Chapter-7. Med Chemistry pptx

CHAPTER 7
GASTROINTESTINALAGENTS
By; Mona F(Msc)

Introduction
Gastrointestinal Tract (GIT)
Continuous tube extending from the
Mouth to the anus
Major function:
 Convert complex compounds into simpler
compounds that can be absorbed and used by
cells
Also excretes waste products from the body
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Introduction cont.
Characteristic feature of mammalian stomach
It has an ability to secrete acid as part of its involvement in food
digestion
Presence of acid in the stomach or low pH
 Stimulates production of proteolytic pepsin enzymes
 Acidic pH and proteolytic enzymes
Required for hydrolysis of proteins & other foods
 Gastric acid secretion is stimulated by food-related signals that
stimulate
The release of acid from specialized cells within the stomach,
i.e. parietal cells
4

Gastric Acid (HCl)
 Uses:
Kill bacteria found in ingested food & drink
Soften fibrous foods
Promotes formation of the proteolytic enzyme, pepsin
Pepsin:- formed from pepsinogen when the pH of the
gastric content drops below 6 (pH<6)
Thus, the lack of gastric HCl could reasonably cause
gastrointestinal disturbances
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Phases of Gastric Secretion
 The gastric secretory process has been divided into three
phases:
Cephalic
Gastric &
Intestinal
With each phase leading to different amounts of acid
being secreted
Mona. F(Medchem I)

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Cephalic Phase
The sight, smell, taste, and sensation of
swallowing food causes central
stimulation of the vagus nerve leading to
 ACh release from synapses within
the fundic and antral regions of the
stomach
 Direct stimulation of the parietal cells
within the fundus and
To a lesser degree, the indirect
stimulation of Histamine release, through
vagally stimulated gastrin release from G-
cells within the antrum
Causes the parietal cells to secrete
acid into the stomach

Gastrin is the main mediator of acid secretion
Acid secretion occurs in response to both the presence of
nutrients and the physical distension produced by food entering
the stomach
Distension-induced gastric acid secretion, relative to the total
amount of acid released, is species dependent (human=20%;
dog=50%; rat = 38%)
The chemical constituents of a meal are the strongest stimulant
of gastrin release and acid output during the gastric phase
With peptides and amino acids being greater stimulants of
gastrin than proteins, carbohydrates, and fats
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Gastric Phase
Mona. F(Medchem I)

Intestinal Phase
Only a relatively small amount of acid is secreted
 Because of the numerous inhibitory mechanisms stimulated
by the presence of nutrients within the intestinal lumen
Acid is secreted by the parietal cells of the gastric mucosa
Parietal cells contain H+ ion pump
A unique H3O+/K+ ATPase system
That secretes H3O+ in exchange for the uptake of K+ ion
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Introduction cont.
 The secretion of gastric acid occurs at the level of parietal cells
of the oxyntic gland in the gastric mucosa
Producing 2-3 L of gastric juice per day
 Ultimately, this secretory process occurs via H+/K+-ATPase
that exchanges hydronium ion with uptake of a potassium ion
 Several mediators regulate this secretion by way of receptor
systems on the basolateral membrane
The H2 histaminergic pathway is cAMP dependent
Gastrin & muscarinic receptors also regulate the secretion of
gastric acid through calcium ion dependent pathways
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Introduction cont.
 In parietal cells, E-series prostaglandins work in opposition to
the histaminergic pathways
Inhibiting histamine-stimulated adenylyl cyclase activity
 Other epithelial cells in the mucosal lining under the influence of
prostaglandin-mediated pathways secrete bicarbonate &
mucus
Both of which are important in protecting the gastric lining
from the effects of acid secretion
 In many cases, hypersecretion of gastric acid appears to be
associated with H.pylori infection
Which may contribute to defects in mucosal protective
defenses
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12

