peptic ulcers: Helicobacter pylori infection and the
use of non-steroidal anti-inammatory drugs.
Helicobacter pylori infection and ulcers
It was not until the 1990s that the medical establishment
nally accepted the ndings of two Australian doctors,
Barry Marshall and Robin Warren, which identied the
bacterium H. pylori as the causative agent in most peptic
ulcers. Until this time, the condition had been largely
attributed to increased acid production arising from
stress. It is now known that the vast majority of duodenal
and gastric ulcers are due to infections by this microorganism (estimated to be as high as 95% and 85% of
cases, respectively). Helicobacter pylori eradication has
therefore become the focus of the prevention and
treatment of peptic ulcers.
Pictured in Figure 12.4, H. pylori is a curved rod-shaped
Gram-negative bacterium that requires oxygen, but at lower
than atmospheric levels (a micro-aerophile). A number of
strains exist which have varying virulence. Colonization of
the stomach by H. pylori is common, but only around
5–10% of those infected go on to develop peptic ulcers.
H. pylori employs several strategies that enable its survival
in the harsh acidic environment of the stomach and
duodenum.
• A number of tail-like appendages enable it to burrow
through the thick alkaline mucus layer that protects the
stomach mucosa
• It preferentially inhabits the antrum area of the
stomach, where acid-secreting parietal cells are sparse,
if not absent, and therefore the acidity is not as great.
(Gastric juices from the upper areas of the stomach do,
however, still reach this area.)
Figure 12.4 Helicobacter pylori
Image courtesy of AJC ajcann.wordpress.com. This file is
licensed under the Creative Commons Attribution-ShareAlike
2.0 Generic license.
• It produces the enzyme urease which converts urea,
generated in the digestion of proteins, to ammonia
(NH3). is buers the acidity in the area immediately
surrounding the bacterium, through the reaction:
NH3 + H+ ⇄ NH
+
.
4
H. pylori infection damages the gastric lining and
contributes to inammation through the secretion of
toxins at the site of colonization. It disrupts the tight
junctions between epithelial cells, and so weakens the
mucosal barrier. is allows the inltration of acid and
pepsin, which damages the mucosal and submucosal
layers of the stomach wall. H. pylori infection also aects
secretions from the gastric mucosa. e number of
gastrin-secreting G-cells is increased, while somatostatinsecreting D-cells decrease in number. e overall eect is
an increase in acid secretion by parietal cells (see Box 12.1).
H. pylori infection can be detected through a number of
non-invasive tests, or by endoscopy with biopsy. e
preferred test is usually the [13C] urea breath test, in which
radiolabelled urea is administered to the patient. Where
infection is present, the urease activity of H. pylori
generates radiolabelled CO2 which is excreted in the
patient’s breath. An alternative test detects H. pylori
antigen in the patient’s faeces. More invasive tests using
gastroscopy are indicated where there is suspicion of a
more sinister pathology, such as gastric cancer.
12.4 Treatment of gastro-oesophageal reflux disease and peptic ulcers 313
Non-steroidal anti-inflammatory drugs and ulcers
Aspirin, and other NSAIDs, have been implicated in the
production of peptic ulcers for decades. ey contribute
to mucosal damage primarily by decreasing the
production of protective prostaglandins in the
gastrointestinal mucosa, although local toxic eects may
also be involved (see below). e NSAIDs inhibit
prostaglandin (and thromboxane) synthesis by inhibiting
cyclo-oxygenase enzyme (COX; see Chapter 9, Sections
9.1.1 and 9.3.1, for more details). COX exists in two main
isoforms: COX-1 and COX-2. COX-1 is responsible for the
production of protective prostaglandins, principally PGE2
and PGI2, which are local regulators of mucosal cell
function. As noted in Section 12.2.3, prostaglandins
stimulate the secretion of mucus and neutralizing
bicarbonate, both of which protect the mucosal layer
from the erosive action of the HCl. ey also inhibit the
release of histamine by enterochroman-like (ECL) cells.
Non-specic NSAIDs (e.g. aspirin, ibuprofen, diclofenac)
inhibit both COX-1 and COX-2. e gastrointestinal
toxicity associated with these drugs is the result of the
inhibition of COX-1; the consequent reduction in
protective prostaglandins can lead to gastric bleeding
and ulcers. COX-2-selective NSAIDs have been
developed (e.g. celecoxib and parecoxib) which are
largely free of gastrointestinal eects; they do, however,
present a risk of cardiovascular complications (see
Chapter 9, Section 9.3.1).
