I do not have any conflicts to disclose.

Sean Thatcher, PhD

sean.thatcher@temple.edu

Upper GI drugs
At the end of the lecture, the student should be able to:
1. Explain the neurohumoral control of H+ secretion by gastric parietal cells and the mechanism
of H+ production by the parietal cell H+-K+ ATPase.
2. Explain the role of histamine in the different phases of H+ secretion.
3. Identify the causes of H+ hypersecretion.
4. Describe the mechanism of action (MOA) of proton pump inhibitors and why they are selective
for the parietal cell proton pump.
5. Identify and explain causes for disruption of the cytoprotective barrier.
6. Explain the role of H. pylori in peptic ulcer disease.
7. Describe tests for evaluating H. pylori infection.
8. Discuss the use of triple and quadruple therapy regimens used for H. pylori eradication, and
explain how each agent works.
9. Discuss the potential for antibiotic resistant strains of H. pylori
 The process of acid secretion in the stomach
Local distension
Vagus Chemical components of gastric contents (peptides, caffeine)
+
BB2
+ Gastrin-releasing cells
Lon GRP
gp
Ach re-
gan
Somatostatin
g l io
ENS nic
fi + -
be
r +
Antral
Ach D
Ach Ach Gastrin Cells
Somatostatin
M3
M1 H2 receptor blockers CCK-B
-
ECL + (e.g., cimetidine) Parietal Cell
Histamine Somatostatin
cell
H2R K +
Prostaglandins
CCK-B and growth factors
Gastrin
+++ Cl- H+ Proton-pump inhibitors
(e.g., omeprazole)
 The cephalic, gastric, and intestinal phases of
digestion
• Cephalic phase is when gastric acid is
released in anticipation of a meal via
the vagus nerve (histamine released).
• Gastric phase is when the food
activates chemo- and
mechanoreceptors that will further
increase the release of gastric acid
(histamine release is enhanced).
• Intestinal phase will allow for gastrin
to briefly stimulate acid production,
however other peptides such as GIP,
CCK, secretin, and enterogastric
reflex will inhibit acid production.
ANS and ENS control of digestion
• Parasympathetic (“rest and digest”)
• Contraction of smooth muscle in wall
• Relaxation of sphincters
• ↑ salivary secretion (increase in volume and water composition)
• ↑ gastric secretion (previous slide) Extrinsic
• ↑ pancreatic secretion (e.g., lipases) Pathway
• Sympathetic
• Relaxation of smooth muscle in wall
• Contraction of sphincters
• ↑ salivary secretion (less in volume compared to para- and higher in protein content)
• ENS (intrinsic)
• Modulates activity of autonomic system by releasing a number of peptides within the GI tract.
Ganglia are found in the submucosal and myenteric plexus.
 Anatomy and other hormones in upper GI
• The lower esophageal sphincter
help to prevent acid from
entering the esophagus. If this
barrier is compromised, it can Fundus
Lower
lead to esophagitis or possibly esophageal
esophageal cancers. sphincter
• Parietal cells also release
intrinsic factor to aid Body
absorption of Vitamin B12
(cobalamin).
Antrum
• Mucus is cytoprotective and
prostaglandins help with this.
NSAIDs, aspirin and ethanol will
block prostaglandin production. NSAIDs, aspirin, ethanol inhibit PG formation
Proton-pump inhibitors (PPIs)
• Omeprazole, S-isomer is esomeprazole
• Lansoprazole, S-isomer
• Rabeprazole
• Pantoprazole
• Dexlansoprazole, R-isomer of lansoprazole
• Decreases daily production of acid, both basal
and stimulated by 80-95%.
• Requires activation by H+ ion.
• Irreversible binding to sulfhydryl groups of Acid-base balance is important in the stomach
and can influence drug absorption!
cysteines in H+-K+-ATPase pumps (selectivity).
• Short half-life (0.5-3 hours)
PPI characteristics
• All of the PPIs have similar efficacy at comparable doses. First time to
enter market was 1989.
• Can be given in different formulations
• Enteric-coated
• Delayed-release
• Powdered omeprazole with sodium bicarbonate
• These formulations help to improve oral bioavailability.