Inhibition of gastric acid secretion
 Also occurs during the cephalic, gastric, and intestinal phases
In the cephalic phase, the release of various neuropeptides may contribute to
the inhibition of gastric acid secretion
 Central injection of neuropeptide Y (NPY), corticotrophin-releasing
factor, bombesin, calcitonin, calcitonin gene-related peptide, neurotensin,
interleukin 1, and prostaglandins have all been shown to inhibit gastric
acid secretion
 The hypothalamus appears to be an important site of action of many
peptide inhibitors of acid secretion
 Of the peptides studied so far, only NPY exerts
Both stimulatory and inhibitory effects on acid secretion when
injected into different hypothalamic sites
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Inhibition of gastric acid secretion cont.
In the gastric phase
Increasing gastric acidity initiates
A mechanism that turns off gastric acid secretion
Once the acidity of the lumen has reached pH 2
Gastrin release is inhibited and therefore acid
secretion is reduced
Stimulation of somatostatin release from D-cells in the
antrum of the stomach
Inhibits the release of gastrin from G-cells and thus
reduces gastric acid secretion
In patients with a duodenal ulcer, this inhibitory
process is less efficient, especially when
intraluminal pH falls below 3
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Inhibition of gastric acid secretion cont.
In the intestinal phase
Inhibition of acid secretion is produced by the presence of
fat, acid, or hyperosmolar solutions within the intestinal
lumen
Fat, the most potent inhibitor, was proposed to cause the
release of inhibitory substances from the intestine although
no substances were formally identified, they were termed
enterogastrones
The release of cholecystokinin (CCK) and somatostatin,
in response to intestinal acid, inhibits gastric acid
secretion
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Gastrointestinal Disorders
 Gastritis
 Irritation and superficial erosion of the stomach lining
 Ulcerative colitis
 Form of inflammatory bowel disease
Irritation and inflammation of the large bowel
Characterized by bloody mucus leading to watery diarrhea with blood,
mucus, and pus (A fluid product of inflammation)
 Crohn’s disease
 Inflammatory bowel disease
Can affect any portion of tubular GI tract
 Malabsorption syndrome-Impaired intestinal absorption of nutrients
 Cystic fibrosis: GI and pulmonary disease
 GI tract: increased viscosity of mucus secretions and deficiency in pancreatic
enzymes
GI therapy consists of replacing pancreatic enzymes and vitamin
supplementation
 Gastroesophageal reflux disease (GERD) 16

