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Gastrointestinal Tract
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Review of Pharmacology
These drugs are weak bases that neutralize gastric acid (do not decrease the volume of
acid secreted). Their major role in peptic ulcer is to provide prompt relief from ulcer pain.
Antacids may be systemic (absorbed from the GIT) or local (poorly absorbed). Sodium
bicarbonate is rapidly acting systemic antacid. It is not indicated for long term use because:
These are prodrugs (active moiety is sulfenamide) and act by irreversibly inhibiting
H+ K+ ATPase in gastric parietal cells. The drugs in this group include omeprazole,
pantoprazole, esomeprazole, lansoprazole and rabeprazole. These drugs are
weak bases and can be destroyed by gastric acid. To protect them from gastric acid,
these are given as enteric coated tablets. This coating dissolves in alkaline medium
(intestinal juice) and prodrugs are absorbed. On reaching parietal cells, active moiety
(sulfenamide) is formed and gets trapped. These can inhibit both basal acid output
(nocturnal acid secretion) as well as meal stimulated acid output (maximal acid output).
PPIs are given orally in early morning empty stomach (just before breakfast).
Pantoprazole, esomeprazole and lansoprazole can be given i.v. These drugs have
short t1/2 but can inhibit acid secretion for more than 24 hours (hit and run drugs,
inhibit proton pump irreversibly).
PPIs are the drugs of choice for peptic ulcer disease (PUD) due to any etiology
(even NSAID induced). These are also the agents of choice for gastroesophageal
reflux disease (GERD) and Zollinger Ellison Syndrome (ZES). For prevention of stress
induced gastric bleeding, H2 blockers (i.v. infusion) are preferred over PPIs. In patients with
nasoenteric tube, immediate release omeprazole (by nasogastric tube) is currently
preferred.
PPIs are quite safe drugs and have diarrhea, headache and abdominal pain as
adverse effects. These have been shown to be carcinogenic in rodents but no such
case has been reported in humans.
m inhibitors (PP s)
p
Proton
Gastrointestinal Tract
It releases CO2 that can cause belching and gastric distension (ulcer perforation
can occur).
Sodium chloride formed in the neutralization reaction can be absorbed that
can exacerbate fluid retention in patients of CHF and hypertension.
Systemic and urinary alkalosis may occur.
Rebound hyperacidity can occur.
pu
ntacids
Contd...
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Gastrointestinal Tract
Contd...
nticholinergics
Note:
Famotidine is most potent H2 blacker.
All H2 blockers except famotidine inhibits the gastric first pass metabolism of ethanol
Loxatidine is a non-competitive blocker of H2 receptors.
Nizatidine also possess anti-AChE activity and can cause bradycardia and enhanced gastric
emptyding
Nizatidine is having negligible first pass metabolism (~100% bioavailability)
Gastrointestinal
Tract
General
Pharmacology
Note:
Lanoprazole is most potent PPI
Lansoprazole is safest PPI in pregnancy.
Esomeprazole, lansoprazole and pantoprazole can be given by i.v. route.
Omeprazole and esomeprazole are microsomal enzyme inhibitors. These may decrease the
metabolism of diazepam.
Lansoprazole enhances the metabolism of theophylline
Note:
Acid suppressing agents (like PPIs, H2 blockers etc.) can result in tolerance and rebound hyperacidity due to secondary hypergastrinemia.
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Review of Pharmacology
and by increasing the mucosal blood flow. PGs also inhibit H+ K+ ATPase and decrease the
acid production. Misoprostol (PGE1 analogue) is the MOST SPECIFIC drug for treatment
and prevention of NSAID induced peptic ulcer (DOC is PPI). Enprostil and rioprostil (PGE2
analogue) are other drugs in this group. Commonest side effect of PG analogues is diarrhea
and colicky abdominal pain.
These drugs form a covering over the ulcer bed that prevents its exposure to gastric acid.
Sucralfate and colloidal bismuth subcitrate are two important ulcer protective drugs.
Sucralfate: It is aluminium salt of sulfated sucrose. At pH below 4, its molecules
polymerize to form a sticky layer that covers the ulcer base and acts as a physical
barrier to prevent acid exposure. It can bind phosphates also and can result in
hypophosphatemia. It should not be given with antacids because it acts only in
acidic medium (antacids raise the pH by neutralizing the gastric acid). Most common
side effect of sucralfate is constipation.
Colloidal bismuth subcitrate: It also forms an acid resistant coating over the ulcer.
It also dislodges H. pylori from the surface of gastric mucosa and kills it. Adverse
effects include blackening of tongue and bismuth toxicity (osteodystrophy and
encephalopathy).
