GASTROINTESTINAL

DISEASES & IT'S DRUGS

RAYMUND N. TAPAOAN, RPH
INTRODUCTION
This section reviews diseases and tr
eatment of different gastrointestinal
diseases:

A. constipation
B. diarrhoea
C. peptic ulcer
D. reflux disease
E. cholelithiasis
F. pancreatitis
GI ANATOMY
The anatomy of the wall of the gastr
ointestinal tract is shown and the co
mmon structures that are seen throu
ghout the tract are identified. The sm
all intestine is represented by the sh
arp spikes in the mucosa, whereas t
he rounded waves represent the larg
e intestine. The gray areas represent
the neuronal network of the enteric n
ervous system.
GI MOTILITY CONT
ROL
Gastrointestinal motility is regulated by gastro
intestinal hormones as well as by both the intr
insic (enteric) and extrinsic (central) nervous
systems.
Although it is important to remember that mo
st gastrointestinal functions are regulated wit
hin the intrinsic system. In instances where dr
ugs are used to try to control gastrointestinal
motility (i.e. for the treatment of nausea, vomi
ting, constipation, diarrhea and gastro-oesop
hageal reflux disease) their mechanisms are
aimed at neuronal mechanisms. In the graphi
c, visceral receptors on the afferent fibers are
represented by the larger nerve endings to re
present the gathering of information. The effe
rent fibers have smaller nerve endings that d
epict the provision of information.
INTRINSIC NERVOU
S SYTEM
Gastrointestinal motility is enhanced by stimulati
on of cholinergic receptors located in the smoot
h and long muscle layers. Stimulation can occur
both directly (extrinsic stimulation of the cholinge
rgic receptors) or indirectly (intrinsic stimulation
of the myenteric plexus and then the cholinergic
receptors). The myenteric plexus can be stimula
ted by neuronal factors (i.e. serotonin, dopamin
e), neurocrines (i.e. substance P, motilin, cholec
ystokinin) and GI peptides (i.e. gastrin, VIP).
The effects of the various nervous systems are
as follows:
Extrinsic parasympathetic neurons (from vagus
and pelvic nerves) are predominantly excitatory,
but may also be inhibitory.
Most vagal fibers project to the enteric nervous s
ystem neurons.
Extrinsic sympathetic postganglionic nerve fiber
s will cause an inhibition of motility.
A. CONSTIPATION
This figure depicts the causative factors f
or constipation. Common physiological f
actors include:
overstimulation of the sympathetic syste
m
inhibition of the parasympathetic system
significant resorption of water in the larg
e bowel
lack of significant bulk in the lumen
These physiological effects can arise fro
m co-morbid disease states and/or conc
omitant drug use (see drug-induced cons
tipation for a listing of drugs that can cau
se constipation). However, patient-relate
d factors are also common and includ lac
k of exercise or water intake.
FIBRE
Unfortunately, few people eat enough fibre e
ach day. As such, fibre is often the first line o
f therapy for constipation. Patients should h
ave a minimum daily intake of 10 grams of d
ietary fibre. This is best achieved by eating f
ruits, vegetables, and cereals.
Most patients will see an effect after three to
five days after the change in their diet. A trial
of a high-fibre diet should continue for at lea
st a month before the effects on bowel functi
on are evaluated. However, many patients w
ill not be able to maintain a high-fibre diet an
d another intervention must be utilized.
For patients with chronic constipation, fibre
products (containing psyllium fibre) are the b
est choice for therapy. However, patients sh
ould be warned of an increase in abdominal
distension and flatulence that can occur duri
ng the first few weeks of therapy.
OSMOTIC LAXATIVE
S
These sugar-derived agents (lactulos
e, its synthetic analogue lactitol, and
sorbitol) increase water secretion int
o the bowel via osmotic action, result
ing in increased bulk size, thereby sti
mulating colonic peristalsis.
These agents are often employed in
patients with slow peristaltic activity
who do not respond to fibre agents.
OSMOTIC LAXATIVE
S
Lactulose is a synthetic derivative of l
actose and is administered orally. Ha
rdly absorbed by the GI tract, colonic
microorganisms convert it into organi
c acids such as lactic acid and acetic
acid. The consequent decrease in pH
as well as lactulose'sosmotic effects
result in increased motility and impro
ved consistency of the faeces.
Treatment with lactulose usually resu
lts in a softening of the faeces in one
to three days.
OSMOTIC LAXATIVE
S
Sorbitol is a hyperosmotic laxative an
d has been recommended as a prim
ary agent in the treatment of function
al constipation or as a vehicle for rect
ally administered enemas.
In extremely high dosages, oral sorbi
tol can exert a rapid laxative effect.
STIMULANTS LAXATI
VES
Stimulant laxatives are also known as co
ntact laxatives and include the drugs that
contain senna and bisacodyl.
The mechanism of action of these agents
is just beginning to be understood. For ex
ample, bisacodyl is believed to exert its l
axative effect through stimulation of the
myenteric plexus. Other agents promote t
he accumulation of electrolytes and thus
water in the GI lumen by affecting Na+/K
+-ATPase.
This class of laxatives is commonly used
to treat acute constipation and usually pr
oduce a soft or semi-liquid stool in 6 to 1
2 hours. These agents are not recommen
ded for daily use.
STOOL SOFTENERS
Stool softeners are detergents, lowering
the surface tension of stool to allow incre
ased uptake of fats and water in the faec
es. This softens the bulk and allows for e
asier passage through the bowel without
straining.

