DRUGS IN TREATING

PEPTIC ULCER DISEASE

(PHA 308)
DR. KAZEEM ADEOLA OSHIKOYA
 BACKGROUND
• Peptic ulcer disease can involve the stomach or
duodenum.
• Clinically, it may difficult to differentiate between gastric
and duodenal, although some findings may be suggestive.
• Epigastric pain is the most common symptom of both
gastric and duodenal ulcers, characterized by a gnawing or
burning sensation and that occurs after meals—classically,
shortly after meals with gastric ulcers and 2-3 hours
afterward with duodenal ulcers.
• In uncomplicated peptic ulcer disease, the clinical
findings are few and nonspecific.
• “Alarm features" that warrant prompt
gastroenterology referral include bleeding, anemia,
early satiety, unexplained weight loss, progressive
dysphagia or odynophagia, recurrent vomiting, and a
family history of gastrointestinal (GI) cancer.
• Patients with perforated peptic ulcer disease usually
present with a sudden onset of severe, sharp
abdominal pain.
• In most patients with uncomplicated peptic ulcer
disease, routine laboratory tests usually are not helpful;
instead, documentation of peptic ulcer disease depends
on radiographic and endoscopic confirmation.
• Testing for H pylori infection is essential in all patients
with peptic ulcers.
• Rapid urease tests are considered the endoscopic
diagnostic test of choice.
• Of the noninvasive tests, fecal antigen testing is more
accurate than antibody testing and is less expensive
than urea breath tests but either is reasonable.
• A fasting serum gastrin level should be obtained in
certain cases to screen for zollinger-Ellison syndrome.
• Most patients with peptic ulcer disease are treated
successfully with cure of H pylori infection and/or
avoidance of nonsteroidal anti-inflammatory drugs
(NSAIDs), along with the appropriate use of
antisecretory therapy.
• The recommended primary therapy for H pylori infection
is proton pump inhibitor (PPI)–based triple therapy.
• These regimens result in a cure of infection and ulcer
healing in approximately 85-90% of cases.
• Ulcers can recur in the absence of successful H
pylori eradication.
• In patients with NSAID-associated peptic ulcers,
discontinuation of NSAIDs is paramount, if it is
clinically feasible.
• For patients who must continue with their NSAIDs, proton
pump inhibitor (PPI) maintenance is recommended to
prevent recurrences even after eradication of H pylori.
• Prophylactic regimens that have been shown to
dramatically reduce the risk of NSAID-induced gastric and
duodenal ulcers include the use of a prostaglandin analog
or a PPI.
• Maintenance therapy with antisecretory medications (eg,
H2 blockers, PPIs) for 1 year is indicated in high-risk
patients.
PATHOPHYSIOLOGY OF PEPTIC ULCER
DISEASE
• Peptic ulcers are defects in the gastric or duodenal
mucosa that extend through the muscularis mucosa.
• The epithelial cells of the stomach and duodenum
secrete mucus in response to irritation of the epithelial
lining and as a result of cholinergic stimulation.
• The superficial portion of the gastric and duodenal
mucosa exists in the form of a gel layer, which is
impermeable to acid and pepsin.
• Other gastric and duodenal cells secrete bicarbonate,
which aids in buffering acid that lies near the mucosa.
• Prostaglandins of the E type (PGE) have an important
protective role, because PGE increases the production
of both bicarbonate and the mucous layer.
• In the event of acid and pepsin entering the epithelial
cells, additional mechanisms are in place to reduce
injury.
• Within the epithelial cells, ion pumps in the basolateral cell
membrane help to regulate intracellular PH by removing
excess hydrogen ions.
• Through the process of restitution, healthy cells migrate to
the site of injury.
• Mucosal blood flow removes acid that diffuses through the
injured mucosa and provides bicarbonate to the surface
epithelial cells.
• Under normal conditions, a physiologic balance exists
between gastric acid secretion and gastroduodenal mucosal
defense.
• Mucosal injury and, thus, peptic ulcer occur when the
balance between the aggressive factors and the
defensive mechanisms is disrupted.
• Aggressive factors, such as nonsteroidal anti-
inflammatory drugs (NSAIDs), H pylori infection,
alcohol, bile salts, acid, and pepsin, can alter the
mucosal defense by allowing the back diffusion of
hydrogen ions and subsequent epithelial cell injury.
• The defensive mechanisms include tight intercellular
junctions, mucus, bicarbonate, mucosal blood flow,
• The gram-negative spirochete H. pylori was first linked to
gastritis in 1983.
• Since then, further study of H pylori has revealed that it is a
major part of the triad, which includes acid and pepsin, that
contributes to primary peptic ulcer disease.
• The unique microbiologic characteristics of this organism,
such as urease production, allows it to alkalinize its
microenvironment and survive for years in the hostile acidic
environment of the stomach, where it causes mucosal
inflammation and, in some individuals, worsens the severity
of peptic ulcer disease.
• When H pylori colonizes the gastric mucosa, inflammation
usually results.
• The causal association between H pylori gastritis and duodenal
ulceration is now well established in children and adult.
• H pylori infection is associated with high levels of gastrin and
pepsinogen and reduced levels of somatostatin.
• In H pylori infected patients, exposure of the duodenum to acid
is increased.
• Virulence factors produced by H pylori, including urease,
catalase, vacuolating cytotoxin, and lipopolysaccharide, have
been described.