In addition to their eects on COX enzymes, NSAIDs also
have local irritant eects on the mucosa. Most are weak
organic acids and are non-ionized in the acidic
environment of the stomach. is allows the molecules to
cross the lipid membranes of the gastric mucosal cells.
Once inside, the neutral surroundings favour reionization, temporarily trapping the drug inside the
epithelial cells. Damage may result through uncoupling of
oxidative phosphorylation in the mitochondria, depleting
the cells of ATP and disrupting cell function. Direct
epithelial injury is, however, not believed to play a large
part in the pathogenesis of NSAID-mediated
gastrointestinal toxicity; this is mainly ascribed to
prostaglandin deciency following COX-1 inhibition.
12.4 Treatment of gastro-oesophageal reflux disease and
peptic ulcers
e principal approach to treating gastro-oesophageal
reux disease is to reduce stomach acidity either directly
through neutralization, or by inhibiting acid secretion by
parietal cells. e aim is to increase the stomach’s pH to
above 4, in order to prevent further damage, and to allow
the aected area to heal. Drugs which increase intestinal
motility to speed transit of the gut contents can also be
useful. Such prokinetic agents are benecial in nausea
and vomiting, and are considered later in this chapter.
Reducing acid secretion is also central to treating peptic
ulcers, although removal of the causative agent, most often
infection with H. pylori, is of paramount importance. With
ulcers arising from use of NSAIDs, a number of agents that
protect the mucosal lining are also used (see Section
12.4.2); healing is impaired if NSAIDs are not discontinued.
12.4.1 Drugs that reduce gastric acidity
Antacids
e simplest way of treating the symptoms of excessive
acid secretion is by neutralization with antacids. ose
most commonly used are combinations of aluminium
hydroxide (Al(OH)3) and magnesium salts, e.g.
magnesium hydroxide (Mg(OH)2) or magnesium
carbonate (MgCO3). e compounds are relatively
insoluble, and so have a long-lasting eect of 4–6 hours
(maximum when taken 2 hours after eating). ey are
generally well tolerated, but aluminium or magnesium
toxicity is a risk, particularly where renal function is
compromised. e main side eect of magnesium salts is
diarrhoea, while aluminium salts cause constipation. In
combination, therefore, the side eects often cancel out,
although either condition remains a possibility.
Aluminium- and magnesium-based antacids can
potentially chelate a number of drugs and thereby reduce
their absorption. Important examples include
tetracycline antibiotics (e.g. doxycycline), quinolone
antibiotics (e.g. ciprooxacin), and bisphosphonates (e.g.
alendronate). e antacid should be taken at least 2 hours
before the interacting drug.
A similar regime should be followed with drugs that
require an acidic environment in order to be absorbed.
Examples include the azole antifungals, such as
314 Chapter 12 Upper gastrointestinal tract disorders
ketoconazole, and some antiretrovirals, such as
atazanavir.
Calcium carbonate is unsuitable as an antacid as it
stimulates acid secretion. Sodium bicarbonate, present in
many indigestion remedies, is also not suitable for sole use
as an antacid. Its eect is very short-lived, and the sodium
ions can be reabsorbed from the gastrointestinal tract and
cause Na+ overload, of particular concern to hypertensive
patients. In addition, the CO2 generated in the
neutralization reaction leads to bloating and discomfort.
Many preparations of simple antacids contain additional
ingredients, such as simethicone and alginate.
Simethicone is an anti-foaming agent, which alters the
surface tension of gas bubbles in the stomach so that they
coalesce; this reduces problems of bloating and
atulence. Alginate, a seaweed extract, forms a oating
viscous gum when exposed to gastric juices. If the
stomach contents enter the oesophagus, the gum coats
the mucosal layer, protecting it from the damaging eects
of gastric acid. Both simethicone and alginate are without
adverse eects, but neither has been convincingly shown
to provide any advantage over antacids alone.
antagonists (up to 12–24 hours); increased doses of the
interacting drug may be required, and its eectiveness
should be monitored.
Proton pump inhibitors
Proton pump inhibitors reduce the secretion of gastric
acid by irreversibly blocking the action of the H+/
K+-ATPase on parietal cells in the mucosal lining of the
stomach. ese drugs block the nal stage of acid
production (see Box 12.1). ey are therefore more
eective at maintaining the stomach pH above 4 than H2
receptor antagonists, which block only histaminestimulated secretion of acid. e rst proton pump
inhibitor to be developed was omeprazole. is exists as
R- and S-isomers; both are active but the S-isomer is more
resistant to metabolism than the R-isomer.
Esomeprazole is the S-isomer alone, and therefore
provides more eective acid control than omeprazole.
