Chapter 7-GI Agents - Handout!

Medicinal Chemistry I
Mona Fekadu
(B. Pharm, MSc in Medicinal chemistry,
HU, CHMS, School of Pharmacy)
2022 G.C
CHAPTER 7
GASTROINTESTINAL AGENTS
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
1/26/2022 Mona. F. (MSc.) MedChem I 3

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

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

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

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
Gastric Phase
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

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

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

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

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

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
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
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
1/26/2022
Gastroesophageal reflux disease (GERD) Mona. F. (MSc.) MedChem I 17
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
 Achlorhydria
Acidifying agents
 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
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
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

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)

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

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

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

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

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

Antacids cont.
An ideal antacid should be
Rapid in onset & provide a continuous buffering action
Not liberate CO2 & cause rebound hyperacidity
Not produce systemic alkalosis
Not interfere with absorption of food
Palatable & inexpensive
Classification of antacids
 There are differences in the types of antacids in terms of their
Cationic content
Neutralizing capacity &
Duration of action
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

Antacids cont.
Sodium antacids
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
Cause diarrhea
Used for constipation
Aluminum antacids
Cause constipation

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

H2-receptor antagonists
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%)

 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

 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

 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

 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

 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
Famotidine
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

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

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 ortho to the chain leads to a drop in activity
(unlike the cimetidine series)
 3 of the 4 hydrogen's in the 2NH2 groups are required for activity
1/26/2022 Mona. F. (MSc.) Famotidine

MedChem I 41
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
Secretagogues
Histamine
Gastrin
Acetylcholine

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

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

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

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®

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
 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

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

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

 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

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
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

 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

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®)

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
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
 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
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
 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
 Bulk laxatives
 Act by increasing stool volume
 Examples are Psyllium based laxatives such as Metamucil®;
Methylcellulose containing laxatives

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
Peppermint spirit
Activated charcoal

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)

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

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 effect

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
 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

Antiemetics cont.
 Ondansetron (Zofran®) and Granisetron (Kytril®)
 Are selective 5-HT3 serotonin antagonists
 Prevent nausea in patients receiving cancer chemotherapy
 Corticosteroids: Dexamethasone and methylprednisolone used

alone are effective against mildly to moderately emetogenic
chemotherapy

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
Cleavage of Sulfasalazine by azo-reductase enzyme

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Medicinal Chemistry I

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Acid is secreted by the parietal cells of the gastric mucosa

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Drug Adverse Effect

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1/26/2022 Mona. F. (MSc.) Famotidine

 PPI blocks acid secretion by inhibiting the hydrogen-potassium

 Inhibition of the proton pump blocks basal and stimulated

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 If the chemical energy is present to run the pump

Which increases the acid content of the surrounding gastric

 The PPIs bind irreversibly to the proton pump

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A good example is omeprazole (Prilosec®)

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 Meclizine; Dimenhydrinate & Cyclizine are H1-R antagonist

 Dimenhydrinate is a combination drug of diphenhydramine and 8-

 Scopolamine (Muscarinic Receptor antagonist) patches are also effective

 Are very useful in motion sickness, but are ineffective against

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 Ondansetron (Zofran®) and Granisetron (Kytril®)