Generally, they are prescribed for acute

and subacute constipation in patients wh
o should avoid straining during defaecati
on.

Products include rectally administered so

dium docusate glycerol or sodium docus
ate sorbitol.
B. DIARRHOEA
In this picture, the causative factors for diarr
hoea are shown. Common physiological fact
ors include:
Over-stimulation of the parasympathetic syst
em
Inhibition of the sympathetic system
Presence of bacteria or viruses
Over-secretion of water and electrolytes sec
ondary to gastrointestinal irritation
These physiological effects can arise from c
o-morbid disease states and/or concomitant
drug use. However, since the most common
aetiologies are self-limiting, drug therapy is r
arely indicated. In severe cases or in cases i
nvolving paediatric or elderly patients, oral r
ehydration therapy should be initiated.
OPIATE RECEPTORS
IN GI
Opioids markedly reduce peristaltic and pro
pulsive motor activity while at the same tim
e increasing pyloric, ileocolic, and anal sphi
ncter tone.
They increase segmental contractions of th
e small and large bowel, prolonging transit
and increasing the resistance to flow throug
h the lumen.
Natural opioids such as morphine and codei
ne are very effective anti-diarrhoeal drugs.
Loperamide is a synthetic opioid that has th
e advantage over classical opioids that it do
es not cross the blood-brain barrier as readi
ly.
Loperamide is used for specific presentatio
ns of chronic diarrhoea.
INTRODUCTION NAU
SEA/VOMITTING
This graphic shows the proposed patho
physiology of emesis. In contrast to peri
stalsis, in which intrinsic pathways domi
nate, central mechanisms play a key rol
e in nausea and vomiting.
These phenomena are regulated by the
chemoreceptor trigger zone (CTZ) and
the vomiting centre, both located in the
medulla. The vomiting centre reflex can
be stimulated by:
Sensory input from receptors in the gas
trointestinal tract via the CTZ. These in
volve mainly signals from the pharynx,
pylorus, and intestine. A dysfunctioning
sphincter can be a stimulus.
INTRODUCTION NAU
SEA/VOMITTING
Emetogenic drugs such as cytotoxic
agents and L-DOPA. The blood-brai
n barrier is more permeable around t
he CTZ and thus emetic drugs can a
ct directly on the CTZ.
Pain, smells (waste, faeces), sights
(strobe lights, severe accidents, dea
d people) and emotional factors give
sensory inputs via higher brain centr
es to the vomiting centre.
INTRODUCTION NAU
SEA/VOMITTING
Motion sickness information reaches
the CTZ via the vestibular nuclei.
The CTZ stimulates the vomiting cen
tre, which induces closing of the pylo
rus and contraction of the stomach.
The resulting vomiting can cause gre
at discomfort to the patient and resul
t in dehydration and electrolyte imbal
ances.
ANTI-EMETICS
This figure shows the different sites of a
ctions of anti-emetics. The agents used t
o treat emesis generally exert their effec
t by blocking one neurotransmitter recep
tor and can thus be grouped into classe