Other members of this drug class are lansoprazole,
pantoprazole, and rabeprazole; all have the same mode
of action. e structures of proton pump inhibitors are
shown in Figure 12.5.
Histamine H2 receptor antagonists
Competitive antagonists of histamine H2 receptors are
used to relieve symptoms in gastro-oesophageal reux
disease, and to aid healing of gastric and duodenal ulcers.
ese drugs target histamine receptors on the parietal cells
which are coupled to increased acid secretion. Examples
include cimetidine, famotidine, nizatidine, and
ranitidine. ese drugs dier only in terms of
pharmacokinetics; cimetidine is taken three to four times a
day (although high once-daily doses can sometimes be
used), whereas the other drugs are taken once or twice
daily. All inhibit acid secretion by at least 90%. ey are
generally very well tolerated, with very few adverse eects.
e most problematic H2 receptor antagonist is cimetidine,
which has some anity for androgen receptors and is
occasionally associated with gynaecomastia in men. It also
inhibits cytochrome P450 enzymes, which results in a
number of potential interactions with drugs such as
phenytoin, theophylline, and warfarin. For these reasons,
cimetidine is no longer widely prescribed.
H2 receptor antagonists reduce the absorption of drugs
that require an acidic environment for absorption (e.g.
ketoconazole). Such interactions are dicult to manage
because of the long duration of action of H2 receptor
Proton pump inhibitors (PPIs) are used in the treatment
of gastro-oesophageal reux disease and duodenal and
peptic ulcers, and in combination with antibacterials for
the eradication of H. pylori (see below). ey are most
commonly taken orally, although injectable preparations
are also available. Oral preparations are enteric-coated,
protecting against degradation in the stomach; tablets or
capsules should not be chewed or crushed as this would
damage the coating of the drug granules. Proton pump
inhibitors are absorbed across the small intestine and are
delivered in the blood to parietal cells. ey are weak
bases and accumulate in the acidic environment of the
secretory canaliculi of the parietal cell. Here they are
converted to the active form (sulfenic acid), which
irreversibly binds to cysteine residues on the H+/K+ATPase (proton pump) molecule. e individual proton
pump inhibitors bind to dierent residues on the pump,
explaining their dierent potencies. e plasma half-lives
of these drugs are short, at around 1 hour, yet a single
dose aects gastric acid secretion for 2–3 days. is is due
to accumulation of the active drug molecules in the
canaliculi, and also because the inhibition of the pump is
irreversible. As the drugs are degraded at low pH, the
inhibition of acid secretion increases their own
bioavailability. A steady state of inhibition is achieved
after around 5 days of therapy.
12.4 Treatment of gastro-oesophageal reflux disease and peptic ulcers 315
O
Figure 12.5 Structures of common proton pump inhibitors.
H
N
N
Omeprazole Pantoprazole
H
N
N
Rabeprazole Lansoprazole
O
S
O
S
N
O
N
O
O
Proton pump inhibitors are generally well tolerated,
with few side eects, although headache and diarrhoea
are sometimes reported. e reduction in acidity of the
stomach may result in an increased risk of infection by
decreasing the defence against micro-organisms. When
used in the long term, proton pump inhibitors have
been associated with an increased risk of bone
fractures, of particular concern for those with an
increased risk of osteoporosis, particularly elderly
patients. Long-term use can also result in decreased
plasma magnesium levels, which can lead to tetany
(muscle spasms) or ventricular arrhythmia. Lastly, and
importantly, proton pump inhibition may mask the
signs of gastric cancer.
Proton pump inhibitors lack signicant interactions, with
one exception—clopidogrel. e activity of this
antiplatelet pro-drug is reduced by proton pump
inhibitors, particularly omeprazole. Lansoprazole and
pantoprazole appear to interact less with clopidogrel, and
are therefore the preferred choice if prescribing alongside
clopidogrel. As noted previously, all drugs that raise
stomach pH can reduce the absorption of drugs that
require an acidic environment.
H. pylori eradication
Eradication therapy for H. pylori combines acid
suppression (with a proton pump inhibitor) and two
antibiotics (usually clarithromycin with either amoxicillin
OF
F
H
N
N
H
N
S
N
O
O
S
O
N
O
N
F
F
O
or metronidazole; see Chapter 22). e reduction in acid
production resulting from proton pump inhibition aids
ulcer healing. e reduced acidity also favours H. pylori
growth, but this is countered by the increased cytotoxicity
of the antibiotic agents against actively dividing microbes.
e use of two antibiotics improves eradication rates by
reducing the possibility of microbial resistance. e
selection of ‘triple therapy’ is based on patient
characteristics (e.g. allergy to penicillin), cost, and,
importantly, local H. pylori resistance patterns.
