Transcript 2- Regulation of gastric acid secretion A

Drugs acting on
gastrointestinal tract
Dr. Nahla Othman
Pharmacology lecture
3rd class
Medical college
Drugs acting on gastrointestinal
tract
1- Drugs used for peptic ulcer disease
2- Drugs used for to control chemotherapy
induced emesis
3- Antidiarrheals
4- Laxatives
5- Drugs acting on inflammatory bowel
diseases.
Drugs used to treat peptic ulcer disease
Peptic ulcer
Psychosomatic disorder in about 10% of
adults, due to imbalance between
gastric acid secretion and mucosal
resistance (production of mucus and
bicarbonate).
The major causative factors for peptic ulcer
1- Non-steroidal anti-inflammatory drugs
(NSAIDs)
2- Infection with gram negative Helicobacter
pylori (H. Pylori ): in 70% of G.U and 90% of
D.U
3- Increased hydrochloric acid secretion
4- Inadequate mucosal defense against gastric
acid and pepsin
Treatment approaches include
1- Antimicrobial therapy : Eradication the H.
pylori infection.
2- Drugs that decrease gastric acid secretion:
use of H2 antagonists and /or proton pump
inhibitors.
3- Drugs that neutralize gastric acid: Use of non
absorbable antacids.
4- Drugs that enhance mucosal defense:
Providing agents that protect the gastric mucosa
from damage, such as misoprstol and sucralfate.
5- Stop smoking
1- Antimicrobial agents
To document infection with H. pylori,
endoscopic biopsy of the gastric mucosa or
various noninvasive methods are utilized
including serologic tests and urea breath
tests.
Eradication of H. pylori is closely associated
with the gastric ulcers and low recurrence
rates
1- Antimicrobial agents
Currently, either triple therapy consisting of a PPI
with either metronidazole or amoxicillin plus
clarithromycin, or quadruple therapy of bismuth
subsalicylate and metronidazole plus tetracycline
plus a PPI.
Course: administered for a 2-week course.
This usually results in a 90 percent or greater
eradication rate.
Note:
 Single antimicrobial drug is less effective
 Switching of antibiotics is also not recommended (do
not substitutes one antibiotic with other)
2-Drugs that decrease gastric acid
secretion:
A- H2 -receptor antagonist
B- Inhibition of the H/K- ATPase proton
pump
C- Prostaglandins
D- Antimuscarinic agents (anticholinergic
agents)
2- Regulation of gastric acid secretion
A- H2 -receptor antagonist
By blocking the binding of histamine to H2
receptor, these agents reduce the intracellular
concentrations of cyclic AMP and thereby
secretion of gastric acid. They inhibit basal,
food stimulated and nocturnal secretion of
gastric acid after a single dose.
 Cimetidine (prototype, its utility is limited
because of adverse effects and drug interaction).
 Ranitidine
 Famotidine
 Niatidine
H2-receptor Blockers
Scientific
name
Trade
name
Relative
potency
Daily
dosage
Cimetidine
Tagamet
1x
800 mg H.S
or 400 mg
Bid
Ranitidine
Famotidine
Nizatidine
Zantac
Pepcid
Axid
4-10x
20-50x
4-10x
300 mg H.S or
150 mg Bid
40 mg H.S or
20 mg Bid
300 mg H.S or
150 mg Bid
A- H2 -receptor antagonist
Therapeutic uses
1- Peptic ulcer ( G. U, D.U)
2- Gastrophageal reflux disease (GERD)
3- Hhypersecretory conditions :
A. Zollinger – ellison syndrome ( gastrin secreting tumor)
B. Systemic mastocytosis
C. Multiple endocrine neoplasia ( MEN ) .
4- pre-anesthesia: (emergency and labour) to decrease
incidence of mendelson's syndrome (aspirating
gastric
acid causing aspirating pneumonitis).
5- Controlling symptoms of gastric carcinoma.
6- Hiatus hernia (H.H).
7- Acute stress ulcer
8-Iatrogenic ulcer.
Side effects
Headache, diarrhea, dizziness, and muscle
pain
For cimetidine can also have antiandrogen
effects gynecomasa and galactorrhea.
Cemitidine also inhibit liver metabolism
cause many drug interactions
2- Regulation of gastric acid secretion
B- Inhibitors of the H⁺/K⁻-ATPase proton
pump
Omeprazole- the prototype
Lansoprazole
Pantoprazole
Rabeprazole
Esomeprazole
Uses
1- Erosive esophagitis and active duodenal
ulcer
2- Long-term treatment of pathologic
hypersecretory condition conditions
(Zollinger-Ellison syndrome in which gastrin
is increased)
3- In the treatment of GERD
4- Reduce risk of bleeding from an ulcer by
NSAIDs
Adverse effects
1- Generally well tolerated, but concerns
about long term safety have been raised
due to increased secretion of gastrin (in
animal studies with increase in gastric
carcinoid tumors)
2- Drug interaction in the oxidation of many
drugs such as warfarin.