• If oral route is unavailable, then parenteral route can be given

(esomeprazole and pantoprazole).
• Omeprazole (Prilosec®), esomeprazole (Nexium®), and lansoprazole
(Prevacid®) are all approved OTC drugs (2003).
 Clinical indications and ADME insights for
PPIs
• Clinical indications
• Treatment of peptic ulcer disease (PUD, NSAID-induced or not), GERD including erosive
esophagitis especially if unresponsive to H2R antagonist.
• Used in conjugation with antibiotics to eradicate H. pylori infections.
• Used in treatment of pathological hypersecretory conditions (Zollinger-Ellison syndrome).
• ADME
• PPIs are rapidly absorbed, highly protein bound, and metabolized by hepatic CYPs (P450 system)
• Requires 2-5 days of treatment before significant inhibition is seen at steady state, since not all
pumps on parietal cells are activated simultaneously.
• Metabolized by CYP2C19 (omeprazole) and CYP3A4. Asians have a pharmacogenetic
polymorphism of CYP2C19 which slows the metabolism of the PPI. This can cause increases in
toxicity due to reduced metabolism.
• PPIs are mainly eliminated by the liver and so patients with severe hepatic disease should be
monitored for drug dosing levels (specifically for esomeprazole and lansoprazole).
 PPIs have few adverse effects and a high
therapeutic index
• Adverse effects of PPIs
• Nausea, abdominal pain, constipation, flatulence, and diarrhea. Some patients have
reported skin rashes, headaches, myopathy, and arthralgias.
• Drug-drug interactions (important for drugs that have a narrow therapeutic range
or low therapeutic index)
• Warfarin (esomeprazole, lansoprazole, omeprazole, rabeprazole, inhibit elimination)
• Diazepam (esomeprazole, omeprazole, inhibit elimination)
• Methotrexate (All PPIs, inhibit elimination)
• Loss of gastric acidity may affect bioavailability of drugs (eg. iron salts, ampicillin esters)
• Drug-food interaction
• Chronic treatment with PPIs can decrease the absorption of vitamin B12.
Twice-a-day dosing may be required for patients with severe
symptoms and nocturnal acid breakthrough
• Twice-daily dosing with a PPI may be needed for more severe
symptoms of GERD. Very difficult to cause a patient to be
achlorhydric.
• Can sometimes add an H2 receptor antagonist at night to help with
symptoms.
• Severe GERD can cause noncardiac chest pain, asthma, laryngitis,
chronic cough, and other ear/nose/throat conditions. It can also lead
to Barrett esophagus.
• Anti-reflux surgery may be utilized if drug therapy fails.
 Rebound acid hypersecretion can occur with
prolonged treatment of PPIs
• Chronic treatment of a PPI can elevate gastrin
production which can significantly elevate
histamine release from the ECL cell.
• Once the PPI is withdrawn, excessive acid
secretion can occur (rebound acid
hypersecretion). Therefore, if the PPI is to be
withdrawn, then drug tapering should be
performed.
• This can induce dyspepsia and exacerbate
symptoms of GERD.
• Endoscopy to evaluate the severity of the
GERD and to use the lowest dose of the PPI is
warranted.
Chronic treatment of PPIs
• Chronic treatment of PPIs has been associated with:
• Increased risk of bone fracture
• Increased susceptibility to certain infections (pneumonia, C. diff)
• Hypergastrinemia which could lead to ECL hyperplasia, fundic gland polyposis,
and atrophic gastritis.
• Hypomagnesemia
• Chronic kidney disease
• Dementia

