1

Outlines 2

 Introduction

 Pharmacology of drugs used for treatment of

 GERDs and PUD

 diarrheal disease

 Constipation,

 nausea and vomiting

GIT Pharmacology by Nardos 6/5/2025

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1. Peptic Ulcer Disease (PUD)

 Localized defect in the mucosa of any part of the GIT.

 The three common forms of peptic ulcers include:

1. Helicobacter pylori (H.pylori) – associated ulcer

2. Nonsteroidal anti-inflammatory drug (NSAID)–

induced ulcers

3. Stress-related mucosal damage (also called stress

ulcers)
GIT Pharmacology by Nardos 6/5/2025
1. Peptic Ulcer Disease (PUD)

Duodenal ulcer Gastric ulcer

 5
[Symptoms and complications]

 The most important symptom is abdominal pain and discomfort.

 Epigastric pain, which comes 90 min to 3 h after eating

 Atypical symptoms are abdomen distention, inappetence, belching,

reflux of gastric acid.

 The severe complications are hemorrhage, perforation, obstruction

and canceration.
GIT Pharmacology by Nardos 6/5/2025
 6
Pathogenesis of peptic ulcer]

 There are 3 glands in the stomach

 Cardiac

 Pyloric

 Gastric*

 Gastric gland has primary importance in acid peptic

disease.

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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Pathogenesis …….Cont.

 The 3 cells of gastric gland;

 Parietal cells--Produce and secrete HCl

 Chief cells--- Secrete pepsinogen

 Mucoid cells--- Mucus-secreting cells

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

 Pathogenesis …….Cont.

 The imbalance of the three cells of the gastric gland

and their secretions causes acid-peptic diseases.

1. Defensive factors…↓ ulcer formation

 Mucus-bicarbonate barrier, prostaglandins

2. Aggressive factors….↑ ulcer formation

 H. Pylori, NSAIDs, gastric acid and pepsin

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1. Mucosal ulcer Defensive factors

Mucus-bicarbonate barrier

 The epithelial layer of the mucosa is composed of tightly

adjoined cells

 Mucous coat the epithelial cells and it creates a physical

barrier that protects the ulcer from pepsin, acid and
H.pylori, allowing the ulcer to heal.

 Bicarbonate is alkali which neutralizes gastric acid

6/5/2025

GIT Pharmacology by Nardos

 10
Mucosal ulcer Defensive factors
cont’d…
Prostaglandins(PGs)

 Prostaglandins are thought to enhance resistance to

injury by:

o Maintaining blood flow to the mucosa.

o Facilitates mucous and bicarbonate production

o Inhibits gastric acid secretion

GIT Pharmacology by Nardos 6/5/2025
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2. Mucosal ulcer aggravating
factors
 Helicobacter Pylori ( H. Pylori)

 In PUD, despite the imbalance Over 90% of peptic ulcers

are caused by infection with the bacterium Helicobacter
pylori or by use of NSAIDs.

 H.pylori is the most important pathogenic factor to

peptic ulcer which can directly damage mucosal layer

 “No H.pylori, No ulcer.”

 Discovered by 2 Australian scientists. 6/5/2025

GIT Pharmacology by Nardos

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Aggravating factors cont’d….

Pepsin
 Can decompose mucosal protein molecule.
 But its activity is depended on the pH value. Active at low
PH
 When local pH value elevates to 4, pepsin can’t work well.
NSAIDs
 Inhibits the synthesis of prostaglandins.
Gastric acid (HCl)
 Is the key-factor of the formation of peptic ulcer.
 Gastric acid can directly damage mucosal layer
 We can also say that “No acid, no ulcer.” 6/5/2025
 13
Physiology of acid secretion

 Parietal cell contains receptors for gastrin (CCK-B), histamine

(H2), & acetylcholine (muscarinic, M3).