2- Regulation of gastric acid secretion
C- Prostaglandins –
Misoprostol –prostaglandin analogue of E1
Synthetic analog of PGE1, it prevents G.U in
patients taking NSAIDs, chronic D.U and
G.U.
Side Effects: Dysmenorhea and rash
Contraindications: Pregnancy
2- Regulation of gastric acid secretion
D- Antimuscarinic agents
Dicycamine, a cholinergic antagonist, can
be used as an adjunct in the management
of peptic ulcer and zollinger-Ellison
syndrome.
Side effects:
1- cardiac arrhythmias
2- urinary retention
limit its use.
3- Neutralization of gastric acid:
Antacid
They are weak bases that react with gastric
acid to form water and salt.
Pepsin is inactive at a pH greater than 4.
Antacid reduces H. pylori and stimulate
prostaglandin synthesis.
Therapeutic uses





Combination of aluminum and magnesium
can be used for duodenal ulcer.
Aluminum hydroxide- causes constipation
Magnesium trisilicate- causes diarrhea
Calcium carbonate is used as calcium
supplement for the treatment of osteoporosis
Antacid containing sodium such as sodium
bicarbonate should be considered in patients
with hypertension or congestive heart failure.
- Enhancement of mucosal resistance:
Mucosal protective agents
Sucralfate
This complex of aluminum hydroxide and
sulfated sucrose binds to positively charged
groups in proteins of both normal and
necrotic mucosa. By forming complex gels
with epithelial cells. Sucralfate creates a
physical barrier that impairs that diffusion of
HCl and prevents degradation of mucus by
pepsin and acid.
It also stimulates prostaglandin release as
well as mucus and bicarbonate output.
Bismuth chelate:
Colloidal bismuth
In addition to their antimicrobial actions,
they inhibit the activity of pepsin, increase
secretion of mucus, and interact with
glycoprotein in necrotic mucosal tissue to
coat and protect the ulcer crater ‫الحفر‬
3- Drugs used to control vomiting

Vomiting : is a protective mechanism to
remove harmful or irritant substances from
upper GIT , controlled by vomiting center in
medulla
2- Drugs used to control vomiting
2- Drugs used to control vomiting
1-Anticholinergic : Hyosine or Scopolamine
(Atropine)
2-H1-blockers: Cyclizine , Meclizine ,
Diphenhydramine, dimenhydrinate ,
promethazine
3-Dopamine ( D2) antagonists:
-Metoclopramide ( plasil) , Domperidone (CRTZ ,
gut).
-Haloperidol (CRTZ).
-Chlorpromazine(largactil), Promazine ,
prochlorperazine (Stemetil) (CRTZ,vomiting
center)
2- Drugs used to control vomiting
4- 5-HT3-Blockers : Ondansetron,
Tropisetron & granisetron.
5-Others : Dexamethasone ,
methylprednisolone , Diazepam &
lorazepam.
3- Drugs used to control chemotherapy
induced emesis
Mechanism of action-
Drugs used to control vomiting
Phenothiazines
Prochlorperazine acts by blocking
dopamine receptors. Although increasing
the dose improves antiemetic activity, side
effects including:
 Hypotension and restlessness are dose
limiting.
 Extrapyramidal symptoms and sedation.
5-HT3 serotonin-receptor blockers
Ondansetron, granisetron are selectively
block 5-HT3 receptor in the periphery
(visceral vagal afferent fibers) and in the
brain. (chemoreceptor trigger zone).
Headache is the common side effect. These
drugs are costy.
Substituted benzamides
Metoclpramide is highly effective at high
doses against the highly emetogenic
cisplatin.
Antidopaminergic side effects, including
sedation, diarrhea and extrapyramidal
symptoms.
The adverse reaction are most common in
younger patients
1-Metoclopramide (plasil):
Prokinetics(drugs
promoting
GIT
motility )
Antiemetic , prokinetic , blocks
dopamine receptors in CRTZ ,
enhances actions of Ach on Mreceptors in GIT, elevates the tone of
lower esophageal sphincter, increasing
peristalsis & emptying upper GIT , it
also stimulates prolactin secretion
leading to galactorrhea .
Indications:
Nausea , vomiting , pre-anesthesia ,
GERD , radiotherapy , endoscopy &
migraine .