• Most patients with duodenal ulcers have impaired
duodenal bicarbonate secretion, which has also proven to
be caused by h pylori because its eradication reverses the
defect.
• The combination of increased gastric acid secretion and
reduced duodenal bicarbonate secretion lowers the PH in
the duodenum, which promotes the development of
gastric metaplasia (i.e, the presence of gastric epithelium
in the first portion of the duodenum).
• H pylori infection in areas of gastric metaplasia induces
duodenitis and enhances the susceptibility to acid
injury, thereby predisposing to duodenal ulcers.
• Duodenal colonization by H pylori was found to be a
highly significant predictor of subsequent
development of duodenal ulcers.
 H. PYLORI TRAETMENT
• The 2017 American College of Gastroenterology (ACG)
guidelines for the treatment of H pylori infection strongly
recommend 10-14 days of quadruple therapy with :
• Bismuth, a PPI, tetracycline, and a nitroimidazole.
• An alternative strongly recommended option is 10-14
days of concomitant PPI, clarithromycin, amoxicillin, and
a nitroimidazole.
• PPI–based triple therapy was the previous
recommendation.
• These regimens result in a cure of infection and ulcer
healing in 〰️ 85-90% of cases.
• Ulcers can recur in the absence of successful H
pylori eradication.
• Dual therapies; an alternative regimens for treating H
pylori infection, are usually not recommended as first-
line therapy, because of a variable cure rate that is
significantly less than the cure rate achieved with triple
 TRIPLE REGIMENS
• PPI-based triple therapy regimens for H pylori consist of a
PPI, amoxicillin, and clarithromycin for 7-14 days.
• A longer duration of treatment (14 d vs 7 d) appears to be
more effective and is currently the recommended
treatment.
• Amoxicillin should be replaced with metronidazole in
penicillin-allergic patients only, because of the high rate of
metronidazole resistance.
• In patients with complicated ulcers caused by H pylori,
treatment with a PPI beyond the 14-day course of
antibiotics and until the confirmation of the
eradication of H pylori is recommended.
• Polymorphisms in the host CYP2C19 gene and
antibiotic-resistance attributes of H pylori isolates
appear to influence the outcome of triple therapy.
• CYP2C19 affects peptic ulcer healing, H
pylori eradication, and PPI therapeutic efficacy.
• When a patient’s CYP2C19 genotype is unknown, H
pylori eradication may be achieved with
fluoroquinolones/metronidazole/clarithromycin-
based triple therapies.
• PPI-based triple therapies are a 14-day regimen as
outlined below.
• Omeprazole (Prilosec): 20 mg PO bid OR
Lansoprazole (Prevacid): 30 mg PO bid OR
Rabeprazole (Aciphex): 20 mg PO bid OR
Esomeprazole (Nexium): 40 mg PO qid
• PLUS Clarithromycin: 500 mg PO bid AND
Amoxicillin (Amoxil): 1 g PO bid.
ALTERNATIVE TRIPLE-THERAPY REGIMENS
• The alternative triple therapies, also administered for
14 days, are as follows:
• Omeprazole: 20 mg PO bid OR Lansoprazole: 30 mg
PO bid OR Rabeprazole: 20 mg PO bid OR
Esomeprazole: 40 mg PO qid PLUS Clarithromycin:
500 mg PO bid AND Metronidazole: 500 mg PO bid
QUADRUPLE THERAPY
• Therapies are generally reserved for patients in whom the
standard course of treatment has failed.
• Quadruple treatment includes the following drugs,
administered for 14 days:
• PPI, standard dose PLUS Bismuth 525 mg PO qid PLUS
Metronidazole 500 mg PO qid PLUS Tetracycline 500 mg PO
qid.
• Consider maintenance therapy with half of the standard doses
of H2-receptor antagonists at bedtime in patients with recurrent,
refractory, or complicated ulcers, particularly if cure of H
H2-receptor Antagonists
• H2 blocker antihistamine agents are used in the short-
term treatment of an active duodenal ulcer and as
prophylaxis in the long term.
• Cimetidine can be used as primary therapy to heal ulcers
not associated with H pylori infection.
• The duration of treatment is 6-8 weeks.
• A longer treatment course might be required for gastric
ulcers.
• Famotidine competitively inhibits histamine at H 2
receptor of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and hydrogen
ion concentrations.
• Nizatidine competitively inhibits histamine at H 2
receptor of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and hydrogen
ion concentrations.
• Ranitidine inhibits histamine stimulation of the H 2
receptor in gastric parietal cells, which, in turn,
reduces gastric acid secretion, gastric volume, and H+
concentrations.
• As of April 1, 2020, ranitidine was withdrawn from the
market due to an increasing number of products
containing the contaminant known as N-
nitrosodimethylamine (NDMA), a possible carcinogen.
 PHYSIOLOGY OF GASTRIC ACID SECRETION
• The H+-K+-ATPase acid-secreting (proton) pump is
located in the parietal cell.
• Gastric acid secretion by the parietal cell is regulated
mainly by three stimuli—acetylcholine (Ach), gastrin,
and histamine.
• Ach is the principal neurotransmitter modulating acid
secretion and is released from the vagus and
parasympathetic ganglionic cells; it mainly exerts
effects on M3 receptors.