Gastrointestinal Agents
 Agents used to treat gastrointestinal disturbance are known as
gastrointestinal agents
 Agents used to treat gastrointestinal disorder include:
Products for altering gastric pH ,i.e. acidifying agents and
antacids
Protectives for intestinal inflammation
Adsorbents for intestinal toxins
Histamine H2-receptor antagonists
Proton pump inhibitors
Cathartic or laxatives for constipation
Antidiarrheal agents for diarrhea
Prostaglandins
Bismuth salt and antibiotic combinations
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Acidifying agents
 Achlorhydria
 Is the absence of hydrochloric acid in the gastric secretion
 Patients with this condition fall into two groups:
I) Those who remain free of gastric HCl after stimulation with histamine
phosphate
Caused by
Subtotal gastrectomy (Surgical removal of all or part of the
stomach)
Atrophic gastritis (chronic gastritis with atrophy of the mucous
membrane & glands)
Carcinoma of the stomach
II) Those in whom there is normally a lack of gastric HCl but who respond to
stimulation by histamine phosphate
These patients include those with
Chronic nephritis ( inflammation of the kidney)
Chronic alcoholism
Tuberculosis, hyperthyroidism, pellagra
Sprus (a periodic fatty, frothy diarrhea)
Parasitic infections
Common in normal individuals after age 50
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Achlorhydria
 Symptoms of Achlorhydria
 Mild diarrhea or frequent bowel movement
 Epigastric pain/ upper middle portion of the abdomen/
 Sensitivity to spicy food
 Drugs used for treatment of Achlorhydria
 Diluted hydrochloric acid has been utilized
5 ml of HCl added to 200 ml of water for administration
In order to prevent (avoid) exposure of dental parts to HCl, the use of a
drinking straw laid well back is recommended
Give 15 meq HCl
 Glutamic acid hydrochloride (Acidulin)- a capsule
Ineffective (concluded by National Research Council)
Expensive
Give 1.7 meq HCl
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Gastric Acid cont.
 The inhibition of gastric acid secretion is a key therapeutic
target for
 Ulcer disease
 Gastroesophageal reflux disease (GERD)-Pathologic gastric hypersecretory
conditions (Commonly called heartburn)
 Zollinger-Ellison syndrome (Syndrome consisting of intractable
peptic ulceration with gastric hypersecretion and hyperacidity )
 Gastritis
 Currently, this is achieved either by
Blocking the acid-secretory effect of histamine (HA)
through the use of Histamine H2-receptor antagonists or
Irreversibly binding to the H+/K+-ATPase with proton-pump
inhibitors (PPIs)
To prevent the release of H+ ions from the parietal cell
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Gastric Acid cont.
The discovery that ulcers are linked to Helicobacter
pylori (H. pylori) infection has led to a new
therapeutic approach
Eradication of the bacteria is the principal target
In addition to ulcer disease
H2-receptor antagonists and PPIs are still
effectively used for alleviating the symptoms of
Gastritis, Zollinger-Ellison syndrome &
Gastroesophageal reflux disease (GERD)
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Peptic ulcer disease
 Peptic ulcer disease
Consists of a group of upper GIT disorders that result from
erosive action of acid & pepsin
Local defect or excavation of the surface of an organ or tissue
Duodenal ulcer and gastric ulcer are the most common forms
It also occurs in the esophagus and small intestine
Factors involved in the pathogenesis include
Hypersecretion of acid & pepsin
GI infection by Helicobacter pylori, a Gram-negative spiral bacteria
Three common types of Ulcer disease
• Gastric
• Duodenal
• Stress
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Peptic Ulcer cont.
 Gastric Ulcers
– Local excavation in the gastric mucosa
– Have malignant potential
– Occur more in men than women
– Prevalent in smokers and populations in the Western Hemisphere
– H. pylori is a common contributing factor
 Duodenal Ulcers
– Peptic lesion in the duodenum
– Occur more in hypersecretors
– More difficult to treat than gastric ulcers due to the difficulty in
getting the medication to the duodenum.
 Stress Ulcers
– Occur in the clinical setting
– Caused by severe physiological stress from serious illness; many times
patients are in the ICU
– Patients in ICU usually receive prophylactic therapy of H2-antagonists
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Peptic Ulcer cont.
H. pylori
Is the cause of most peptic ulcers
Secretes enzymes that neutralize stomach acid
 Antibiotics are the mainstay of therapy
Mixed with an antacid or proton pump inhibitors
 Goals of peptic ulcer disease therapy
To promote healing
Relieve pain
Prevent ulcer complications and recurrences
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Drugs That May Cause Ulcers
Drug Adverse Effect
Alcohol Irritating to the GI tract
Aspirin Irritating to the GI tract
Anti-inflammatory drugs Reduce production of mucus
Corticosteroids Reduce the mucosal barrier
Potassium chloride Irritating to the GI tract
Methotrexate Irritating to the GI tract, ulceration,
hemorrhage
Iron Causes esophageal ulcers
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Antacids
 Most frequent therapy for gastric hyperacidity that involves the use of
basic inorganic antacids
 Are drugs that react with HCl; hence neutralizes gastric HCl
 pH rises and inhibits proteolytic activity of pepsin
 They do not coat the mucosal lining, but may have a local astringent
effect
Astringents are drugs, which on local application precipitate the
surface proteins
Thus, protect the abraded mucus membrane & skin from
irritants & bacterial attack
Reduce inflammation of mucus membrane promote
healing, toughen the skin & decrease sweating
E.g. tannic acid, alum, aluminum acetate, aluminum chloride,
zinc oxide, calamine
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Antacids cont.
An ideal antacid should be
Insoluble in water
In fine particle form
Rapid in onset & provide a
continuous buffering action
Longer duration of action
Not cause constipation
Not cause laxative effects
Not liberate CO2 & cause
rebound hyperacidity
Not produce systemic
alkalosis
Not interfere with
absorption of food
Not interfere with digestion
Palatable & inexpensive
Stable and readily available
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Antacids cont.
Classification of antacids
There are differences in the types of antacids in terms of
their
Cationic content
Neutralizing capacity &
Duration of action
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Antacids cont.
Antacids, which locally neutralize the hyperacidity, are
broadly grouped into two groups
Systemic (Absorbable) antacids
E.g. NaHCO3
Non-systemic (Non-absorbable) antacids
E.g. Aluminum salts, magnesium salts, CaCO3,
Sodium carboxymethyl cellulose
Those classified by their cationic metal includes
Sodium, Magnesium, Aluminum derivatives
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Antacids cont.
Sodium antacids
Used in the treatment of metabolic acidosis
Should be avoided in hypertensive patients
NaHCO3 cause evolution of CO2
Belching (sudden escape of food or gas) &
flatulence (collection of gas in the stomach or bowel)
Magnesium antacids
Used for treatment of constipation
Cause diarrhea, decreased sense of taste
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Aluminum antacids
Used to relieve acid indigestion and upset stomach
Cause constipation
Magnesium hydroxide and calcium carbonate have
a short, rapid effect.
Aluminum hydroxide has a slow, persistent effect
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Combination antacid preparations
 Antacids are used commonly in combination for three reasons:
 To combine fast & slow reacting antacids in order to obtain a product
with a rapid onset & relatively sustained action
 To lower a dose of each component & minimize the possibility of
certain adverse effects &
 To use one component to antagonize one or more side effects of
another component
E.g. Laxative Vs constipation
 E.g. aluminum hydroxide gel-magnesium hydroxide combination
alone or with Simethicone [Aludrox]
Simethicone
Not an antacid
Antiflatulant used in antacid combinations to defoam gastric
juice in order to decrease the incidence of gastroesophageal
reflux
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H2-receptor antagonists
33
H2-receptor antagonists
Have an application in the treatment of acid-
peptic disorders such as
Peptic ulcer
Zollinger-Ellison syndrome (ulceration of duodenum)
Gastroesophageal reflux disease (GERD)
Acute stress ulcers