Side effects :
-extrapyramidal dystonia , torticollis ,
Parkinsonism , gynaecomastia &
lactation .
Oculogyric crisis :
Oculogyric Crisis usually occurs as a side
effect of neuroleptic drug treatment. It is
one
of
the
acute
dystonic
reaction(torticollis & blepharospasm) ,
treated
by
procyclidine
or
diphenhydramine & diazepam .
Drug interactions:
Atropine(anti-M) as it enhances the action of
Ach on M-receptors .
Butyrophenon
Domperidone and haloperidol act by
blocking dopamine receptor. They are
moderately effective antiemetics.
Benzodiazepines
The antiemetic potency of lorazepam and
alprazolam is low. Their beneficial effects
may be due to their sedative, anxiolytic
and amnesic properties
Corticosteroids
Dexamethazone and methylprednizolone,
used alone, are effective against mildly to
moderately emetogenic chemotherapy.
They are used in combination with other
agents.
Their antiemetic mechanism is not known,
but it may involve blockade if
prostaglandins.
Drugs used to treat diarrhea:
Treatment of the cause
 Correction of fluids and electrolytes
imbalance .
 Treatment is by increasing viscosity
(pectin ,kaolin ,chalk ) ,binding
toxines ,delaying passage of contents
(opiods) ,and decreasing the motility
of intestine (by inhibiting Ach.
Release ).

Antidiarrheals
A- Antimotility drugs
Diphenoxylate, loperamide are analogues of
meperidine and have opioid like action on
the intestine.
Side effects
Drowsiness, abdominal cramp, dizziness,
toxic megacolon. They should not be used
in young children and in patients with
severe colitis.
B- Adsorbents
Kaolin, pectin, methyl cellulose, Aluminum
silicate, Aluminum hydroxide
They act by adsorbing intestinal toxins or
microorganisms and /or by coating or
protecting the intestinal mucosa.
They are much less effective than
antimotility agents. They can interfere
with the absorption of other drugs.
C- Agents that modify fluid and
electrolyte transport
Bismuth subsalicylate, used for traveler
diarrhea, decreases fluid secretion in the
bowel. Its action may be due to its
salicylate component as well as its coating
action.
Laxatives
Laxatives are commonly used to accelerate
of food through the gastrointestinal tract.
Laxative- ‫ملين‬
Cathartic - ‫مسهل‬
Small doses of these drugs are laxative
High doses (except balk are cathartics)
Laxatives
A- Irritant and stimulants
Caster oil- promptly increases peristalsis.
Cascara, senna, aloe- delayed for 6-8 hours,
because they contain emodin which is
excreted into the colon after these agents are
absorbed.
Bisacodyl is a potent stimulant of the colon
Side effects
Abdominal cramps and the potential of atonic
colon with prolonged use.
B- bulk laxatives
Hydrophilic colloids (indigestible parts of
fruits and vegetables. They form gels in
the large intestine, causing water retention
and intestinal distension, thereby
increasing peristaltic activity.
Similar actions are produced by agar, and
bran
C- Saline cathartics
Magnesium sulfate and hydroxide are non
absorbable salts that hold water in the
intestine by osmosis and distinct the
bowel increasing intestinal activity
Lactulose is a semisynthetic disacharide
(fructose and galactose) also act as an
osmotic laxative
D- Stool softeners (emollient laxatives or
surfactants)
Surface-active agents that become
emulsified with the stool produce softer
feces and ease passage.
Docusate sodium
Mineral oil
Glycerin suppositories
Drugs used to treat Irritable Bowel
Disorders:(Crohn’s disease , Ulcerative colitis)
1-Sulphasalazine: It’s a combination of
sulphapyridine and 5-aminosalicylic acid
,used to treat ulcerative colitis more
than crohn’s disease.
MOA: cytoprotective action ,or
inhibition of breakdown of PGF2 alpha
,or by suppressing immune response.
Side Effects: serum sickness ,bone
marrow suppresion ,and oligospermia.
2-Prednisolone
3-Azathioprime
4-Mercaptopurine
Drugs used to treat Hemorrhoids:
1-Soothing agents:
a-Astringents: Bismuth , Zinc oxide , and
Benzylbenzoate .
b-Local anesthetics: Lignocaine.
2-Corticosteroids: Betamethasone ,
hydrocortisone , and prednisolone.
3-Rectal sclerosants: Oily phenol
injection 5%.
Drugs used to treat gall bladder disease:
1-Ursodiol
2-Chenodiol
MOA:
supress hepatic synthesis of
cholesterol and cholic acids.
Side Effects: change hepatic function and
diarrhea.