 When acetylcholine (from vagal postganglionic nerves) or

gastrin (released from antral G cells into blood) bind to parietal
cell receptors

 cause increase in cytosolic calcium → stimulates protein

kinases → stimulate acid secretion from a H+,K+ ATPase
(proton pump) on canalicular surface.
GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
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Fig; Schematic model for physiologic control of hydrogen ion (acid) secretion by
GIT Pharmacology by Nardos for pc-II medical students 2015
the
6/5/2025
parietal cells of the gastric fundic glands.
 15
Physiology of acid secretion…..cont.

 In close proximity to parietal cells are gut endocrine cells

called enterochromaffin-like (ECL) cells

 ECL cells have receptors for gastrin & acetylcholine, which

stimulate histamine release.

 Histamine binds to H2 receptor on parietal cell, resulting in

activation of adenylyl cyclase, which increases cAMP &
activates PKs that stimulate acid secretion by H+,K+ ATPase.
GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
 Mechanism of HCl, HCO3- and mucous production
ACh
Gastrin Cl-, K+
M1
transport
+
G
Protein K+
Histamine H2 + kinase H+, K +
ATPase
PG
_ H+
ECL cells
Parietal cells

Prostag Mucous
landin
PG
+ + HCO3-
+ Mucous Gastric
Superficial epithelial cells lumen lumen
PH=7 PH=2
 17
Cont.…

 Therefore when mucosal aggravating factors overwhelmed

the defensive factor, Acid-peptic disorder, so that

 we need a drug,

 that reduce intragastric acidity

 that promote mucosal defense

 eradicate the H. pylori infection, (Triple & Quadruple

6/5/2025
therapy)
 Classification of drugs for PUD & 18
GERD

I. Antacids (neutralizes the acid )

Ⅱ. Agents decreasing secretion of gastric acid

Ⅲ. Agents protecting mucosal barrier

(Cytoprotective agents)

Ⅳ. Agents eradicating H.pylori (Antimicrobials)

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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I. Antacids

 Are weak alkalis that bring about:

 Neutralization of the already formed gastric acid

in the stomach

 They provide symptomatic relief in PUD and GERD

 They were the mainstay of treatment for PUD until

the advent of Antisecretory agents.
6/5/2025
 20
Antacids Cont.…

Weak bases : Mg(OH)2, Al(OH)3, CaCO3, NaHCO3

Actions: neutralization that enables to:

Reactions

NaHCO3+HCl → Nacl+H2O+CO2↑

Al(OH)3+3HCl → AlCl3+3H2O

Mg(OH)2+HCl → MgCl2+2H2O

CaCO3+2HCl → CaCl2+H2O+CO2 ↑
6/5/2025
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Antacids Cont.…

They can be classified as systemic or non-systemic antacids

1. Systemic antacids :

 Sodium bicarbonate

 After oral administration it is absorbed and may cause alkalosis.

 It is usually present in compound indigestion remedies.

 It should be used with care in patients on salt restricted intake (e.g. patients with

hypertension, CHF).
6/5/2025

 Should be used for short-term periods.

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Antacids Cont.…

 calcium-containing salts

 These can induce rebound acid secretion and so should not be used for
prolonged periods.

 Prolonged high doses may also cause hypercalcemia and alkalosis.

2. Non-systemic antacids

 These are antacids that are not absorbed & free of systemic toxicity

 They include aluminum salts, magnesium salts and mixture of

aluminum- magnesium preparations.
6/5/2025
 23
Antacids Cont.…

Mixtures of Magnesium trisilicate and Aluminium

hydroxide

 First line for non-H.pylori associated PUD along

with H2-receptor blockers.

 Dosage forms: chewable tablet, 400mg + 400 mg,

suspension, 195mg + 220mg in 5 ml.