H2-Receptor Antagonists cont.
Histamine is a basic organic compound which has pKa
values of 9.4 (aliphatic primary amine) and 5.8
(imidazole)
Thus, it exists as an equilibrium mixture of tautomeric
cations at physiologic pH (7.4) with the
Monocation dominating (about 96%) over the dication
(about 3%) and the non-protonated species (about 1%)
34

 H2-Receptor antagonist were result of modification of histamine
structure
 It reversibly block action of histamine at H2 receptor and decreases
production of acid.
 Attempts were made to develop specific histamine H2 receptor
antagonists based on the observation that
4-methyl histamine is a potent selective H2-receptor
agonist
 N-guanyl histamine, a valuable lead compound was
subsequently discovered
Showed definite but weak H2 antagonism
Also showed a partial agonistic activity
35

 Increasing length of the side chain of N-guanyl histamine
From two to four & coupled with replacement of the strongly
basic guanidino group by the neutral methyl thiourea
function gave
Burimamide, a specific H2 antagonist
With no detectable agonist activity & has low potency
and was poorly available orally but could not reach the
market
 Modification of burimamide led to the discovery of other
drugs
36

 Modification of the structure of burimamide gave metiamide
 Has a methyl group at position 5 and isosteric replacement of one of the
carbons on the side chain of burimamide with sulfur
X-ray crystallography studies have indicated that
The longer thioester linkage in the chain increases the flexibility of
the side chain and
The 5- methyl substituent in the imidazole ring may help to
orientate the imidazole ring correctly for receptor binding
 Metiamide is 10x more active than burimamide, and showed promise as
an anti-ulcer agent (full H2 antagonist)
 Had higher potency and improved oral bioavailability
But toxic due to presence of thiourea
37

 Replacement of thiourea sulfur of metiamide with a cyano-imino
function led to production of
Cimetidine (Tagamet®)
 The name Tagamet (derived from anTAGonist and ciMETidine
Additional research gave related products such as
Ranitidine (Zantac®); Famotidine (Pepcid®), Nizatidine
(Axid®) were also produced with modification on the ring and
side chain
 Ranitidine (Zantac)
– An aminoalkyl furan
– 4-10 times more potent than cimetidine
– Replacement of the furan ring by a thiazole group generates nizatidine
38

 Nizatidine
– 5-18 time more potent than cimetidine
– Introduced into the UK in 1987 by the Lilly Corporation
– It is equipotent to ranitidine
– The furan ring in ranitidine is replaced with a thiazole ring
 Famotidine (Pepcid)
– The basic dimethylaminomethyl group of nizatidine was replaced by the
guanidine functionality
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Famotidine
Mona. F(Medchem I)