Guidelines in the UK and the rest of Europe recommend
one week of therapy, whereas 10–14 days are
recommended elsewhere, including the USA.
Ecacy rates are reasonably high (80–85%) for all
triple-therapy combinations. Failure to eradicate H. pylori
may indicate bacterial resistance, and necessitate a
dierent combination of antibiotics in triple therapy
(usually metronidazole, and either amoxicillin or
tetracycline). Quadruple therapy, in which a
cytoprotective bismuth agent (see below) is added, is
sometimes recommended. e most common adverse
eect associated with eradication therapy is diarrhoea.
Quadruple therapy is, not surprisingly, associated with a
greater number of side eects. Patients must be
encouraged to complete the course of medication, as the
development of antibiotic resistance is otherwise a risk.
Where eradication is successful, ulcers usually heal
without the need for further treatment.
F
316 Chapter 12 Upper gastrointestinal tract disorders
O
O
O
O
OH
O
OH
HO
Misoprostol
Figure 12.6 Comparison of the structure of prostaglandin E1 and its analogue misoprostol.
12.4.2 Agents that protect the gastric
mucosa
Misoprostol
Misoprostol is a stable analogue of prostaglandin E1
(PGE1; see Figure 12.6). It promotes healing of NSAIDassociated ulcers by acting at G-protein-coupled EP
receptors in the gastric mucosa. Misoprostol thereby
mimics the protective eects of endogenous
prostaglandins (see Section 12.2.3), increasing mucus and
bicarbonate production, and decreasing acid secretion.
Misoprostol is given orally. Its side eects include
diarrhoea, which can be severe, and abdominal pain.
Misoprostol potently stimulates uterine contractions
through its actions on EP3 receptors on uterine smooth
muscle; it should be avoided in pregnancy as it can
induce premature labour.
Other cytoprotective agents
e heavy metal bismuth is an older cytoprotective agent
with ulcer-healing properties. In the treatment of peptic
ulcers it can be given as bismuth chelate (tripotassium
dicitratobismuthate). is complex salt forms a colloidal
dispersion at neutral or alkaline pH. When it reaches the
acidic environment of the stomach, however, it
precipitates as bismuth oxide and bismuth citrate. Its
mode of action is unclear, but may involve bismuth
coating, and thereby protecting, the damaged area by
binding to exposed glycoproteins.
By disrupting outer membrane proteins, bismuth is toxic
to H. pylori, and may also inhibit the adherence of bacteria
to the stomach wall. ese antibacterial eects account for
its inclusion in quadruple therapy for H. pylori eradication
HO
HO
Prostaglandin E
when standard triple therapy has failed. Additional
protective eects have been postulated, including
stimulating PGE2 production and neutralization of pepsin.
Bismuth chelate can be given alone or in combination
with H2 receptor antagonists (usually ranitidine). It has a
few unpleasant side eects, including nausea and
vomiting, and turning the tongue and faeces black. (e
blackened faeces can be confusing, as they are also a sign
of bleeding in the upper gastrointestinal tract, which can
result from a peptic ulcer.)
Sucralfate is a complex of aluminium hydroxide and
sulphated sucrose. In the acidic surroundings of the
stomach, aluminium is released. e residual negatively
charged complex binds to positively charged groups, for
instance those on exposed proteins or glycoproteins in
ulcerated areas of the mucosal lining. is forms a
physical barrier at the ulcer’s surface, and enables
healing. e complex also binds to mucus, thereby
decreasing its degradation by pepsin. e action of
sucralfate is reduced at pH >4 and for this reason it should
not be given with antacids. is pH dependency also
means that sucralfate is less eective for ulcers located in
the duodenum than for those in the stomach.
Sucralfate may have additional benecial actions on
mucosal cells, including stimulation of bicarbonate and
mucus secretion, and prostaglandin generation.
Sucralfate is taken orally and is generally well tolerated,
with constipation being the most common side eect.
ere is a risk with its use, though, of developing an
obstruction in the stomach, known as a bezoar. It can also
bind drugs in the stomach lumen to interfere with their
absorption; it should be taken 2 hours after other
medication.
1
12.5 Nausea and vomiting 317
12.5 Nausea and vomiting
Nausea and vomiting can arise from a number of causes
including:
• bacterial and viral infections
• migraine
• motion sickness
• pregnancy (usually, but not always, limited to rst
trimester)
• anxiety
• side eects of many therapeutic drugs (particularly
chemotherapy and opiates).
