12
Drugs acting on the gastrointestinal tract I:
hari
minimal
2x
14
peptic ulcer
FERD PII
"
:
f.
simethicme
Anhlsida
Antacids
NaHCO3
CaCO3
Mg(OH)2
AI(OH)3
R–
PROTON PUMP INHIBITORS
–
M1
H+
H+
ACh
Vagus
+
Ca2+
K+
+
H+
Cl–
Helicobacter pylori
eradication
}2H
-
cimetidine
ranitidine
Cl–
2 X
'
+
cAMP
Mucus
omeprazole
lansoprazole
I
others
H2-ANTAGONISTS
G Gastrin
neutralization
RH
Acid secretion
reducers
-
Parietal cell
H2
ATP
TRIPLE THERAPY
o
.
•
•
.
•
omeprazole O
clarithromycin C
A
amoxicillin
ACh
+
Mucus cell
0
omeprazole
M
amoxicillin
metronidazole A
Mucosal
protectants
sucralfate
bismuth
chelate
misoprostol
M1
Paracrine
cell
(urease)
HCl
G
Gastrin
Coat ulcer
base
Parietal cells
? Kill H. pylori
Gastrin
pH 2
pH 7
H+
HCO3–
The term peptic ulcer refers to any ulcer in an area in which the
mucosa is bathed in the hydrochloric acid and pepsin of gastric juice
(i.e. the stomach and upper part of the duodenum). Drugs that are
effective in the treatment of peptic ulcer either reduce gastric acid
secretion (left centre and right) or increase mucosal resistance to
acid–pepsin attack (bottom left).
Acid secretion from the parietal cells ( ) is reduced by H2histamine antagonists (right) or by proton pump inhibitors (right),
which can produce virtual anacidity by inhibiting the pump ( ) that
transports H+ ions out of the parietal cells. Proton pump inhibitors are
very effective in promoting ulcer healing, even in patients who are
resistant to H2-antagonists. The ‘mucosal protectants’ (bottom left)
). This
increase ulcer healing by binding to the ulcer base (left,
provides physical protection and allows the secretion of HCO3− to
re-establish the pH gradient normally present in the mucus layer
) that originates from mucus-secreting cells ( ). Misoprostol is
(
a prostaglandin analogue that promotes ulcer healing by stimulating
protective mechanisms in the gastric mucosa and by reducing acid
secretion. It is sometimes used to prevent ulcers in patients taking
non-steroidal anti-inflammatory drugs (NSAIDs, Chapter 32).
30
+
Histamine
Cytokines?
G-cells
Without continuous drug administration, peptic ulcers, however
healed, will often recur. This is because chronic infection of the
) is an important aetiological
stomach with Helicobacter pylori (
factor in ulcer formation. H. pylori infection is associated with about
95% of duodenal ulcers and 70% of gastric ulcers. The infection may
result in a chronic hypergastrinaemia, which stimulates acid production and causes ulcers (bottom right). Uncomplicated peptic ulcers
associated with H. pylori infection are treated by the eradication of H.
pylori using a combination of a proton pump inhibitor (e.g. omeprazole) with antibiotics (left, centre). Before treatment, infection with
H. pylori is confirmed by a urea breath test, in which some [13C]urea
is ingested. H. pylori possesses urease, an enzyme that breaks down
the urea and produces [13C]carbon dioxide, which can be detected in
a sample of breath. The breath test is also used after treatment to verify
H. pylori eradication.
Antacids (top left) are bases that raise the gastric luminal pH by
neutralizing gastric acid (middle left). They provide effective treatment for many dyspepsias and symptomatic relief in peptic ulcer and
oesophageal reflux. Many proprietary mixtures, usually containing
magnesium or aluminium salts, are available.
Medical Pharmacology at a Glance, Seventh Edition. Michael J. Neal. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.
Drugs acting on the gastrointestinal tract II:
motility and secretions
13
Drugs used in
inflammatory
bowel disease
Anti-inflammatory
drugs
Dissolve
gallstones
Liver
BILE ACIDS
ursodeoxycholic acid
CORTICOSTEROIDS
hydrocortisone
prednisolone
(suppositories,
enemas, foam)
oral prednisolone
Bile duct
Gall
bladder
Gut lumen
Aminosalicylates
sulfasalazine
mesalazine
Antispasmodics
MUSCARINIC
ANTAGONISTS
Pancreatic
supplements
pancreatin
Pancreas
atropine
propantheline
dicycloverine
Stretch
receptor
ACh
+
-0
Bulk
Laxatives
ACh
+
bran
ispaghula
OSMOTIC
-
MgSO4
lactulose
–
-
FAECAL SOFTENERS
(docusate)
arachis oil (enema)
O
ACh
Motility stimulants
-
metoclopramide
domperidone
=
Muscular contractions of the gut and secretion of acid and enzymes
are under autonomic control. The enteric part of the autonomic nervous
) with complex intersystem consists of ganglionated plexuses (
connections supplying the smooth muscle, mucosa and blood vessels.
) (parasympathetic) receive extrinsic excitatory
The ganglia (
fibres from the vagus and inhibitory sympathetic fibres. Other transmitters in the gut include 5-hydroxytryptamine (5HT), adenosine triphosphate (ATP), nitric oxide and neuropeptide-Y.