SAR OF CIMETIDINE
• The finding that metiamide and cimetidine were both good H2-
antagonists of similar activity shows that the cyanoguanidine group
is a good bioisoster for the thiourea group
– Due to the possibility of three tautomeric forms for the guanidine group
compared to only one for the isothiourea group
• The imidazole ring can be replaced with other heterocyclic rings
such as a furan ring bearing a nitrogen containing substituent
– This led to the introduction of ranitidine
40

SAR of Ranitidine
 The nitroketeneaminal group is optimum for activity
 But may be replaced by other planar π systems capable of hydrogen bonding
 Replacing the sulfur atom with a methylene group leads to a drop
in activity
 Replacing the furan ring with more hydrophobic rings such as
phenyl or thiophene reduces activity
 2,5-disubstitution is the best substitution pattern for the furan ring
 Substitution on the dimethylamino group may be varied,
 Showing that the basicity and hydrophobicity of this group are not crucial to
activity
 Methyl substitution at carbon 3 or 4 of the furan ring
 Eliminates activity, whereas the equivalent substitution on the imidazole
series increases activity
41

SAR of Famotidine
 The sulfonylamidine binding group is not essential
 May be replaced by a variety of structures as long as they are planar, have a dipole
moment, and are capable of interacting with the receptor by hydrogen
bonding
 Activity is optimum for a chain length of 4 or 5 units
 Replacement of sulfur with a CH2 group increases activity
 Modification of the chain is possible with, for example, inclusion of an
aromatic ring
 A methyl substituent on heterocyclic ring, ortho to the chain leads to a
drop in activity (unlike the cimetidine series)
 3 of the 4 hydrogen's in the 2 guanidine NH2 groups are required for
activity
Famotidine
42

Proton pump inhibitors (PPIs)
 Final step in gastric acid secretion is “proton pumping”, which is
mediated by an enzyme called H+/K+ ATPase
 PPI blocks acid secretion by inhibiting the hydrogen-potassium
ion pump in parietal cells
 Inhibition of the proton pump blocks basal and stimulated
secretion, i.e. Acid production due to
Histamine
Gastrin
Pentagastrin, a synthetic gastrin
Acetylcholine
43

Proton pump inhibitors (PPIs) cont.
 The action of the H+/K+ ATPase pump (Proton pump)
Is the final step in the acid-secretion process of the parietal cell
B/C hydrogen ions are protons, this ion pump is also called the
proton pump
 If the chemical energy is present to run the pump
It will transport the hydrogen ions out of the parietal cell
Which increases the acid content of the surrounding gastric
lumen and lowers the pH
 The PPIs bind irreversibly to the proton pump
44

PPIs bind to the gastric proton pump (H+/K+-ATPase) on
the parietal cell membrane
Inactivating the exchange of H+ for K+ ions
This prevents the transport of HCl across the cell
membrane to the lumen of the stomach
Thus blocking the final step of acid production
 PPI effectively stop over 90% of acid production in the stomach
 For acid secretion to return to normal after the patient stops the PPI
The parietal cell must synthesize new H+/K+-ATPase
45

Discovery of proton pump inhibitors
 Swedish medicinal chemists noticed that certain pyridylmethyl
benzimidazole sulfides were active PPIs
 Conversion of these compounds to sulfoxide derivatives
Gave highly potent, irreversible inhibition of the Proton Pump
 Substituted benzimidazoles are potent proton pump inhibitors
A good example is omeprazole (Prilosec®)
A prodrug that forms the active drug in the acidic biophase of parietal cells
o The active form irreversibly interacts with the target ATPase of the
pump
46

Mechanism of action of omeprazole
Omeprazole, in presence of an acid,
rearranges to a sulfenamide analogue
The sulfenamide analogue acts as
an irreversible inhibitor to the
ATPase
By forming a covalent disulfide
bond with a crucial sulfhydryl
group in the active site
The enantiomerically pure S-isomer
Esomeprazole has been marketed
separately as Nexium®
47

Figure: Acid-catalyzed activation of omeprazole to reactive sulfonamide. At the
parietal cell, H+/K+-ATPase, a cysteine residue, reacts to form disulfide-attached
enzyme inhibitor
48