Vomiting is essentially a defensive mechanism. It is
triggered by neural input into the vomiting (or emetic)
centre, located in the medulla oblongata of the
brainstem. is area receives signals from many sources,
explaining the range of triggering stimuli.
A potentially harmful substance in the stomach signals
the release of mediators by enterochroman cells in the
mucosal lining. Of particular importance is the release of
serotonin (5-hydroxytryptamine; 5-HT). e act of
vomiting, to rid the body of the oending toxin, is
coordinated by the central nervous system. Signals are
sent from the stomach to the chemoreceptor trigger
zone (CTZ) of the area postrema in the brainstem, and
from there to the vomiting centre. Input into the vomiting
centre is also received from the labyrinths in the inner
ear, a part of the vestibular system, and from the
cerebellum. Conicting sensory information received
from the eye and the vestibular system can result in
motion sickness.
An outline of the neural and sensory inputs that can
trigger nausea and vomiting is provided in Box 12.2.
Initially, there is a deep intake of breath and closure of the
glottis to protect the airways. e soft palate in the mouth
rises to block o the nasal passages. e diaphragm
contracts and pushes downwards, and at the same time
the abdominal muscles contract, to compress the
abdominal cavity. Together these forces push the
stomach contents up through the relaxed lower
oesophageal sphincter, expelling the stomach contents
through the mouth.
Prolonged or repeated bouts of vomiting can have serious
consequences, the most obvious of which are
dehydration and electrolyte disturbances, and may be of
particular concern in elderly patients, infants, and
pregnant women. Occasionally tears to the oesophagus
(called Mallory–Weiss tears) can also occur.
12.5.1 Role of serotonin in the
gastrointestinal tract
As well as acting as a major neurotransmitter in the brain
and the peripheral nervous system, serotonin (or 5-HT)
acts as a local hormone in the gut, and as a
neurotransmitter in the enteric nervous system. In fact,
over 90% of the body’s serotonin is synthesized in the
endocrine enterochroman cells in the mucosal layer
lining the stomach and small intestine. Serotonin exerts
its eects through specic receptors, seven families of
which have been identied; most of these are further
divided into one or more subtypes. (e distribution and
function of some of these subtypes is, as yet, unclear.)
With the exception of 5-HT3 receptors, which are
ligand-gated cation channels, all serotonin receptors so
far identied are G-protein-coupled receptors (see
Chapter 2, Section 2.2).
e area postrema has no typical blood–brain barrier,
and so chemicals, toxins, and drugs circulating in the
blood can be detected directly by the CTZ. e area
postrema also receives input from visceral aerents
from the gastrointestinal tract; distension of the
stomach or irritation of the gastric mucosa can
therefore directly stimulate the CTZ of the area
postrema.
e vomiting centre (or emesis centre) is responsible for
coordinating the events that can lead to the physical act of
vomiting. is is often preceded by a feeling of nausea
and accompanied by a slowing of gastric motility.
Serotonin receptors in the gut
Four of the seven families of serotonin receptors are
represented in the human gut: 5-HT2B, 5-HT3, 5-HT4, and
5-HT7 (Table 12.2). Receptors are located on the enteric
(intrinsic) and extrinsic neurons (see Introduction to
Part 4), and on smooth muscle and secretory cells. By
acting at these receptors, serotonin controls most aspects
of gastrointestinal function, from motility to levels of
secretions. Of the receptors present, the 5-HT3 and 5-HT4
receptors have been most extensively studied, and are the
targets of drugs used in the treatment of gastrointestinal
conditions (see below).
318 Chapter 12 Upper gastrointestinal tract disorders
Box 12.2
The processes involved in nausea and vomiting
(6)
Higher cortical centres
(NK-1, GABA, 5-HT)
Sensory input
(pain, smell, sight)
(2)
Emesis centre
(M, H
, 5-HT2, NK-1)
1
Cerebellum
(H1, M)
Chemoreceptor
trigger zone
(5-HT3, D2)
(1)
(4)
Figure b
1. The chemoreceptor trigger zone (CTZ) lies in the area postrema that is located in the medulla oblongata of the
brainstem. The area postrema is a ‘circumventricular’ region and is surrounded by ventricular fluid from the
fourth ventricle. It therefore has no typical blood–brain barrier, and so the presence of chemicals and toxins in the
bloodstream is sensed directly by the CTZ. The area postrema receives neural input from the stomach via
afferent nerve fibres, and expresses numerous receptors, notably D2 and 5-HT3 receptors; these are the targets
for the dopamine antagonists (e.g. metoclopramide) and 5-HT3 antagonists (e.g. ondansetron) used to treat
nausea and vomiting.