• Vagal fibers not only have a direct effect on parietal cells,
but also modulate peptide release from G cells (antrum and
duodenum) and ECL cells, as well as inhibit somatostatin
secretion.
• Gastrin has direct hormonal effects on the parietal cell and
also stimulates histamine release.
• Histamine has paracrine-like effects on the parietal cell and
plays a central role in the regulation of acid secretion by the
parietal cell after its release from ECL cells.
• Somatostatin exerts inhibitory actions on gastric acid
secretion.
• Release of somatostatin from antral D cells is stimulated
in the presence of low intraluminal PH as well as
vasoactive intestinal peptide (VIP) and gastrin.
• After its release, somatostatin inhibits gastrin release
through paracrine effects and modifies histamine
release from ECL cells.
• Consequently, the precise state of acid secretion by the
parietal cell depends on the overall influence of the
positive and negative stimuli.
 ANTACIDS
• Antacids are a group of drugs that have been in use for
many years.
• They were initially first-line defense against peptic
ulcer disease; however, the discovery of proton pump
inhibitors (PPIs) revolutionized the treatment of peptic
ulcer disease.
• Currently, antacid use is restricted to relieve mild
intermittent gastroesophageal reflux disease (GERD)
with associated heartburn.
Indications
• Antacids are medications that do not require a
prescription; in other words, they are self-prescribed.
• They are a combination of various compounds with
various salts of calcium, magnesium, and aluminum as
active ingredients.
• They act by neutralizing the acid in the stomach and by
inhibiting pepsin, which is a proteolytic enzyme.
• Each of these cationic salts has a
characteristic pharmacological property that determines
• Antacids have therapeutic • Diarrhea caused by bile-
use for the following: acid

• Heartburn symptoms in • Biliary reflux

GERD • Constipation
• Duodenal and gastric • Osteoporosis
ulcers • Urinary alkalinization
• Stress gastritis • Phosphate binding in
• Pancreatic insufficiency chronic renal failure
• Non-ulcer dyspepsia
Mechanism of action
• The antacids reduce the acid reaching the duodenum by
neutralizing the acid present in the stomach.
• The main therapeutic objectives are:
oAlleviating pain
oRelieving pylorospasms
oAvoid digestion and corrosion by acid chyme
oThe salts' mechanism of neutralization of acid varies, and
each salt has a different mechanism with the ultimate goal
of acid neutralization.
Aluminum hydroxide
• The formulation of aluminum hydrochloride and water
results in the neutralization of the acid in the stomach.
• It is also known to inhibit pepsin activity.
• Aluminum hydroxide is complexed with a sulfated
polysaccharide sucrose octasulfate to form sucralfate.
• This complex does not have a significant buffering action
against the acid or has no effect on the pepsin secretion,
and does not alter the gastric acid production in any
way.
• Nevertheless, it is known to heal chronic ulcers and
prevent acute mucosal damage induced chemically by
reducing access to pepsin and acid.
• Sucralfate, like its aluminum hydroxide component, is
known to stimulate angiogenesis and granulation
tissue formation.
• Aluminum hydroxide is also useful in
hyperphosphatemia due to its ability to bind
phosphate in the gastrointestinal (GI) tract and
subsequently prevent the absorption of phosphate.
Calcium salts
• Calcium salts neutralize gastric acidity, resulting in
increased gastric and duodenal bulb PH; they also
inhibit pepsin's proteolytic activity if the PH is greater
than 4 and increase lower esophageal sphincter tone.
• The calcium released from calcium carbonate is known
to increase peristalsis in the esophagus, pushing the
acid into the stomach and providing relief from
heartburn symptoms.
• The calcium salts also form combined insoluble
compounds with dietary phosphate and prevent the
absorption of the latter.
• The acid-neutralizing mechanism of the antacids is
well understood, as mentioned above.
• In addition to this, other mechanisms add to the ulcer
healing properties of this class of drugs.
• The exact mechanism is still unclear, but it is believed
to be a combination of:
• Ability to promote angiogenesis
oBind to bile acids
oInhibit peptic activity
oSuppress helicobacter pylori growth
Pregnancy and Breastfeeding
• Antacids containing aluminum salts are safe to be used in
pregnant women as well as for women during labor for
aspiration prophylaxis.
• The information regarding the use of aluminum-containing
antacids in breastfeeding females has not been studied, but
aluminum is known to be endogenous to breast milk.
• In the case of calcium-containing antacids, excessive use is
to be avoided in pregnant women as calcium crosses the
placenta.
• The amount of calcium reaching the fetus is dependent
on the physiological changes in the mother.
• Maternal calcium intake also affects the amount of
calcium excreted in breast milk; the currently
prevailing opinion is that the use of calcium-
containing antacids is safe during breastfeeding.
 Adverse Effects
Adverse effects are prominent in the infant and the elderly populations.
The chronic use of antacids in this population is not a recommendation due to safety concerns.

Aluminum hydroxide o Microcytic anemia

• Aluminum use is associated Neurotoxicity
with an increased risk of o Osteomalacia Constipation
toxicity in individuals with o Fecal impaction Nausea
renal failure and infants. o Vomiting Abdominal cramps
o It presents as: o Hypomagnesemia
o Osteopenia o Hypophosphatemia
 Calcium Carbonate
The adverse reactions often seen with this group of antacids are:

oAbdominal pain oFlatulence

oAnorexia oXerostomia
oConstipation oHeadache
oAcid rebound oHypercalcemia
oNausea oHypophosphatemia
oVomiting oMilk-alkali syndrome
• Antacids can exhibit clinically significant
interactions with other medication a patient may
be taking.