6/5/2025
 24
Antacids Cont.…

Side-effects of antacids
 Aluminum: constipation, phosphate depletion

 Magnesium: diarrhea

 Mixed compound is free of constipation and diarrhea

 Calcium carbonate: rebound acid secretion, hypercalcemia,

alkalosis

 Sodium bicarbonate: hypernatremia, bicarbonate alkalosis,

increases BP 6/5/2025
 25
Ⅱ Agents reducing secretion of gastric acid

1. H2-receptor antagonists

2. Antimuscarinic agents

3. Inhibitors of the proton pump

4. Gastrin-receptor antagonists

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

Anti-secretary agents cont’d…

PPIs
H2RBs Cl-, K+
M1
transport
+
G
K+
H2 + PK H+, K +
ATPase
MRBs
_
PG r H+
Parietal cells

Mucous
Proglumide
PG
+ + HCO3-
+ Mucous Gastric
Superficial epithelial cells lumen lumen
PH=7 PH=2
 27
H2-R antagonists

Cimetidine, Ranitidine, Famotidine , Nizatidine

MOA:

 Competitively & reversibly block the binding of histamine to H2

receptor in the parietal cells.

 Completely inhibit gastric acid secretion induced by histamine

characteristics:

 More effective than M-R antagonists; long duration; high rate of

healing up; but rebound acid secretion is the major problem
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Pharmacokinetics

 High bioavailability with oral route of administration

 Cimetidine, ranitidine, and famotidine are also available in IV form.

 Distribute widely throughout the body (including breast milk and

across the placenta)

 Cimetidine inhibits hepatic microsomal (CYP 450) enzymes

 Excreted mainly in urine.

 The half-life of all of these agents may be increased in patients with

renal dysfunction, and dosage adjustments are needed.
 29
[Clinical uses]

① PUD :

 All four agents are equally effective in promoting the

healing of duodenal and gastric ulcers without H.pylori.

 However, recurrence is common if H. pylori is present and

the patient is treated with these agents alone.

 Patients with NSAID-induced ulcers should be treated

with PPIs, because PPIs heal and prevent future ulcers
more effectively than H2 antagonists do.
 30
[Clinical uses] cont’d…

① PUD cont’d…

 These drugs can be given as an IV infusion to prevent and

manage acute stress ulcers associated with high-risk

patients in intensive care units.

 However, because tolerance may occur with these agents in

this setting, PPIs have gained favor for this indication.

 31
[Clinical uses] cont’d…

② Zollinger-Ellison syndrome (ZES) :

 A fatal disorder in which a gastrin-producing tumor on

pancreas causes hypersecretion of gastric acid.

 In many patients, H2 receptor antagonists can effectively

keep the acid secretion to safe levels so as to control

symptoms related to excess acid secretion due to ZES

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[Clinical uses] cont’d…

③ Gastro esophageal reflux disorder (GERD):

 Back flow of HCl to esophagus and irritate its lining and cause
burning sensation at the chest. AKA heart burn

 H2-receptor antagonists are effective for the treatment of heartburn

(GERD) in only about 50% of patients.

 Antacids more quickly and efficiently neutralize stomach acid, but

their action is only temporary.

 For these reasons, PPIs are now used preferentially in the treatment
of GERD, especially for patients with severe heartburn.
 33
Brainstorming

 H2 antagonists are especially effective at

inhibiting nocturnal acid secretion. But they
have a modest impact on daytime meal-
stimulated acid secretion.

 ????

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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[Adverse reactions]

 In general, the H2 antagonists are well tolerated.

 The common side effects includes: headache, dizziness,

diarrhea and muscular pain, skin rash

 Cimetidine can have anti-androgen and prolactin-

stimulating effects.

o Gynecomastia ( in male) and galactorrhea (continuous

release/discharge of milk in female).
GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
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[Adverse reactions]..cont’d

 Cimetidine inhibits several cytochrome P450 isoenzymes and

can interfere with the metabolism of many other drugs, such
as warfarin, phenytoin, and clopidogrel

 CNS effects (confusion and altered mentation) occur

primarily in elderly patients and after IV administration.

 All H2 antagonists may reduce the efficacy of drugs that

require an acidic environment for absorption, such as
ketoconazole.
 36
Cont.….