2. The vomiting (emesis) centre is, like the area postrema, situated in the medulla oblongata, and coordinates
neural output to produce nausea and vomiting. It receives input from the CTZ of the area postrema, the solitary
nucleus, and the higher cortical centres. The emesis centre is a site of action for the anticholinergic drugs (e.g.
hyoscine).
3. The solitary nucleus lies close to the area postrema of the medulla oblongata. It receives signals from
chemoreceptors and mechanoreceptors in a wide range of locations, including the tongue and pharynx, and is
responsible for the gag (pharyngeal) reflex that can result in retching and vomiting. The solitary nucleus is a site
of action for the antimuscarinic drugs (e.g. hyoscine) and antihistamines (e.g. promethazine).
4. The CTZ of the area postrema also receives input from the nearby vestibular nuclei of the medulla oblongata
in the brainstem, which in turn receive sensory input from the vestibular apparatus (labyrinths) in the inner ear
and the cerebellum. The vestibular nucleus provides the brain with information about orientation and position
and is, like the cerebellum, essential for balance. Stimulus from this system, through the vestibular nuclei, can
produce motion sickness. Transmission between the vestibular apparatus and the emesis centre involves
cholinergic and histaminergic synapses, and so is a site of action for antimuscarinic drugs (e.g. hyoscine) and
antihistamines (e.g. promethazine).
(fear, dread, anticipation)
Memory
(3)
Solitary nucleus
(M, H
)
1
5-HT
3
(5)
12.5 Nausea and vomiting 319
Box 12.2 The processes involved in nausea and vomiting
5. Enterochromaffin cells in the gastrointestinal tract release serotonin in response to stimuli such as chemotherapy anticancer
drugs, or damage caused by radiation. Serotonin stimulates 5-HT3 receptors on sensory afferent nerve fibres, sending
signals to the CTZ. The 5-HT3 receptor antagonists, including ondansetron, inhibit this response.
6. The emesis centre receives afferent input from higher centres in the brain cortex. These afferent fibres are responsible for
vomiting induced by emotional factors, pain, repulsive sights or smells, etc.
Receptors: NK-1 neurokinin-1; M muscarinic; H1 histamine; D2 dopamine; 5-HT
5-hydroxytryptamine (serotonin).
2,3
5-HT3 and 5-HT4 receptors are widely expressed on
excitable cells in the gastrointestinal tract. Both receptor
types mediate increased gut motility through activation of
peristaltic reexes. e levels of secretions are also
promoted following activation of 5-HT3 and 5HT4
receptors on sensory neurons. ese neurons transmit
the signal to secretomotor neurons, which in turn release
neurotransmitters, such as acetylcholine and vasoactive
the gut. Signals are thereby transmitted to the
chemoreceptor trigger zone in the area postrema of the
brainstem to induce vomiting. Antagonists at 5-HT3
receptors are useful in the treatment of vomiting and to
some extent nausea (see below). e pathways
underlying nausea are not fully understood, and this
unpleasant sensation is often not particularly well
controlled by antiemetic drugs.
intestinal peptide, and thereby increase Cl– and
bicarbonate secretion. Activation of the 5-HT3 and 5-HT4
receptors also initiates activity in the intrinsic reex
circuits leading to vasodilatation in the gastrointestinal
tract, facilitating absorption and digestion.
5-HT3 receptors are involved in sensations of bloating and
satiety (feeling full), and notably in the regulation of
emesis. is receptor subtype is located on vagal aerent
bres, and is stimulated by serotonin released from
enterochroman cells in response to harmful stimuli in
Serotonin reuptake in the gut
Essentially all cells of the intestinal mucosa express the
serotonin transporter (SERT), which rapidly removes
serotonin following its release from enterochroman
cells. is transporter protein therefore regulates the
availability of serotonin, and this in turn alters the
digestive process. Decreased expression of SERT by
mucosal cells is implicated in the pathogenesis of irritable
bowel syndrome (IBS; see Chapter 13).