• Some examples include:
oUsing antacids concomitantly with acidic drugs
(e.g., digoxin, chlorpromazine isoniazid) can result
in impaired absorption of these acidic
drugs, reducing the blood concentrations of the
drugs and impairing their therapeutic effects.
oConcurrent antacid use with some drugs (e.g.,
Pseudoephedrine, levodopa) can result in increased
absorption of the drugs, leading to potential toxicity
or adverse events from increased serum concentration
of these drugs.
oAntacids containing magnesium trisilicate and
magnesium hydroxide can bind to drugs like
tetracycline and fluoroquinolone antibiotics,
impeding their absorption and therapeutic effects.
• Sodium bicarbonate significantly affects urine acidity,
which can alter the renal elimination of some drugs by
the kidney; sodium bicarbonate inhibits the excretion of
basic drugs such as amphetamines and quinidine while
increasing the excretion of acidic drugs like aspirin.
Contraindications
The absolute contraindication is hypersensitivity
to any component of the formulation.
Also, antacid agents require caution in patients
with:
• Renal failure • Uremia
• Heart failure • GI hemorrhages
• Edema • Hyperparathyroidism
• Cirrhosis • Renal calculus
• Low-sodium diets • Achlorhydria
HISTAMINE (H2RAs) RECEPTOR ANTAGONISTS
Mechanism of Action
• The selective histamine type 2 receptor
antagonists/blockers (H2RAs) are widely used in the
treatment of acid-peptic disease, including duodenal
and gastric ulcers, gastroesophageal reflux disease and
common heartburn.
• The H2RAs are very well tolerated, but have been linked
to rare instances of clinically apparent liver injury.
• The H2RAs act by binding to histamine type 2
receptors on the basolateral (anti-luminal) surface of
gastric parietal cells, interfering with pathways of
gastric acid production and secretion.
• The selectivity of H2RAs is of key importance, as they
have little or no effect on the histamine type 1
receptors, which are blocked by typical antihistamines
that are used to treat allergic reactions and have little
effect on gastric acid production.
• They competitively inhibit histamine binding at
H2 receptors on the basolateral aspect of parietal cells,
resulting in a reduction of gastric acid secretion.
• The inhibitory effect can be overcome with high
gastrin levels, as occurs postprandially.
• The selective H2RAs are less potent in inhibiting acid
production than the PPIs (which block the common,
final step in acid secretion) but, nevertheless, suppress
24 hour gastric acid secretion by about 70%.
• Tolerance may develop, probably due to down-
regulation of receptors.
• The effect of H2RAs is largely on basal and nocturnal acid
secretion, which is important in peptic ulcer healing.
• The initial H2RAs approved for use in the United States
was cimetidine (1977), which was followed by ranitidine
(1983), famotidine (1986), and nizatidine (1988).
Pharmacokinetics and Dosage
• H2RAs are given orally and are well absorbed.
• All four of these agents are available by prescription
and as over-the-counter oral formulations.
• Since there is anecdotal evidence that peptic
ulcer healing with H2RAs correlates best with
suppression of nocturnal acid secretion, many prefer to
give these drugs as a single evening dose (e.g.
Ranitidine 150–300 mg).
• Intravenous and intramuscular forms are available for
cimetidine, ranitidine and famotidine.
• The four H2RAs available in the market have similar
spectra of activity, side effects and clinical indications.
• These medications are extremely well tolerated and are
used by a high proportion of the general population to
treat peptic ulcer disease, heartburn, esophagitis, and
miscellaneous minor upper gastrointestinal symptoms.
• However, their indications are for treatment of gastric
and duodenal ulcer and esophageal reflux disease, and
to prevent stress ulcers.
Adverse Effects and Interactions
• H2RAs are generally well tolerated.
• Side effects are uncommon, usually minor and include
diarrhea, constipation, fatigue, drowsiness, headache
and muscle aches.
• The H2RAs are metabolized in the liver by the CYP P450
system.
• Among the four agents, cimetidine is distinctive in its
potent inhibition of the P450 system (CYP 1A2, 2C9 and
2D6), which can result in significant drug interactions.
• All four H2RAs have been implicated in rare cases of
clinically apparent, acute liver injury.
• The most cases have been linked to ranitidine and
cimetidine, but these two agents are also the most
commonly used.
• Adverse effects and interactions are few with short-term
use.
• Cimetidine is a weak anti-androgen, and may cause
gynecomastia and sexual dysfunction in males.
• Cimetidine inhibits CYP P450 and there is potential for
increased effect from any drug with a low therapeutic
index that is inactivated by these isoenzymes, e.g.
Warfarin, phenytoin.
• Ranitidine and famotidine avoid these unwanted effects.
• A potential danger is that patients with serious
pathology such as gastric carcinoma will self-medicate,
allowing their disease to progress.
 MUCOSAL PROTECTIVE AGENTS
• Mucosal protective agent is any drug that protects the
mucosal lining of the stomach from acidic gastric
juices.
• The mucosal barrier is the name given to the barrier in
the stomach that resists the back-diffusion of hydrogen
ions.
• The barrier is a layer of thick mucus secreted together
with an alkaline fluid.