Rebamipide and Ecabet are cytoprotective drugs acting by increase in PG generation
and by scavenging reactive oxygen species.
Carbenoloxone is obtained from the roots of licorice. It causes epithelisation of ulcer without
decreasing acid production. It can displace aldosterone from plasma protein binding sites
and result in hypertension, sodium and water retention and hypokalemia.
Triple drug therapy for H. Pylori
CClarithromycin
AAmoxycillin
PProton pump inhibitor
Gastrointestinal Tract
H. pylori infection can be detected by urea breath test. It is responsible for relapse of PUD.
Drugs used for the treatment of H.pylori include:
Metronidazole/tinidazole
Amoxicillin
Clarithromycin
Tetracycline
Colloidal bismuth subcitrate
Omeprazole/lansoprazole
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nti metic Dr gs
E
Gastrointestinal Tract
Vomiting (emesis) occurs due to stimulation of vomiting centre (VC) in lateral medullary
reticular formation. It receives input from GI mucosa, chemoreceptor trigger zone (CTZ) and
vestibular apparatus.
Irritation of GI mucosa by drugs or irritants leads to release of serotonin that
stimulates VC via 5HT3 receptors.
CTZ is rich in dopamine (D2) and serotonin (5HT3) and neurokinin (NK1) receptor.
Motion sickness occurs due to stimulation of vestibular apparatus and cerebellum.
These structures result in stimulation of VC by activating M1 and H1 receptors.
By stimulation of H1 receptors, histamine plays a permissive role in all types of
vomiting.
orning ickness
S
Drugs for
otion ickness
Hyoscine is used as i.m. injection or transdermal patch (applied behind pinna) for
prophylaxis of motion sickness. It has no role in treatment, once the vomiting
starts.
Antihistaminics like promethazine, diphenhydramine, cyclizine or meclizine can
also be used for prophylaxis.
Cinnarizine (antihistaminic with anticholinergic and antiserotonergic properties) is
used for treatment of vertigo.
M
Gastrointestinal
Tract
General
Pharmacology
Drugs For
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Review of Pharmacology
brain. It is metabolized by CYP3A4 enzymes and can also inhibit the metabolism of
drugs metabolized by this enzyme e.g. warfarin.
Fosaprepitant is an intravenous prodrug of aprepitant.
Netupitant is a newer NK1 antagonist approved for chemotherapy induced vomiting
(both acute and delayed in combination with palonosetron)
metic Dr gs
u
It is a condition in which acid in the stomach reaches the esophagus and causes mucosal
inflammation. Two strategies for the management of this condition are either to decrease the acid
production (by PPIs) or to increase the forward movement of GIT (so that the contents do not reflux
upwards). The drugs used for increasing the GI motility are known as prokinetic drugs.
These drugs can also be used for the treatment of gastroparesis, post operative paralytic ileus
and constipation.
Prokinetic Drugs
ACh is the main excitatory neurotransmitter in the GIT. Cholinergic neurons contain
excitatory (5-HT4) as well as inhibitory (5HT3, D2) presynaptic receptors.
Thus D2 and 5HT3 antagonists and 5 HT4 agonists will increase the release of ACh and
stimulate the GI motility.
etoclo rami e
p
Gastrointestinal Tract
Apomorphine and ipecacuanha can be used to produce vomiting for treatment of poisonings.
Emetics should not be used for kerosene and corrosive (acid and alkali) poisonings.
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Gastrointestinal Tract
d
HT
ther Prokinetic Dr gs
Gastrointestinal
Tract
General
Pharmacology
IBS
Cisapride, mosapride, renzapride, prucalopride and tegaserod are 5-HT4 agonistic drugs
with no action on D2 receptors (no antiemetic property). These drugs increase whole GI motility
including colon.
Cisapride was previously used for the treatment of GERD but it has been withdrawn
in some countries due to its QT prolonging action. It is metabolized by CYP 3A4
and therefore should not be administered with microsomal enzyme inhibitors
like ketoconazole and erythromycin (increased chances of torsades de pointes,
an arrhythmia with QT prolongation). Mosapride and renzapride do not prolong QT
interval. Tegaserod can be used for constipation dominant irritable bowel syndrome.
However, recently it has also been withdrawn from India due to increased incidence
of myocardial infarction and stroke.