Table 12.2 5-HT receptor subtypes found in the human gastrointestinal tract
5-HT receptor
type
5-HT
2B
5-HT
3
5-HT
4
5-HT
7
Mode of signal
transduction
Activation of phospholipase
C, increasing IP3, Ca2+ and
diacylglycerol
Ligand-gated cation
channel
Stimulation of adenylyl
cyclase
Stimulation of adenylyl
cyclase
Location Major effects/role
Small intestine
Stomach (smooth muscle of the fundus)
Smooth muscle
Enterochromaffin cells
Enteric neurons
Extrinsic neurons
Myenteric plexus in the stomach
Smooth muscles of the colon and rectum
Oesophagus
Enterochromaffin and goblet cells
Enterocytes
Stomach
Smooth muscle of the colon and small
intestine (ileum)
Stimulation of gastric motility
Contraction of gastric fundus
Stimulation of gastric motility
Stimulation of intestinal secretions
Satiety
Nausea and emesis
Stimulation of gastric emptying and
intestinal secretions
Inhibition of gastric motility
320 Chapter 12 Upper gastrointestinal tract disorders
SERT is also expressed in the brain where it terminates
the neurotransmitter actions of serotonin. is neuronal
SERT is the molecular target for the most commonly
prescribed antidepressant drugs—selective serotonin
reuptake inhibitors (SSRIs) such as citalopram and
12.6 Antiemetic therapy
e main targets for antiemetic therapy are receptors in
the chemoreceptor trigger zone (CTZ) and those involved
in the pathways to the emesis centre. Vomiting is much
easier to prevent than to stop once started, and a
prophylactic approach should therefore be taken.
12.6.1 Antihistamines
e term antihistamine is used for antagonists at the H1
histamine receptor, distinguishing such drugs from the H2
receptor antagonists described above (Section 12.4.1). H1
histamine receptors are central to the pathways
underlying motion sickness, and the rst-generation
sedating antihistamines are useful in the prophylaxis of
nausea and vomiting. ese agents cross the blood–brain
barrier to produce central eects, and are particularly
associated with sedation. Among the antihistamines used
for the treatment and prevention of motion sickness are
cyclizine, promethazine, and diphenhydramine. A
number of over-the-counter preparations for this
indication contain dimenhydrinate—a combination of
diphenhydramine and chlorotheophylline, a mild
stimulant which counteracts drowsiness.
Some of the older antihistamines, such as promethazine,
are safe to use for severe morning sickness (although
most manufacturers advise against their use during
pregnancy). For more details on antihistamines see
Chapter 10, Section 10.2.1.
12.6.2 Muscarinic receptor antagonists
Hyoscine (also called scopolamine) is a naturally
occurring plant alkaloid. Like the closely related atropine,
it is a non-selective antagonist at muscarinic receptors. It
is used as an antiemetic, most usually in the prevention of
travel sickness, targeting the cholinergic synapses
involved in the transmission between the vestibular
apparatus of the inner ear and the vomiting centre (see
Box 12.2).
Hyoscine is administered as a hydrobromide compound,
which does not readily cross the blood–brain barrier, and
uoxetine (see Chapter 19). Such drugs will also inhibit
SERT in the gastrointestinal tract to enhance the local
eects of serotonin. is explains the gastrointestinal
disturbances including nausea, which are frequently
experienced with SSRIs.
is therefore not associated with signicant sedation. It is
more eective than antihistamines against motion
sickness, but is not always as well tolerated, with
constipation, urinary retention, dry mouth, and blurred
vision the most common side eects. It can be given
orally or as a transdermal patch.
12.6.3 Dopamine receptor antagonists
Dopamine receptor antagonists are central to the
treatment of psychotic disorders such as schizophrenia
(see Chapter 18). e presence of D2 dopamine receptors
in the chemoreceptor trigger zone (CTZ) underlies the
use of some older rst-generation antipsychotics as
antiemetic agents. ese include chlorpromazine,
droperidol, haloperidol, and prochlorperazine. Some
of these drugs possess additional antihistamine and
antimuscarinic properties, which may add to their
eectiveness. e most popular is prochlorperazine,
which is marketed primarily as an antiemetic. e drugs
have a range of unpleasant side eects, such as sedation
and Parkinsonian-type extrapyramidal symptoms,
including tremor, rigidity and bradykinesia (Chapters 17
and 18).
Levomepromazine (methotrimeprazine) is closely
related to chlorpromazine. It is a ‘broad-spectrum’
antiemetic, acting as an antagonist at receptors for
dopamine (D2), histamine (H1), acetylcholine (muscarinic
M1), and serotonin (5HT2). It has additional analgesic
properties, and may also act as an antidepressant. is
makes it an attractive antiemetic, particularly in the
palliative care setting. e wide spectrum of action,
however, has obvious drawbacks, including causing
signicant sedation and postural hypotension through
antagonism of 1 adrenoceptors in the vasculature.