SUCRALFATE
PK-PD
• Salt of sucrose is complexed to sulphated hydroxide
• Dissolution in water or acidic solutions forms a viscous
and tenacious paste that binds to ulcers for about 6 hours
• Solubility is limited; it breaks down to sucrose sulphate
and aluminum salt.
• Less than 3% of the drug and its aluminum is absorbed
from the intestinal tract and the rest excreted in the faeces.
• The precise mechanism of action is unclear.
• It is believed that the negatively charged sucrose
sulphate binds to positively charged protein in the base
of ulcers, forming a physical barrier that restricts further
gastric damage and stimulate mucosal prostaglandin
and bicarbonate secretion.
• Because sucralfate is not absorbed, it is virtually devoid
of systemic adverse effects
• Common adverse effects are: constipation (in 2% of
cases), which is attributed to the aluminum salt.
• A small amount can be absorbed, therefore prolonged
use in individuals with renal insufficiency is
inappropriate.
• It may bind to other drugs, thus impairing their
absorption.
BISMUTH
• Bismuth subsalicylate (BSS) is a DRUG used to manage
and treat gastrointestinal discomfort and traveler's
diarrhea.
• It belongs to the salicylates class of drugs.
• BSS is effective in situations where patients are
experiencing mild
• Gastrointestinal discomfort, as it reduces the severity
and incidence of flatulence and diarrhea.
• BSS is used off-label to eradicate Helicobacter pylori (H.
Pylori); a gastrointestinal tract infection.
• When used as part of a quadruple therapy regimen
containing a PPI, tetracycline, and metronidazole, can
eradicate up to 90% of H. Pylori infections.
• Another off-label indication for BSS is for the prophylaxis
and treatment of traveler's diarrhea.
• In developing countries, traveler's diarrhea affects at least
20% to more than 50% of tourists.
• BSS demonstrated effectiveness in the acute treatment of
traveler's diarrhea in patients with mild symptoms.
Mechanism of Action
• BSS exhibits many of its properties due to its
formulation as an insoluble salt of salicylic acid and
trivalent bismuth.
• Exhibits complex mechanism of action.
• In the stomach, BSS hydrolyzes into two compounds,
bismuth and salicylic acid.
• The salicylate compound is almost completely absorbed
into the bloodstream, while bismuth salt is minimally
absorbed.
• The bismuth that remains in the GIT forms other
bismuth salts, which contains bactericidal and
antimicrobial activity and prevent bacteria from binding
and growing on the mucosal cells of the stomach.
• This is the mechanism by which BSS helps eradicate H.
Pylori.
• Furthermore, the prevention of bacterial binding to the
mucosal cells provides many benefits, including
preventing intestinal secretion, promoting fluid
absorption, reducing inflammation, and promoting the
healing of any present ulcer in the stomach.
• It appears as though BSS does not alter the normal flora
of the stomach; however, its antimicrobial and
antisecretory properties play a significant role in
combating diarrhea.
• The antidiarrheal effect of BSS is most likely due to:
oThe reduction in prostaglandin formation, as BSS inhibits
cyclooxygenase.
oProstaglandin induces inflammation and hypermotility.
oThe stimulation of reabsorption of fluids, sodium, and
chloride - this action helps decrease fluid loss.
 oThe inhibition of intestinal secretions.
• While, in peptic ulcer disease, the likely mechanism of
BSS involves its cytoprotective and demulcent activity.
• In H. Pylori specifically, BSS blocks the adhesion of the
bacteria to the gastric epithelial cells.
• Additionally, BSS inhibits H. Pylori's enzyme activities,
including phospholipase, protease, and urease
Adverse Effects
• The common adverse effects associated with the
administration of bismuth subsalicylate are nausea,
bitter taste, diarrhea, and dark/black stools.
• Although rare, bismuth toxicity can result from the
overconsumption of BSS over an extended period
of time and can result in the blackening of the
tongue and teeth, fatigue, mood changes, and
deterioration of mental status.
• BSS can be fatal in very rare circumstances and can lead
to neurotoxicity.
• Other adverse effects with an unknown frequency of BSS
include hearing loss or tinnitus, muscle spasms or
weaknesses, anxiety, confusion, depression, headaches,
and potentially slurred speech.
Contraindications
• BSS should be avoided in:
oPatients undergoing oral treatments for gastric and
intestinal conditions with anticoagulants, sulfinpyrazone,
probenecid, methotrexate, or any medication with high
salicylate concentrations
oPatients with bleeding PUD or hemophilia
oPatients with bleeding problems or bloody/black stools
before administration of BSS
oThere is limited data for BSS use in children under the age
of 12 years old; other treatment options may be preferred.
oChildren or adolescents with flu-like
symptoms although not yet reported, BSS may
potentially cause Reye's syndrome in paediatrics or
adolescents recovering from influenza or varicella.
oPatients sensitive or allergic to salicylates or those who
have demonstrated sensitivity toward aspirin, it is
advisable not to use BSS.
oFor patients with any of the listed conditions, the
suggestion is that they use alternative treatment options.
oIt can decrease the absorption of doxycycline; an
effective antimicrobial for prophylaxis against malaria.
Prostaglandin Analogues (Misoprostol)
PK-PD
• It is believed that a disruption in the mucosal barrier (e.g.,
gastric and duodenal ulcers) occurs as a result of an
imbalance between the protective properties of the
gastroduodenal mucosa and damaging exogenous and
endogenous luminal factors such as the hydrogen ion
concentration, pepsin, bile acids, alcohol and drugs.