 Ranitidine was withdrawn from the market

in the U.S. in 2020 due to a cancer-causing
impurity.

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

 37
Inhibitors of the proton pump

Omeprazole, lansoprazole, esomeprazole, pantoprazole,

dexlansoprazole, rabeprazole
 These agents are prodrugs with an acid-resistant enteric coating
o To increase their concentration at the site of action and protect them
degradation by gastric acid.

o The coating is removed in the alkaline duodenum

o The prodrug, a weak base, is absorbed and transported to the parietal cell.

o There, it is converted to the active drug and forms a stable covalent bond
with the H+/K+-ATPase enzyme 6/5/2025
 38
Inhibitors of the proton pump
cont’d…
 Bind with proton pump (final steps of acid secretion)

irreversibly.

 At standard doses, PPIs inhibit both basal and stimulated

gastric acid secretion by more than 90%.

 The most efficacious and potent anti-secretory agent

 The prodrug is weak alkali needs basic PH for fast

absorption
GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
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[Pharmacokinetics]

 All of these agents are effectively absorbed orally.

 PPIs should be taken 30 to 60 min before meals. Why???

 Although the plasma half-life of these agents is only a few

hours, they have a long duration of action due to covalent
bonding with the H+/K+- ATPase enzyme.

 It takes about 18 hours for the enzyme to be resynthesized

 Metabolites of these agents are excreted in urine and feces.

 40
[Clinical uses]

 The PPIs are superior to the H2 antagonists in suppressing acid

production and healing ulcers.

 They are the preferred drugs for prophylaxis & treatment of

1. Peptic ulcer: especially stress & NSAID induced

2. H.pylori induced ulcer (as part of triple therapy

3. GERD

4. Zollinger-Ellison syndrome (ZES)

 May be combined with H-2 receptor blockers (but PPIs should
be always taken before H2RBs) 6/5/2025
 41
[Clinical uses]: GERD

 If a once-daily PPI is only partially effective for GERD symptoms,

 Increasing dosing to twice daily or

 Administering the PPI in the morning and adding an H2 antagonist in the

evening may improve symptom control.

 If an H2-receptor antagonist is needed, it should be taken well after the

PPI.

 As H2-receptor antagonists reduce the activity of the proton pump, and

PPIs require active pumps to be effective.
 42
[Adverse reactions]
 Extremely safe

 G.I reactions: Abdominal discomfort, diarrhea

 Due to intestinal bacterial overgrowth
 D/C if patients have diarrhea for several days

 Omeprazole & esomeprazole ↓ the effectiveness of clopidogrel

 Inhibit CYP2C19 and prevent the conversion of clopidogrel to its active metabolite.

 Prolonged acid suppression with PPIs may result:

o Low vitamin B12 & iron in blood…pregnant

o Hypomagnesaemia & hypocalcaemia

o Decreased absorption of some drugs

o They need acidic PH for their absorptionGIT Pharmacology by Nardos for pc-II medical students 2015
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[Adverse reactions] cont’d…

 All PPIs may reduce the efficacy of drugs that

require an acidic environment for absorption, such
as ketoconazole.

 Intestinal bacterial overgrowth

- Increased risk of C.difficile infection

- Increased risk of hospital-acquired pneumonia

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

 44
Ant muscarinic agents

 Muscarinic receptor stimulation increase

gastrointestinal motility and secretion.

 So cholinergic antagonists can be used as adjuncts

in the management of PUD and ZES, particularly

in patients refractory to standard therapies.

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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Ant muscarinic agents…cont.

 In contrast to the classic anticholinergic agents (atropine), the

relatively specific M3-receptor antagonist, Pirenzepine is a

good choice as an anti-secretory agent.

o Because it suppresses cholinergic receptor stimulated gastric

acid secretion at doses having a minimal effect on other

organs (salivary glands, the heart and eye)

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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Ⅲ Agents protecting mucosal
barrier

 Also known as cytoprotective agents

(1) Prostaglandins

(2) Other mucosal protective agents

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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1. Synthetic prostaglandins

 stimulate secretion of mucus and bicarbonate

(cytoprotective effect) .