Metoclopramide is a D2 receptor antagonist used in the
treatment of nausea and vomiting associated with
chemotherapy and radiotherapy. In addition to its eect
on D2 receptors in the CTZ, metoclopramide aects the
upper gastrointestinal tract. It enhances the release of
12.6 Antiemetic therapy 321
acetylcholine in the myenteric plexus, and thereby
increases peristalsis (prokinetic eect), favouring gastric
emptying and increasing intestinal transit. is adds to its
antiemetic eects, and makes this drug useful in the
treatment of gastro-oesophageal reux disease (GORD).
As with the antipsychotic drugs, antagonism of D2
receptors by metoclopramide can give rise to central
eects, including sedation and movement disorders, in
particular torticollis (twisting of the neck) and oculogyric
crises (eyeballs rolling upwards into the socket). ese
adverse eects are more common in the young (especially
females) and the very elderly.
Domperidone is similar to metoclopramide although it is
less able to penetrate the blood–brain barrier, and so has
fewer central side eects, including Parkinsonian
symptoms and sedation. Both drugs are given orally.
12.6.4 Selective 5-HT3 receptor
antagonists
5-HT3 receptor antagonists are used to prevent and treat
post-operative nausea and vomiting, as well as that
caused by radiotherapy or the highly emetogenic
chemotherapy drugs such as cisplatin. ese drugs block
the action of serotonin on 5-HT3 receptors in the CTZ and
those in the gastrointestinal tract which initiate the
emetic reex pathway; an increase in plasma serotonin is
often associated with the most emetogenic chemotherapy
agents. ese drugs have been shown to be superior to
metoclopramide against emesis in the rst 24 hours after
highly emetogenic chemotherapy.
Five drugs are used in clinical practice: ondansetron (the
rst developed), granisetron, dolasetron, palonosetron,
and tropisetron. ey are all equally ecacious.
Intravenous and intramuscular formulations are
available, although these appear no more eective than
when administered orally.
e selective 5-HT3 receptor antagonists are generally
very well tolerated, with the main side eects being
constipation, headache, and ushing. ey do not
produce the extrapyramidal eects seen with
antipsychotics and their derivatives, and appear to be
relatively free of clinically signicant drug interactions.
12.6.5 Neurokinin-1 receptor antagonists
Neurokinin-1 (NK-1) receptor antagonists block the
action of the neuropeptide substance P. is small
peptide (11 amino acid residues) belongs to the
tachykinin family. It is a co-transmitter with numerous
roles, including regulation of vomiting where it has both
peripheral (gastrointestinal vagal aerent and
glossopharyngeal nerves) and central (CTZ and vomiting
centre of the brainstem) actions.
e NK-1 receptor antagonists aprepitant and
fosaprepitant block the eects of substance P in the
vomiting centre. ey are used in combination with 5-HT3
antagonists and corticosteroids for the prevention of
nausea and vomiting associated with chemotherapy.
While the corticosteroids are also thought to act in the
brainstem, their exact mechanism of action remains
unknown; multiple actions are most likely. Aprepitant is
taken orally, whereas fosaprepitant, a pro-drug of
aprepitant, is given by intravenous infusion. Both drugs
have relatively few side eects, but can cause anorexia,
severe fatigue, constipation, and diarrhoea. Fosaprepitant
inhibits the metabolism of the corticosteroids
dexamethasone and methylprednisolone, the dose of
which should be reduced if given concomitantly. is is
clinically signicant as these drugs are combined to
combat emesis associated with chemotherapy.
Key references and suggested reading
Goyal RK, Hirano I. e enteric nervous system. New Engl J Med
1996; 334: 1106–15.
Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological
and functional diversity of 5-HT receptors. Pharmacol
Biochem Behav 2002; 71: 533–54.
Huang JQ, Hunt RH. Pharmacological and pharmacodynamic
essentials of H2-receptor antagonists and proton pump
inhibitors for the practising physician. Best Pract Res Clin
Gastroenterol 2001; 15: 355–70.
Matsui H, Shimokawa O, Kaneko T, Nagano Y, Rai K , Hyodo I.
e pathophysiology of non-steroidal anti-inammatory
drug (NSAID)-induced mucosal injuries in stomach and
small intestine. J Clin Biochem Nutr 2011; 48(2): 107–11.
Montuschi P, Sala A, Dahlèn S-E, Folco G. Pharmacological
modulation of the leukotriene pathway in allergic airway
disease. Drug Discov Today 2007; 12: 404–12.
Shin JM, Sachs G. Pharmacology of proton pump inhibitors.
Curr Gastroenterol Rep 2008; 10(6): 528–34.