• It, therefore, has been suggested that a deficiency of
prostaglandins in the mucosa may be involved in the
pathogenesis of gastroduodenal ulcer.
• Patients with active gastric ulcers have been shown to
have a deficiency in tissue prostaglandins.
• A similar reduction in prostaglandins in the plasma
and gastric juice of patients with duodenal ulceration
compared with normal individuals has been reported.
• Reduction in mucosal prostaglandins results from
genetic factors leading to a deficiency and/or the
ingestion of certain medications (i.e., Nonsteroidal
anti-inflammatory drugs [NSAIDs]).
• Misoprostol is the first synthetic prostaglandin
investigated in the US for the treatment of peptic ulcer
disease and approved by the FDA for the prevention of
NSAID-induced ulceration.
Mechanism of Action
Inhibition of Gastric Acid Secretion
• The exact mechanism of action of misoprostol in the
inhibition of gastric acid secretion remains unclear.
• The presence of high affinity E-type prostaglandin
binding sites in enriched canine parietal cells suggests
that the binding of misoprostol is saturable, reversible,
and highly stereospecific, and results in the inhibition
of gastric acid secretion by inhibiting the activation of
histamine-sensitive adenylate cyclase.
• Cimetidine and histamine do not bind to these sites,
and prostaglandins I and F bind only slightly.
• Misoprostol inhibits basal," nocturnal," coffee-induced
and meal-stimulated gastric acid secretion by
decreasing fluid volume, acid concentration, acid
output, and pepsin activity.
• In human gastric secretion models, misoprostol blocks
acid secretion induced by histamine
• The substance's antisecretory properties do not result in
a change in serum gastrin concentrations, and it has not
been reported to cause the basal or postprandial
hypergastrinemia common with H2RAs.
• This lack of effect on gastrin levels may be responsible
for the decreased incidence of recurrent ulcers
compared with H2RAs following cessation of short-
term treatment.
Cytoprotection
• The exact mechanisms associated with the
cytoprotective properties of misoprostol in humans are
also not completely understood.
• Possible mechanisms include stimulation of
bicarbonate and mucus secretion, an increase in
mucosal blood flow, a decrease in vascular
permeability, and an increase in cellular proliferation
and migration.
• These cytoprotective properties can be observed at
doses lower than those required for the inhibition of
acid secretion.
• Misoprostol stimulates duodenal bicarbonate
secretion, proximal greater than distal, in a dose-
dependent fashion.
• This is to neutralize excess acid before tissue damage
occurs in the duodenum.
• It also stimulates gastric mucus secretion and increases
mucus concentration, resulting in a decreased
penetration of ulcerogens, thus preventing mucosal
injury.
• Ulcerogens destroy mast cells, allowing the liberation of
histamine.
• This histamine release initiates cellular damage by
increasing cellular permeability.
• Misoprostol indirectly decreases the permeability of
ulcerogens by stabilizing mast cells, thus preventing the
release of histamine.
Adverse reactions
• Misoprostol has proven to be a safe and well-tolerated
antiulcer agent in daily doses of 200-800 ug
• There are no significant dose-related ophthalmologic,
hemodynamic, or central nervous system adverse
effects reported.
• Gastrointestinal symptoms have usually been mild and
readily reversible.
• The most common adverse effect is dose-dependent
diarrhea reported to occur in about eight percent of all
patients (range 4-13%).
• However, diarrhea has rarely been the reason for
discontinuing misoprostol.
• Other adverse effects that occur infrequently include
abdominal pain, dyspepsia, lethargy, nausea, headache,
flatulence, constipation, and lightheadedness.
• Prostaglandins are known to have a uterotropic effect
and in pregnant women, which this can result in
termination of pregnancy.
• Misoprostol can endanger pregnancy and should not be
used in women of childbearing age unless adequate
contraceptive measures are used and the drug is
discontinued promptly if pregnancy occurs.
 POTASSIUM-COMPETITIVE ACID BLOCKERS (P-CABS)
• POTASSIUM-COMPETITIVE ACID BLOCKERS (P-CABS) ARE NOVEL DRUGS THAT BIND REVERSIBLY TO K + IONS
AND BLOCK THE H+, K+ATPASE ENZYME, THUS PREVENTING ACID PRODUCTION.
• P-CABS HAVE A FAST ONSET OF ACTION AND HAVE DOSE-DEPENDENT EFFECTS ON ACID PRODUCTION.
• THEY WERE FIRST DEVELOPED IN THE EARLY 1980S AND THE FIRST TWO MOLECULES STUDIED COULD NOT
GO BEYOND PHASE III DUE TO THEIR HIGH HEPOTOXICITY EFFCETS.
• THE FIRST P-CAB USED IN CLINICAL PRACTICE WAS REVAPRAZAN (YH-1885, REVANEX), MARKETED IN SOUTH
KOREA.
• LIKE OTHER P-CABS, IT HAD A QUICK ACTION ONSET, HOWEVER, WAS NOT SUPERIOR TO THE EXISTING
PROTON PUMP INHIBITORS (PPIS).