 Increases blood flow to the site ( cause vasodilation)

 So, deficiency of prostaglandins is thought to be

involved in the pathogenesis of peptic ulcers.

 Synthetic prostaglandin are unstable so they are not

indicated clinically 6/5/2025
 48
Misoprostol

 Stable analog of PG E1

 Only approved synthetic prostaglandin for NSAID-induced ulcer

 However, PPIs are preferred agents for the prevention of

NSAID-induced ulcers.

Adverse reactions:

 C/I in pregnancy since it can stimulate uterine contractions and

cause miscarriage (abortion). 6/5/2025
GIT Pharmacology by Nardos for pc-II medical students 2015
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Other mucosal protective agents

Sucralfate

 This complex of aluminum hydroxide and sulfated sucrose binds to

positively charged groups in proteins of both normal and necrotic GI

mucosa.

 By forming complex gels with epithelial cells, it creates a physical

barrier that protects the ulcer from pepsin, acid and H.pylori,

allowing the ulcer to heal.

 50
Sucralfate cont’d..

 Although it is effective for the treatment of

duodenal ulcers and prevention of stress
ulcers, its use is limited due to

– The need for multiple daily dosing

– It requires an acidic pH for activation, it

cannot be administered with PPIs, H2
antagonists, or antacids. 6/5/2025

GIT Pharmacology by Nardos for pc-II medical students 2015

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Sucralfate cont’d..

– It can interfere with the absorption of other drugs

by binding to them.

– It does not prevent NSAID-induced ulcers, and

does not heal gastric ulcers.

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Bismuth subsalicylate

 This agent is used as a component of quadruple therapy to

heal peptic ulcers. Doesn’t need acid PH

 Effects includes:
 Antibiotic actions

 Increase prostaglandin synthesis

 Inhibits pepsin activity

 Interacts with glycoproteins in necrotic mucosal tissue to coat and

protect the ulcer.
6/5/2025
 53
Ⅳ. Agents eradicating H. pylori

 Treatment with a single antimicrobial drug is much less

effective and is not recommended.

 As it results in antimicrobial resistance

 GERD (heartburn) is not associated with H. pylori

infection

 Does not respond to antibiotic therapy. 6/5/2025

 54
Agents eradicating H. pylori
Cont.…
First line

 Amoxicillin, 1g, p.o. BID + Clarithromycin, 500mg p.o. BID + Omeprazole,

20mg p.o. BID(or 40mg once daily) X 7-14 days

 Clarithromycin, 500mg p.o. BID + Metronidazole, 500mg, p.o. BID +

Omeprazole, 20mg p.o. twice daily (or 40mg once daily) X 7-14
days…….Penicillin allergic patients or resistant microorganism

 Bismuth 525 mg QID plus TTC 500 mg QID plus metronidazole 500 mg TID
plus omeprazole 20 mg BID for 14 days…quadruple therapy if clarithromycin
fails
 55
II. Antidiarrheal agents

Diarrhea may be due to:

 Increased motility of the gastrointestinal tract

 Decreased absorption of fluid from GIT to blood

 Increased secretion of fluid from blood to GIT

 So antidiarrheal include anti-motility agents, adsorbents and

drugs that modify fluid and salt transport.
6/5/2025
 56
1. Anti-motility agents

Loperamide, Diphenoxylate….opioid GI motility

 Opioids are the most effective agents for relief of diarrhea.

 Activates opioid receptors in presynaptic parasympathetic nerves→

decrease release of Ach and decrease peristalsis

 Is used to control acute or chronic diarrhea

 They lack analgesic effects as limited access to CNS

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
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2. Adsorbents

Medical charcoal

 They act as absorbents of bacteria, toxins, and fluid, thereby

decreasing stool liquidity and quantity.