 The benzimidazole proton pump inhibitors
 Possess efficiency in treating gastric ulcers and
 With one or more antimicrobial activities can eradicate infection by H.
pylori
 Currently four benzimidazole PPIs are approved for
marketing in the US
Omeprazole
Esomeprazole magnesium the enantiomerically pure S-
isomer
Lansoprazole
Pantoprazole sodium
Rabeprazole sodium
49

SAR of proton pump inhibitors
• Substituted benzimidazole, substituted pyridine and sulfinyl
chain connecting this two is essential for activity
• Benzimidazole substitution by electron withdrawing group will
increase activity.
• Benzimidazole substitution by electron donating group will
decrease activity
• 4 methoxy group on pyridine group increases biological activity
• 4 flouro alkoxy substitution results in strong inhibitory activity.
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Cytoprotective agents and adsorbents
Commonly used for the treatment of mild diarrhea
Diarrhea is a frequent passage of fluid or semi-fluid
stool (more than 3 times daily)
Most products for the treatment of diarrhea will
consists of
A protective-adsorbent,
Antiviral & possibly antibacterial agents
Antidiarrheal agents should act directly on the smooth
muscles that
Decrease peristalysis & Increase segmentation
51

Cytoprotective agents and adsorbents cont.
 They adsorb
Toxins,
Viruses and
Bacteria, along with providing protective coating of the intestinal
mucosa
 They includes
Prostaglandins
Bismuth salts
Special clays
Activated charcoals
Carbenoxylone
Sucralfate
52

 Prostaglandins (PGs)
PG synthetase in the gut wall induce production of
prostaglandins
Are endogenous 20-carbon unsaturated fatty acids
Biosynthetically related to arachidonic acid
Have wide spread action on different parts of the body; such as
Cardiovascular System, Gastrointestinal smooth muscle,
Reproductive system, Nervous system, Platelets, Kidneys, eyes,
etc
53

PGs of the E, F and I series are synthesized and
secreted in gastric juice
Thus, found in significant concentration in the GIT
Role of prostaglandins in GIT includes
Inhibition of basal and stimulated gastric acid and
pepsin secretion
Prevention of irritant induced gross mucosal lesions
of the stomach and intestine
Prostaglandins, in particular PGEs can inhibit histamine
stimulated HCl release with out interrupting mucosal flow
This makes them capable to protect the mucosa
A phenomenon termed cytoprotection
54

Other effects of PGs include
Enhancement of mucosal blood flow
Stimulation of bicarbonate release
Increased mucus production
Because natural prostaglandins are not of pharmacological
selectivity and short-lived in vivo
Generally not possible to use them as cytoprotectants
55

 Prostaglandin E analogues
Are useful as cytoprotectants
A stable analogue for this purpose is misoprostol (Cytotec®)
Misoprostol has two structural features that makes it more stable
to metabolism than PGE1
The hydroxyl substituent is moved from 15 to 16 positions,
where it resides geminal to a methyl group
Greatly reducing metabolism by oxidation
 Misoprostol is administered as the methyl ester
56

The methyl ester is a prodrug form & must be cleaved prior
to activity
Misoprostol retains all cytoprotective attributes of PGE1
Other cytoprotectives related to misoprostol are
 Enisoprost (Searle®)
 Enprostil (syntex®)
57

Cathartics
Are intended to decrease absorption of substances by
Accelerating expulsion of the poison from the GIT
Are agents that increase fluidity of the intestinal
contents by
Retention of water, osmotic forces, indirectly
increase motor motility
Are employed to relieve constipation
Constipation-is an abnormally infrequent and
difficult passage of feces through the lower GI tract
that is characterized by difficult passage of hard &
dry stool
58

Cathartics
 Also called Laxatives or Purgatives
 Are drugs used to
Stimulate or increase the frequency of bowel evacuation or
Encourage the passage of a softer or bulkier stool
 Generally classified in two groups
Osmotic cathartics
Increase fecal water content
Saccharide cathartics such as sorbitol
Sorbitol often combined with activated charcoal
 To improve palatability of charcoal
 To mask grittiness of the charcoal
59