• Possible drug-induced lupus erythematosus (does resolve with

discontinuation of the PPI and is rare).
 Polling question #1
1. Which of the following statements is TRUE concerning proton-pump
inhibitors (PPIs)?
A. PPIs are reversible inhibitors of the H+-K+-ATPase.
B. PPIs have a low therapeutic index.
C. PPIs can only be taken once-per-day.
D. Chronic treatment of PPIs can possibly cause hypomagnesemia.
E. Immediate withdrawal of a PPI cannot exacerbate acid
hypersecretion.
 Histamine and H2R antagonist characteristics
• Histamine from the ECL cell will bind to H2R and cause an increase in
cAMP. This will increase insertion of H+-K+-ATPase pumps in apical
membrane of parietal cell.
• H2R antagonists are reversible and lower cAMP production.
• Four different H2R antagonists are available in the U.S.
• Cimetidine, Ranitidine, Famotidine, and Nizatidine
• These drugs differ based on pharmacokinetics and drug-drug interactions.
• These drugs are no longer recommended for treatment of bleeding ulcers.
• Are available as OTCs and prescription strength.
• Can also be given IV or IM to patients that are critically ill and cannot take orally.
H2R antagonists block the production of cAMP and lower the
H+-K+ ATPase pumps on apical membrane of parietal cells

• Cimetidine (Tagamet®) and famotidine (Pepcid®) are examples

of competitive histamine receptor 2 antagonists.
• Mechanism of action (MOA) block histamine action on H2
receptors on parietal cells.
• Less potent than the PPIs in decreasing acid secretion.
• H2R antagonists can suppress both basal and nocturnal acid
secretion (70% suppression).
• Tolerance may develop with this drug class. Rebound acid
hypersecretion can also occur with these drugs. Ranitidine pulled from
US market due to
nitrosamine impurities
(2019).
Therapeutic indications and ADME insights
• Absorption is rapid (1-3 hours orally)
• Very little of the drug is protein bound in plasma.
• Kidneys excrete these drugs by filtration and renal tubular secretion. It is
important to reduce drug doses in patients with renal disease.
• Hepatic metabolism accounts for 10-35% of clearance.
• Clinical indications are:
• Promote mucosal healing due to gastric and duodenal ulcers (H. pylori-induced).
• Uncomplicated GERD
• Prevent occurrence of stress ulcers
• Due to the fact that there is tolerance to these drugs, they have largely been
replaced by the PPIs.
Adverse effects of H2R antagonists
• Typically well tolerated with a low incidence of adverse effects.
• Typical side effects include: diarrhea, headache, fatigue, muscular pain, and
constipation.
• If given IV to elderly patients, it could cause confusion, delirium,
hallucinations, slurred speech, and headaches.
• H2R antagonists can cross the placenta and are excreted in breast milk (risk
category B).
• Cimetidine inhibits CYPs (CYP1A2, CYP2C9, CYP2D6) and can increase the level
of a variety of drugs. Famotidine has less effects via P450 system.
• Slight increases in blood alcohol concentrations may result with H2R
antagonists and alcohol consumption.
Gastroesophageal reflux disease (GERD)
have better outcomes with PPIs
• PPIs show better therapy for ulcers, GERD, and
H.pylori eradication than the H2R antagonists
(chart on right).
• Strictures associated with GERD also respond
better to PPIs.
• Acid reflux can occur in 30-50% of pregnancies.
Typically ends after delivery. Omeprazole is
category C. For mild cases, antacids or sucralfate
are considered first-line drugs.
• Reflux disease in infants and children can also
occur. PPIs should be weighed carefully due to the
increased risk of bacterial infections and
gastroenteritis when using PPIs.
 Lifestyle modifications that can help in the
treatment of PUD/GERD
• Diet modification
• Limiting foods with caffeine or having a large dinner before
bed.
• Abstain from consuming tobacco products and alcohol.
• Exercise or weight management
• Keeping a journal to track points of stress, food intake,
etc. Be nice to your GI system.
Competitive eating contests are
• Proper mastication of food probably not a wise thing to do!