 They may be useful in acute diarrhea but are seldom used on

a chronic basis

 They are much less effective than anti-motility agents

 They can interfere with the absorption of other drugs.

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
3. Agents that modify fluid and electrolyte58
transport

Bismuth subsalicylate

 Decreases fluid & electrolyte secretion in the bowel.

 Its action may be due to its salicylate component as well as

its coating action.

 Adverse effects may include black tongue and black stools.

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
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III. Laxatives (purgatives)

 Agents used for the treatment of constipation

Types of laxatives

1. Stimulant laxatives : Bisacodyl, senna, castor oil

 Increases peristaltic movements and increases secretions from blood

 With docusate (stool softener), senna is useful in treating opioid-induced

constipation.

 Bisacodyl is available as suppositories and enteric-coated tablets

 Pregnant patients should avoid castor oil because it may stimulate uterine
contractions. It is also an irritating agent
 60
Types of laxatives cont’d..

2. Bulk laxatives: Lactulose, Glycerin, methylcellulose

 Add liquidity & bulkiness on stool so it can pass easily through GI

3. Osmotic laxatives: Magnesium sulfate, magnesium hydroxide

 Non-absorbable salts that hold water in the intestine.

4. Stool softeners (Surfactants,Emolintes): Docusate

 that become emulsified with the stool & produce softer feces

 lower surface tension of fluid in bowel

 61
Types of laxatives cont’d..

 5 Lubricants

 facilitate the passage of hard stools by lubricate the

fecal material and intestinal walls.

 Mineral oil (liquid paraffin) and glycerin suppositories

are lubricants.

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IV Antiemetic

 Brain stem (vomiting center) coordinates

complex act of vomiting

 CTZ, vestibular system, vagal & spinal afferent

nerve from GIT & CNS are Four important
sources of afferent input to vomiting center

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Antiemetic…cont.

 Chemoreceptor trigger zone (CTZ)..rich in

 Rich in dopamine D2, opioid, 5-HT3 & NK1

receptors
 Vestibular system: rich in M1 & H1 receptors
➲ Important in motion sickness
 Vagal & spinal afferent nerves from GIT &CNS
 Rich in SHT3, chemotherapy GI irritation cause
release of 5HT3 and send input to CTZ and VC
GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025
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GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025

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Antiemetic…cont.

 Antiemetic agents: Types

1. Anti-motion sickness (H1 & M blockers)

Scopolamine, dimenhydrinate, meclizine, promethazine, cyclizine

 Are very useful in motion sickness

 Promethazine can be used for vomiting in pregnancy

 Ineffective against substances that act directly on the CTZ & GIT
receptors.
 Xerostomia, hyperthermia, constipation, decrease HR, sedation are some of their
ADRs
 66
Antiemetic…cont.

2. Dopamine-2 receptor blockers

Metoclopramide, haloperidol, chlorpromazine

 Act by blocking dopamine-2 receptors in CTZ.

 Effective against low or moderately emetogenic chemotherapeutic agents

 Can be used for vomiting in pregnancy

 Although increasing the dose improves antiemetic activity, ADRs are dose
limiting.
 Extrapyramidal side effects are common, D2 block in substantia nigra.
 Depression…. D2 block in mesolimbic pathway
 67
Antiemetic…cont.

5-HT3 receptor blockers

Ondansetron, granisetron, palonosetron and dolasetron

These agents selectively block 5-HT3 receptors GIT and CTZ.

 They are important in treating emesis linked with chemotherapy

 Largely because of their longer duration of action and superior efficacy.

 These drugs can be administered as a single dose prior to chemotherapy

(intravenously or orally)

 Efficacious against all grades of emetogenic chemotherapeutics

 Useful in the management of postoperative nausea & vomiting

Table: Choice of antiemetic in specific 68
clinical settings

6/5/2025
 69

GIT Pharmacology by Nardos for pc-II medical students 2015 6/5/2025