Cathartics…
 Saline cathartics
 Increase osmotic pressure within the intestinal tract,
causing more water to enter the intestines
 Magnesium sulfate; Magnesium citrate; Sodium sulfate
are some examples
Magnesium citrate Magnesium sulfate Sodium sulfate
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Laxatives
 Fall into several groups: Surfactants; Irritant laxatives; Bulk
laxatives
 Surfactants
Act by detergent effect which enhances the mixing of fat &
water to soften stool
Prime example is dioctyl sodium sulfosuccinate
dioctyl sodium sulfosuccinate
61

Laxatives…
 Irritant laxatives
Act by direct contact with the gastric mucosa
The resulting irritation causes a decrease in transit time
Examples are Danthron, Bisacodil, Phenolphthalein,
Castor oil and Senna
Danthron Bisacodil Phenolphthalein
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Mona. F(Medchem I)

laxatives…
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Castor oil
Mona. F(Medchem I)

Laxatives…
Bulk laxatives
Act by increasing stool volume
Examples are Psyllium based laxatives such as
Metamucil®; Methylcellulose containing
laxatives
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Mona. F(Medchem I)

Antiflatulant agents
Act by dispersing excess gas in the intestine before the
patient has the opportunity to do so
Examples are
Simethicone
A simple methylated siloxane Simethicone
Peppermint spirit
Activated charcoal
65

Emetics and antiemetics
 Emetics
Used for induction of vomiting in patients who ingested
toxic materials
 A few drugs are known
The morphine analogue – apomorphine
Can be used intravenously
Syrup of ipecac
A solution containing the emetic alkaloid emetine
Used orally to induce emesis
 Both these drugs act by stimulating the stomach and a direct
effect on the chemoreceptor trigger zone (CTZ)
66

Nausea and Vomiting
The vomiting center in the
medulla receives impulses from
 The chemoreceptor trigger zone (CTZ)
The CTZ receives input from
 The cerebral cortex
 The hypothalamus
 Blood-borne stimuli
67

Antiemetics
 Antiemetics
Are used in the treatment of nausea & vomiting
Variety of phenothiazine and related analogues used for this
purpose
Have a direct effect on the CTZ in the CNS
Prochlorperazine (Compazine®)[Phenothiazines]
Used as antiemetic
Not effective to prevent nausea due to motion sickness
Has minimal neuroleptic/Antipsychotic/effect
68

Antiemetics cont.
 Compounds used for motion sickness include [Anticholinergic drugs]
 Meclizine; Dimenhydrinate & Cyclizine are H1-R antagonist
 Dimenhydrinate is a combination drug of diphenhydramine and 8-
Chlorotheophylline
Cyclizine Dimenhydrinate
69

Antiemetics cont.
 Scopolamine (Muscarinic Receptor antagonist) patches are also effective
 Are very useful in motion sickness, but are ineffective against
substances that act directly on the chemoreceptor trigger zone
Scopolamine
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Antiemetics cont.
 Ondansetron (Zofran®) and Granisetron (Kytril®)
 Are selective 5-HT3 serotonin antagonists
 Prevent nausea in patients receiving cancer chemotherapy
•
Ondansetron Granisetron
71

Antiemetics cont.
 Corticosteroids: Dexamethasone and methylprednisolone
used alone are effective against mildly to moderately
emetogenic chemotherapy
Dexamethasone Methylprednisolone
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Inflammatory Bowel Disease
 Drugs used in the treatment of inflammatory bowel disease
 Sulfasalazine (Azulfidine®)
A sulfonamide derivative used for prolonged treatment of ulcerative
colitis
Practically insoluble in water & Poorly absorbed from the intestine that
reaches the colon intact
In the colon bacterial azo-reductase enzymes cleave sulfasalazine
To sulfapyridine and 5-aminosalicylic acid (Mesalamine®)
 5-aminosalicylic acid is the active product
 Mechanism of action involves 5-aminosalicylic acid
• Inhibits synthesis of prostaglandin in the colon
• Thus, relieving the resultant inflammation
 Metronidazole (Flagyl®)
An antibacterial agent, also used in the treatment of inflammatory bowel
Due to its bactericidal activity against H. pylori and other intestinal
bacteria
73

74
Cleavage of Sulfasalazine by azo-reductase enzyme

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