• Sleeping in an inclined position for patients with GERD.

Cytoprotectives
• Cytoprotectives work by promoting prostaglandins or somatostatin to help increase
bicarbonate secretion, mucus production, and inhibition of acid secretion.
• Misoprostol (PGE1 analog)
• Sucralfate
• Somatostatin analog (octreotide)

Misoprostol

Octreotide Sucralfate
 Misoprostol, dinoprostone
• Used to prevent NSAID-induced mucosal NSAIDs
injury. Ethanol

• Binds to EP3 receptor on parietal cells to

stimulate Gi pathway.
• Helps to increase mucin production,
↑bicarbonate secretion, and ↑mucosal
blood flow.
• Absorbs quickly and can last up to 3 hours
(requires multiple-dosing).
K+
• Mainly eliminated by kidneys.
• Adverse Effects Cl-
H+
• ≤ 30% of patients experience diarrhea.
• Can exacerbate inflammatory bowel disease.
• Contraindicated during pregnancy because it
will induce uterine contractility.
Sucralfate (sulfated polysaccharides)
• Many different mechanisms of action (MOAs)
• Reacts with HCl to form cross-links making an acid buffer.
• Acts as a protective barrier to prevent further damage by acid, pepsin, and bile. It can also
bind to pepsin and bile acids to inactivate these proteins.
• Aluminum hydroxide is added so can induce aluminum overload in patients with
renal deficiency.
• By binding to bile acids, it may compromise lipid absorption and cause steatorrhea.
• Can be given rectally for rectal ulcers and radiation proctitis.
• Considered as pregnancy category B.
• Adverse Effects
• Most common is constipation.
• Can block the absorption of other drugs.
• May promote bezoars in some patients.
Should be given on empty stomach
Octreotide (somatostatin analog) can inhibit
intestinal and pancreatic secretions
• Not typically used to suppress gastric acid due to other effects.
• Can inhibit growth hormone (GH), glucagon, insulin, and gastric
hormones such as gastrin, CCK, and vasoactive intestinal peptide
(VIP).
• Can also block feeding behavior.
• Used to treat severe diarrhea associated with metastatic carcinoid
tumor in adults. Can also be used to treat acromegaly, acute variceal
bleeding, GI fistula, and acute pancreatitis.
• Adverse Effects
• Nausea, abdominal cramping, steatorrhea, and gall stones
 Amitriptyline, desipramine (TCA drugs)
• TCAs are the oldest anti-depressants on the market. Tricyclic
• Clinical indications
• Can be used to treat dyspepsia in the absence of ulcers.
• Can also be used in treatment of irritable bowl syndrome and
cyclic vomiting syndrome.
• Pharmacodynamics
• Blocks the reuptake of serotonin and norepinephrine.
• Can also block muscarinic receptors and alpha,1-adrenergics.
• Can also block voltage-gated sodium channels and H1R.
• Adverse effects
• Dry mouth, drowsiness, dizziness, constipation, weight gain.
• Can induce arrythmias, liver toxicity, and glaucoma
Antacids neutralize gastric acid and inhibit pepsin
activity
• Neutralize gastric HCl and increases gastric pH. Can increase urinary pH by 1
unit so helpful with alkalinization of urine.
• Also inhibit pepsin activity
• Composed of inorganic salts (with or without metal cations)
• Examples include calcium carbonate, sodium bicarbonate, aluminum hydroxide, and
magnesium hydroxide
• Aluminum and magnesium hydroxides have been reported to have
cytoprotective effects, such as increase in gastric bicarbonate secretion and
prostaglandin release. Mucus secretion is also increased.
• Must be careful with metal cations as Aluminum-only based antacids can
cause constipation and Magnesium-only based antacids can cause diarrhea.
• These are OTC drugs and have fallen out of favor in the clinic due to lower
efficacy.
Adverse effects of antacids
• Release carbon dioxide therefore antacids can cause nausea, belching, flatulence,