• THE SECOND P-CAB INTRODUCED IN CLINICAL PRACTICE WAS VONOPRAZAN FUMARATE (TAK-438),
MARKETED IN JAPAN IN EARLY 2015; IT BECAME POPULAR BECAUSE OF ITS SUPERIOR PROPERTIES SUCH AS
RAPID ONSET OF ACTION, LONG DURATION OF ACTION, AND CONSISTENT AND POTENT ACID SUPPRESSION
COMPARED TO THE TRADITIONAL PPIS.
• Phase III trials were conducted in South Korea for
reflux esophagitis for comparing the safety and
efficacy of a new P-CAB, Tegoprazan
(RQ-00000004/CJ-12420) 50 mg and 100 mg along with
Esomeprazole.
• The complete and final results of this study are not yet
published.
• Tegoprazan was approved for the treatment of erosive
esophagitis (EE) and NERD in South Korea in July
2018.
Pharmacokinetics, Mechanism of Action
• The P-CABs are weak bases, and the protonated form
of these drugs inhibits the H+ K+ atpase enzyme.
• Linaprazan’s potency was high when exposed to
vesicles that are ion-tight rather than to ion-leaky
vesicles.
• This suggests that the drug gets concentrated under
low pH and acts in the gastric lumen.
• The pKa of these drugs varies: 5.6 (SCH 28080), 6.1
(Linaprazan) and 9.3 (Vonoprazan).
• Since the pKa of Vonoprazan is high at 9.3, most of it
gets protonated easily and exerts its inhibitory action.
• Additionally, since the protonated forms are less prone
to cross membranes than the non-ionic molecules,
these protonated forms of P-CABs concentrate in the
acid-secreting canaliculi of parietal calls where they
exert the effect of H+ K+ ATPase enzyme inhibition.
Clinical Uses
• Vonoprazan has been approved in Japan for the
treatment of gastric and duodenal ulcers.
• The triple therapy of Vonoprazan and two antibiotics
(Amoxicillin and Clarithromycin or Metronidazole) are
useful in the eradication of H. Pylori.
• Vonoprazan has a good efficacy in endoscopic
submucosal dissection (ESD)-induced artificial ulcers
but superior to any PPIs.
• Vonoprazan 10 mg and 20 mg is found to be very well
tolerated and effective for the prevention of nonsteroidal
anti-inflammatory drug (NSAID) related recurrence of
peptic ulcer in Japanese patients, and this preventive
action could be maintained with long-term use.
Adverse Effects
• Liver toxicity
• The earlier P-CABs are not being used clinically
worldwide due to their short duration of action and
hepatotoxicity.
• These earlier P-CABs included SCH28080
(Imidazopyridine), AZD0865, Pyrimidines,
Imidazonaphthyridines and Pyrrolopyridazines.
• The most common treatment-emergent adverse event
(TEAE) of Vonoprazan in clinical studies was
nasopharyngitis.
• Most of the TEAEs were mild, and no deaths were
reported.
• One serious adverse event, diverticulitis, was
reported in the Vonoprazan 10 mg group and was
considered to be likely due to the drug.
• The mean levels of gastrin, pepsinogen I and
pepsinogen II increased after administration of
Vonoprazan.
• Mild to moderate constipation or diarrhea was
reported in certain preapproved clinical studies
where Vonoprazan was used for treating acid-
related disorders.
 PROTON PUMP INHIBITORS

• Proton pump inhibitors (PPIs) are widely utilised for the

treatment of gastro-oesophageal reflux disease, as well as
other acid-related disorders.
• Various classes are omeprazole, lansoprazole, pantoprazole,
rabeprazole and esomeprazole
• All PPIs suppress gastric acid secretion by blocking the gastric
acid pump, H+/K+-ATPase, but the physicochemical
properties of these drugs result in variations in the degree of
acid suppression, as well as the speed of onset of acid
inhibition.
• Such differences may impact on the clinical performance of
PPIs.
• The characteristics of PPIs that have been developed
subsequent to omeprazole offer several advantages over
this prototype PPI, particularly with respect to the onset of
acid suppression and reduced potential for inter-individual
pharmacokinetic variation and drug interactions.
• Newer agents inhibit H+/K+-ATPase more rapidly than
omeprazole and emerging clinical data support potential
clinical benefits resulting from this pharmacological
property.
PK-PD
• All PPIs suppress gastric acid secretion by blocking the
gastric acid pump, H+/K+-ATPase.
• Ideally, the blockade of this enzyme and inhibition of
gastric acid secretion should occur rapidly after the
first dose of the PPI and remain virtually complete in a
dose-dependent manner.
• There are substantial differences among the rates of
inhibition with these drug classes; the most rapid
inhibition occurring with the newer classes.
• The differences in the rate of inhibition of H+/ k+-
atpase activity with the five ppis are probably caused
by differences in their rates of acid-catalysed
conversion to active tetracyclic sulfenamides.
• All ppis are prodrugs, and their acid activation to
sulfenamide metabolites inside the canaliculus of
parietal cells may be an important determinant of their
onset of action.
• Sulfenamide forms of the ppis bind covalently to
h+/k+-atpase and inhibit its activity.
• The rate at which a given PPI is converted to its
sulfenamide derivative is inversely proportional to the
drug’s acid stability.
• The activation half-lives of the PPIs are dependent on
the pKa of the PPI together with the pH to which the
PPI is exposed.
• At a pH of 1.2, the half-lives of activation for the PPIs
were rapid and ranged between 1.3–4.6 minutes.