s of dopamine D2 antagonists, serotonin
5-HT3 antagonists and anticholinergics.
The exception to this is the drug metoclo
pramide which has both D2- and 5-HT3-
antagonist activity. Note that some drug
s act on the level of the CNS, others on t
he level of the GI tract, and yet others o
n both the CNS and GI tract. More infor
mation about these agents is depicted in
the following graphics.
C. INTRODUCTION PE
PTIC ULCER
In this picture, the common causative f
actors for peptic ulceration are shown.
They include the gastrointestinal patho
gen Helicobacter pylori (1), too much g
astric acid (2), too much pepsin (3), an
d a breakdown of the protective mucus
(4).
Peptic ulcer erosions typically extend d
eeper into the muscularis mucosa than
is portrayed.
Other causes of peptic ulcers include th
e use of non-steroidal anti-inflammatory
drugs (5), stress-related damage (6), ra
diation (7), and chemotherapy (5).
BISMUTH COMPOUN
DS
Bismuth compounds have several effects that ar
e beneficial for ulcer healing: anti-microbial activit
y against H. pylori (mechanism unknown), stimul
ation of prostaglandin synthesis thereby increasi
ng mucosal protection, and chelation with expose
d ulcer proteins and protecting the ulcer base.
When given as monotherapy, bismuth compound
s are not very effective in eradicating H. pylori. H
owever, when combined with other agents (anti-
microbials, PPIs or H2 receptor antagonists), ove
r 90% of the cases of H. pylori are eradicated.
The bismuth compounds are also used to treat n
ausea, diarrhoea, and indigestion. Patients may
experience a darkening of the tongue and stool w
hile on bismuth therapy.
Prolonged use of bismuth compounds is not advi
sed because of possible systemic side effects (e
ncephalopathy).
Helicobacter pylori treat
ment
Helicobacter pylori has been established
as aetiologic agent of peptic ulcers and g
astritis, and is a major risk factor for gastri
c adenocarcinoma and mucosa-associate
d lymphoid tissue lymphoma (MALT).
There is much debate on the role of H. py
lori in the pathogenesis of non-ulcer dysp
epsia. Several large randomized trials ha
ve not provided evidence that H. pylori er
adication is associated with symptomatic i
mprovement in non-ulcer dyspeptics.
On the other hand, it is generally agreed t
hat H. pylori eradication is indicated in pe
ptic ulcer disease and MALT lymphoma.
Helicobacter pylori treat
ment
H. pylori is eradicated in over 90% of
cases after administering triple thera
py regimens that consist of
a proton pump inhibitor (PPI)
two anti-microbial agents: usually cla
rithromycin and amoxycillin.
Quadruple therapy consists of
• a proton pump inhibitor
• bismuth subcitrate
• tetracycline
• metronidazole
Helicobacter pylori treat
ment
Antimicrobial resistance to metronidazol i
s a serious problem. Because of side effe
cts (nausea), patient compliance is not o
ptimal and 14-day regimens of triple or q
uadruple therapy are sometimes not com
pleted.