Cholinomimetic drugs (e.g. neostigmine) increase motility and
may cause colic and diarrhoea. They are very occasionally used in the
treatment of paralytic ileus (Chapter 8). More useful motility stimulants (bottom middle) facilitate acetylcholine release from the myenteric plexus and are used in the treatment of oesophageal reflux and
gastric stasis. Laxatives (bottom left) are drugs used to increase the
)
motility of the gut and encourage defaecation. Bulk laxatives (
stimulate stretch receptors in the mucosa. Stimulant laxatives stimulate the myenteric plexus, and some drugs act as lubricants
32
Antimotility
drugs
Myenteric
plexus
+
STIMULANT
senna
bisacodyl
docusate
glycerol
suppositories
gdiare
Submucous
plexus
BULK
① pwudlmpahl
'
ACh
Longitudinal muscle
Circular muscle
Submucosa
Mucosa
MORPHINE-LIKE
AGENTS
morphine
codeine
diphenoxylate
loperamide
fatal
wat
damn
.
Has
). Muscarinic antagonists (top right) reduce gastrointestinal
(
motility and are used to reduce spasm in irritable bowel syndrome
(antispasmodics). Antidiarrhoeal drugs include antimotility drugs
(bottom right), but replacement of water and electrolyte loss is generally more important than drug treatment, especially in infants and in
infectious diarrhoea.
Anti-inflammatory corticosteroids and aminosalicylates (top left)
are used in ulcerative colitis and Crohn’s disease. To reduce the need
for systemic steroids, it is usual to add azathioprine, an immunosuppressant (Chapter 43).
In the duodenum, bile from the liver (top right) and pancreatic
) enter ( ) usually through
juice from the pancreas (right,
a common opening that is restricted by the sphincter of Oddi.
Bile acids (top middle) are sometimes used to dissolve cholesterol gallstones ( ). Pancreatic supplements (left middle) are
given orally when the secretion of pancreatic juice is absent or
reduced.
Medical Pharmacology at a Glance, Seventh Edition. Michael J. Neal. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.
30
Drugs used in nausea and vertigo (antiemetics)
Cannabinoids
nabilone
Circulating emetic agents
e.g. toxins, opioids, apomorphine
Dopamine
antagonists
prochlorperazine
metoclopramide
domperidone
–
Yang }
Substance P
antagonist
+
–
Ooo
aprepitant
CTZ
(D2, 5HT3
receptors)
m
-
Antimuscarinic
drugs
-
hyoscine
EPI : gerda kehumngan dopamine
Antihistamines
Vomiting centre
(M, H, receptors)
TRAP
-
-
O
5HT3
antagonists
X
ondansetron
granisetron
motion
cinnarizine
promethazine
cyclizine
Dimenhydrinate
X
Irritants
e.g. ipecacuanha
5HT
–
Nausea and vomiting have many causes, including drugs (e.g. cytotoxic agents, opioids, anaesthetics, digoxin), vestibular disease, provocative movement (e.g. seasickness), migraine and pregnancy.
Vomiting is much easier to prevent than to stop once it has started.
Therefore, if possible, antiemetics should be given well before the
emetic stimulus is expected. Antiemetics should not be given before
the diagnosis is known because identification of the underlying cause
may be delayed.
Emesis is coordinated by the vomiting centre ( ) in the medulla
(upper figure). An important source of stimulation of the vomiting
centre is the chemoreceptor trigger zone (CTZ, ) in the area postrema. Because the CTZ is not protected by the blood–brain barrier (it
is part of the circumventricular system), it can be stimulated by circulating toxins or drugs (top). The CTZ possesses many dopamine (D2)
receptors, which explains why dopaminergic drugs used in the treatment of Parkinson’s disease frequently cause nausea and vomiting.
However, dopamine receptor antagonists are antiemetics (upper
left) and are used to reduce nausea and vomiting associated with the
administration of emetogenic drugs (e.g. many cytotoxic anticancer
agents).
66
The CTZ also possesses 5HT3 receptors, and 5HT3 antagonists
(e.g. ondansetron, left lower) are effective antiemetics. Because
they have fewer unwanted actions, they are widely used to prevent
or reduce the nausea and vomiting associated with cancer
chemotherapy and general anaesthesia. In some cases, it is uncertain
how 5HT3 antagonists produce their antiemetic effects. There is a
high concentration of 5HT3 receptors in the CTZ, but a peripheral
action may also be important. Many cytotoxic drugs (and Xrays) cause the release of 5HT from enterochromaffin cells ( ) in the
gut, and this activates 5HT3 receptors on vagal sensory fibres
( ) (lower figure). Stimulation of sensory fibres in the stomach by
irritants (e.g. ipecacuanha, bacterial toxins) causes ‘reflex’ nausea and
vomiting.
Dopamine antagonists and 5HT3 antagonists are ineffective in
reducing the nausea and vomiting of0
motion sickness. Antimuscarinic
drugs or antihistamines (right), which act directly on the vomiting
centre, may be effective, although side-effects are common. Vertigo
and vomiting associated with vestibular disease are treated with antihistamines (e.g. promethazine, cinnarizine), phenothiazines or
betahistine.
Medical Pharmacology at a Glance, Seventh Edition. Michael J. Neal. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.