• The pKa of PPIs may also significantly affect their onset
and potency.
• The pKa of these drugs range from about 4.0 for
omeprazole to approximately 5.0 for rabeprazole.
• The pKa of PPIs influence accumulation at their site of
action, the canaliculus of the parietal cell.
• The canalicular space in most parietal cells may have a
pH of 1 during active acid secretion but it may be
much higher in the absence of stimulated acid
secretion.
• All PPIs share similar values for half-life and time to
maximum concentration. There appear to be differences
between the PPIs in terms of maximum plasma concentration
(Cmax) and AUC values.
• Lansoprazole, pantoprazole and rabeprazole showed a linear
correlation between Cmax and AUC0–24 with repeated doses.
• This difference between esomeprazole and omeprazole versus
the other PPIs is a result of the fact that the former drugs
significantly inhibit the cytochrome P450 (CYP) isozyme
primarily responsible for their clearance (CYP2C19).
• This is not the case for lansoprazole, pantoprazole or
rabeprazole.
• All five PPIs undergo extensive hepatic
biotransformation before elimination.
• This metabolism involves oxidative hepatic
metabolism and, in particular, metabolism via the
enzymes CYP2C19 and CYP3A4.
• However, different PPIs vary considerably in the
extent to which their metabolism depends on a given
CYP isoenzyme.
• All PPIs, except rabeprazole, are metabolised
primarily via the CYP2C19 isoenzyme.
• Omeprazole and esomeprazole progressively inhibit
CYP2C19 activity with repeated administration,
resulting in the accumulation of both the drug and its
sulfone metabolite over the first 5 days of treatment.
• Overall, the results of PK studies suggest that
exposure to rabeprazole may be less influenced by
genetic or drug-induced changes in hepatic
metabolism than is the case for other PPIs.
• The genetic polymorphism of CYP2C19 can profoundly
affect PPI metabolism and acid suppression achieved
with these drugs.
• CYP2C19 poor metabolisers represent approximately 3–
5% of Caucasians, a similar percentage of African-
Americans and 12–25% of different Asian populations.
• In clinical practice, the genotype of a patient will be
unknown.
• A patient who is an extensive metaboliser may present as
a non-responder, and his or her PPI dosage should be
increased or the PPI changed to one less susceptible to
such metabolic influences.
• Acid-related diseases are generally chronic conditions
requiring long-term treatment.
• Therefore, most patients taking PPIs are very likely to be
exposed to a wide range of other drugs during the course
of therapy.
• Drug interactions are common for drugs whose clearance
involves CYP-mediated oxidative metabolism in the liver.
• Given the differences in the hepatic metabolism of the
PPIs and their effect on hepatic enzymes, one might
anticipate differences in their potential for clinically
important pharmacokinetic drug interactions.
• Also, PPIs can alter the absorption of some drugs by
decreasing the acidity of the stomach.
• The potential for omeprazole to interact with other
concomitant drugs has been extensively studied.
• Omeprazole alters the absorption, metabolism and/or
excretion of a wide range of drugs, including bismuth,
caffeine, carbamazepine, diazepam, digoxin, mephenytoin,
methotrexate, nifedipine, phenytoin and warfarin.
• Because omeprazole and esomeprazole inhibit their own
CYP2C19-mediated metabolism, they can also inhibit the
metabolism of other drugs that are metabolised by
CYP2C19.
• Other drugs metabolised by CYP2C19 include citalopram,
escitalopram, fluoxetine, olanzapine, pentamidine, sertraline
and voriconazole.
• Some drugs are known to affect the metabolism of
omeprazole.
• Coadministration of ketoconazole markedly inhibits the
metabolism of omeprazole to omeprazole sulfone in both
CYP2C19 poor and extensive metabolisers.
• This interaction is most likely a result of the strong
inhibition of the enzyme CYP3A4, which also participates in
the metabolism of omeprazole, by ketoconazole.
• The clearance of omeprazole is also reduced by
fluvoxamine; an effect that is thought to be mediated by
fluvoxamine- induced inhibition of CYP2C19.
• In addition, coadministration of omeprazole with
triazolam resulted in benzodiazepine toxicity that
produced both dizziness and difficulty in walking.
• Administration of omeprazole to a patient who was also
being treated with warfarin led to
hypoprothrombinaemia and bleeding, presumably
associated with reduced clearance and increased plasma
levels of warfarin.
• Omeprazole has been clinically demonstrated to decrease
the metabolism of diazepam.
• In considering information regarding drug interactions
for the five currently available PPIs, one can predict
that all PPIs will produce similar interactions based on
increased gastric pH.
• However, only omeprazole and esomeprazole will
reduce the metabolism of CYP2C19 substrates.
Clinical Uses
• Healing of erosive oesophagitis due to GORD
• Healing of gastric and duodenal ulcers
• To achieve complete protection against the adverse effects
of NSAID medications on the upper GI mucosa.
Adverse Effects
• Patients have experienced few minor side effects of short-
term PPI use, such as headache, rash, dizziness, and
gastrointestinal symptoms including nausea, abdominal
pain, flatulence, constipation, and diarrhea.
• Patients have experienced few minor side effects of
short-term PPI use, such as headache, rash, dizziness,
and gastrointestinal symptoms including nausea,
abdominal pain, flatulence, constipation, and
diarrhea.18