Eradication of H. pylori results in healing

of gastritis and cure of ulcer disease. Mai
ntenance therapy with PPI or H2-recepto
r antagonists should be stopped. As the g
astritis heals, acid production may increa
se and result in reflux disease. In fact, he
artburn and reflux-oesophagitis are repor
ted more frequently in patients who recei
ved eradication therapy.
Introduction -Systemic
Gastric Acid Control
Gastric acid secretion is controlled b
oth systemically and locally by neuro
crine, endocrine, and paracrine facto
rs. Acetylcholine, histamine, and gas
trin are all stimulating factors. Inhibit
ory factors include somatostatin, pro
staglandins, and epidermal growth fa
ctor (not depicted).
Introduction -Systemic Gastric Acid Contr
ol
Although foods stimulate acid secreti
on, the pH usually rises in the post-p
randial period due to the buffering ca
pacity of the meal. An example of a
24-hour intragastric pH recording in
a healthy volunteer is shown in the fi
gure below.
Parietal Cell
This figure shows in greater detail the many fact
ors influencing parietal cell gastric acid secretio
n. All affected receptors are of the G protein-co
upled type and include H2 = histamine 2, G = g
astrin, and M3 = muscarinic 3, which stimulate s
ecretion. EP = prostanoid E, inhibits parietal cell
gastric acid secretion.

The enterochromaffin-like (ECL) cell (not depict

ed here, but also present in the stomach wall) s
ecretes histamine which in turn affects the parie
tal cell. Gastrin is produced in the G cell and rel
eased into the systemic circulation. When there
are high levels of gastric acid in the gastric lum
en, the release of gastrin from the G cells is inhi
bited
Antacids
The antacids used for the treatment of ulc
er disease or reflux disease are weak bas
es that neutralize gastric acid. Their capac
ity to neutralize acid in the lumen of the st
omach results in a reduction in acid load d
elivered to the duodenum or oesophagus
(in reflux). It also inhibits pepsin activity: at
a pH higher than 4, the activity of pepsin d
ecreases markedly.

Antacids without systemic effects are pref

erred. Non-systemic antacids contain a ca
tion (usually magnesium or aluminium) tha
t is poorly absorbed in the small bowel.
Antacids
Antacids are effective in reducing symptoms be
cause of their rapid onset of action. However, t
he neutralizing effect is of short duration and th
erefore multiple dosages are required per day.

Antacids containing aluminium (algeldrate) and

/or calcium (calcium carbonate) tend to have c
onstipating properties, whereas those with mag
nesium (magnesium oxide) tend to cause diarr
hoea. For this reason, the most commonly use
d products contain both aluminium and magne
sium.
Due to absorption of sodium-containing antacid
s, these drugs should be used with caution in p
atients with heart failure.
H2 antagonists
When the stimulatory histamine H2 receptor is bl
ocked, the production of the second messenger
cAMP via the adenylate cyclase enzyme is inhibi
ted. This decrease in cytosolic cAMP concentrati
ons prevent the stimulation of protein kinase A a
nd its subsequent phosphorylation of the H+/K+
ATPase that pumps acid into the gastric lumen.

H2 receptor antagonists were introduced for the

treatment of peptic ulcer disease in the mid-197
0s. They are very effective and relatively safe ag
ents for the treatment of ulcer disease. Mostly, t
hey reduce basal (nocturnal) but also post-pran
dial acid secretion. By decreasing acid secretion
, H2 receptor antagonists reduce ulcer pain and
promote healing of the mucosa.
H2 antagonists
The effect of these drugs on acid secretion can be evalu
ated by aspiration of gastric contents and measuring the
ir acidity, or by continuous 24-hour pH recording. Acid-re
ducing therapy is considered effective when it raises intr
agastric pH to levels > 4 for several hours.