Anticholinergics
- Dicyclomine
- Hyoscine
Kappa agonist
- Fedotozine
Loxiglumide
Reserpine analog
- Mebeverine
Chloride channel
stimulant
- Lubipristone
5HT3 antagonist
- Alosetron
Guanylate cyclase
agonist-Linaclotide
Constipation dominant
Opioids
- Loperamide
- Diphenoxylate
-
Diarrhea dominant
Tricyclic antidepressants
- Impiramine
- Desipramine
- Nortriptyline
-
Linaclotide is a guanylate
cyclase agonist indicated for
oral treatment of idiopathic
constipation and IBS with
constipation.
onsti ation
p
Clonidine
High fibre diet, adequate fluid intake and regular exercise are best measures to prevent
constipation. Patients not responding to these measures may require laxatives. These can be
classified as
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Review of Pharmacology
Diarrhea
Diarrhea can be treated by antibiotics effective against the causative organism. In noninfective diarrhea, drugs useful are
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ther Dr gs
This long acting somatostatin analog can be used to decrease secretory diarrhea and other
symptoms of carcinoid syndrome and VIPoma. In low doses (50 g, s.c.), it stimulates motility,
whereas at high doses (100-250 g, s.c.), it inhibits motility. In higher doses, it is also useful for
the treatment of diarrhea due to vagotomy, short bowel syndrome and AIDS. It can also be
used for treatment and prophylaxis of acute pancreatitis.
O
ctreoti e
d
ioi s
d
Op
Gastrointestinal Tract
NaCl
3.5 g
2.6 g
KCl
1.5 g
1.5 g
Trisodium citrate
2.9 g
2.9 g
Glucose
20 g
13.5 g
Water
1L
1L
Na
90 mmol/L
75 mmol/L
20 mmol/L
20 mmol/L
Cl
80 mmol/L
65 mmol/L
Citrate
10 mmol/L
10 mmol/L
Glucose
111 mmol/L
75 mmol/L
Total osmolality
311 mosm/L
245 mosm/L
In new formula WHO-ORS, concentration of NaCl and glucose as well as total osmolarity is decreased
because
WHO standard fomula was based on cholera stools in which loss of Na+ was more. There
is a significant decrease in cholera cases and major cause of diarrhea now-a-days is
rota virus. New composition ORS is based on stool composition of rota virus patients.
Use of standard formula ORS has lead to development of edema (excess of sodium) and
increased stool frequency (unabsorbed glucose acts as laxative) in some patients.
Gastrointestinal
Tract
General
Pharmacology
ORS
Gastrointestinal Tract
minosalicylates
Ulcerative colitis and Crohns disease are two distinct disorders classified under inflammatory
bowel disease (IBD).
5-aminosalicylic acid (5-ASA) is the main anti-inflammatory compound that acts
locally in the colon. When given alone by oral route, more than 80% is absorbed in
proximal intestine and very little reaches the diseased site i.e. colon. To decrease the
absorption it may be associated with some inert compound. Sulfasalazine (5-ASA +
sulfapyridine), olsalazine (5-ASA+ 5-ASA) and balsalazide (5-ASA + amino benzoyl
alanine) are effective for the treatment of ulcerative colitis. The inert compound
prevents the absorption in proximal GIT and the combination reaches the colon
where the bacteria cleaves the azo bond to free 5-ASA for action. Approximately 85%
sulfapyridine is absorbed from colon leading to adverse effects.
Different formulations (like time release tablets and coating in pH sensitive
resins that dissolve at pH 7) of 5-ASA have been developed to deliver it to colon.
These formulations are known as mesalamine.
5-ASA is the first line treatment for mild to moderate ulcerative colitis. Efficacy
in Crohns disease has not been established. Absorption of sulfapyridine (in
sulfasalazine) lead to nausea, vomiting, GI upset, bone marrow suppression,
hypersensitivity and oligospermia. Olsalazine may result in secretory diarrhea.
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u
Review of Pharmacology
ethotrexate
It is used for the induction and maintenance of remission of Crohns disease but not
ulcerative colitis.
F-a thera y
p
nti
TN
Gastrointestinal Tract
for
Monoclonal Antibodies
Crohns Disease
Infliximab
Adalimumab
Certolizumab
Natalizumab
Vedolizumab
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hoice
D u
Condition
of
Gastrointestinal Tract
Drug of choice
Peptic ulcer
Gastric ulcer
Duodenal ulcer
PPI
Stress ulcer
PPI
NSAID-induced
PPI
H. pylori associated
PPI
PPI
Vomiting
Chemotherapy induced
Levo-dopa induced
Domperidone
Migraine associated
Metoclopramide
Metoclopramide
Post-operative
Ondansetron
Radiation induced
Ondansetron
Cisplatin - induced
* Early
5-HT3 antagonists
Aprepitant
Hyoscine
Doxylamine + Pyridoxine
* Delayed
-
Methyl naltrexone
Octreotide
ORS
Crohns disease
Corticosteroids
Ulcerative colitis
5-ASA derivatives
Hepatic encephalopathy
Lactulose
Gastrointestinal
Tract
General
Pharmacology
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