Because of the short half-life and duration of action of th

ese agents, more than once-daily administration is requi
red to obtain 24-hour acid reduction. However, since bot
h metabolized and unmetabolized product is excreted in
to the urine, dosage adjustments are required in patient
s with renal insufficiency.
H2 receptor antagonists (particularly cimetidine) may als
o interfere with the metabolism of other drugs by inhibiti
ng hepatic cytochrome P450 enzymes, so the possibility
for drug interactions should be explored.
Ranitidine is the most frequently prescribed H2 receptor
antagonist.
Proton pump inhibitors
Secretion of H+ into the lumen result
s from activation of the parietal cell
H+/K+ ATPase (proton pump). Activa
tion of the proton pump is brought ab
out by activation of histamine, gastri
n, or muscarinic receptors. Inhibition
of the proton pump by proton pump i
nhibitors (PPIs) is the most effective
mechanism to reduce acid secretion.
Proton pump inhibitors
Previously, there were serious concerns about the po
tential side effects of PPIs as a result of their superb
acid-reducing capacity. Serum gastrin levels could inc
rease and enterochromaffin-like cell hyperplasia coul
d occur (and was indeed observed in gastric carcinoi
d tumours in animal models).
However, this has not appeared to be the case in hu
mans during the 15 years of clinical and endoscopic
surveillance while using PPIs. Theoretically, the risk o
f gastrointestinal and nosocomial infections is increas
ed during PPI therapy, but in daily practice this has al
so not occurred.

PPIs (omeprazol, pantoprazol, and rabeprazol) shoul

d be taken on an empty stomach to facilitate absorpti
on. Ulcer patients should be told that pain relief does
not correlate with endoscopic evidence of healing an
d that the drugs should be continued for the duration
of 7 to 14 days, as indicated.
Prostaglandins
When the inhibitory prostanoid EP re
ceptor is stimulated, production of th
e second messenger cAMP is decre
ased via inhibition of the adenylate c
yclase enzyme. This leads to a decr
ease in cytosolic concentrations of c
AMP and the ability of protein kinase
A to phosphorylate H+/K+ ATPase (p
roton pump).
Prostaglandins
In parietal cells, prostaglandins inhibit the adenylat
e cyclase-initiated activity that is stimulated by hist
amine. This is in contrast to most other tissues, wh
ere prostaglandins stimulate adenylate cyclase act
ivity and increase intracellular formation of cAMP, r
esulting in fluid secretion.

Misoprostol is a synthetic prostaglandin E1 analog

ue, which reduces acid secretion in a dose-depen
dent manner. It also has mucosal protective prope
rties. Therefore, misoprostol is used as an adjunct
to reduce the incidence of NSAID-induced ulcerati
on. However, the cost-effectiveness of this co-ther
apy remains controversial. Furthermore, complian
ce can be a problem due to the dose-dependent di
arrhoea that results from its administration.
Sucralfate
Sucralfate can be used for ulcers and for reflu
x disease because of its various actions. Toge
ther with bismuth, sucralfate belongs to the gr
oup of mucosa protectives.

In the treatment of ulcers, sucralfate is helpful

in protecting the surface of the ulcer. In the aci
dic environment of the stomach (pH < 4) it rea
cts with hydrochloric acid to form a cross-link
with tissue proteins at the surface of ulcers an
d other lesions.
This complex protects the tissue from further
damage by acid and pepsin. In this role, the m
echanism of action of sucralfate is similar to th
at of bismuth.
Sucralfate
Sulcralfate also has an indirect role i
n decreasing acid production. It has
been shown to stimulate prostagland
in E2 production. Prostaglandin E2 i
nhibits the acid production by the par
ietal cell.

Side effects include constipation, na

usea, allergic skin reactions, and bez
oar (a mass found trapped in the GI
system).
Sucralfate
Sulcralfate also has an indirect role i
n decreasing acid production. It has
been shown to stimulate prostagland
in E2 production. Prostaglandin E2 i
nhibits the acid production by the par
ietal cell.

Side effects include constipation, na

usea, allergic skin reactions, and bez
oar (a mass found trapped in the GI
system).
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