and abdominal discomfort.
• Simethicone is a surfactant that can reduce the surface tension of gas bubbles
and can be found in most antacids.
• Absorbable bicarbonate can increase blood and urine pH causing transient
metabolic alkalosis. Must be careful with sodium bicarbonate as this may pose a
risk for patients with cardiac or renal failure.
• Some combination of antacids can contain aspirin and should not be used in
patients predisposed to gastric ulcers.
• Al3+ and Mg2+ have the ability to chelate other drugs found in the GI tract. Most
of these interactions can be avoided by taking antacids 2 hours before or after
ingestion of other drugs.
H. pylori infections
• 14-day treatment protocol
• Due to increasing clarithromycin resistance, quadruple therapy may be required to treat H.
pylori infections.
• PPIs may cause false-negative results in patients undergoing urease-based H.pylori testing.
PPIs should be discontinued 2 weeks before performing this test.
Bismuth based
• Antimicrobial therapy PPI (twice daily)
• Amoxicillin Bismuth subsalicylate (4 times per day)
• Clarithromycin Tetracycline (500 mg, 4 times per day)
• Tetracycline Metronidazole (500 mg, 3 times per day)
• Metronidazole
Non-bismuth-based
• Proton Pump Inhibitor PPI (twice daily)
• Bismuth salicylate/subgallate Amoxicillin (1000 mg, twice daily)
Metronidazole (500 mg, twice daily)
Clarithromycin (500 mg, twice daily)
Antibiotics and mechanisms of action
• Amoxicillin
• Beta-lactam antibiotic and inhibits cross-linkage of peptidoglycan polymer chains to disrupt
bacterial wall synthesis.
• Clarithromycin
• A macrolide antibiotic that prevents bacteria from multiplying by acting as a protein synthesis
inhibitor. It binds to 23S rRNA which is a component of the 50S subunit of the bacterial
ribosome.
• Tetracyclines
• Composed of a 4 member ring structure. They also inhibit protein translation by binding to
the 30S ribosomal subunit. They also have the ability to inhibit matrix metalloproteinases
(MMPs) and so are sometimes used to treat acne, rosacea, and other skin disorders.
• Metronidazole
• Belongs to nitroimidazole chemical class and inhibits nucleic acid synthesis by forming nitroso
radicals. Requires reduction (gain of electrons), which happens only in anaerobic bacteria and
protozoans. Little effect upon human cells or aerobic bacteria.
Polling question #2
Which of the following statements is TRUE concerning cytoprotective
drugs?
A. Misoprostol has no effects on uterine contraction.
B. Sucralfate will induce diarrhea in patients.
C. Antacids can help to acidify the urine to eliminate drugs, such
as methamphetamine.
D. Octreotide can inhibit pancreatic secretions and can be used
to treat acute pancreatitis.
Summary of PPIs, H2R antagonists, and
cytoprotectives
• With decreasing acid production in the stomach, this can allow for bacterial
overgrowth which can make its way to the respiratory tract. Patients on
PPIs have an increased risk of developing community-acquired pneumonia.
• PPIs are going to a first-line drug with issues of PUD, GERD, and acid
overproduction. This is due to the fact that they have a direct effect on the
pumps that produce acid.
• Cytoprotectives can help to increase mucosal defense within upper GI,
however efficacy is much lower than the PPIs.
• H.pylori infections require multiple forms of therapy. Antibiotic resistance
can occur so it is important to finish all antibiotics to prevent reoccurrence.
Acute Pancreatitis
• Abrupt onset of deep epigastric pain, often
radiates to the back.
• Can be related to heavy alcohol intake or
history of gallstones. Can also be associated
with smoking, obesity, and high dietary
glycemic load.
• Abdominal tenderness and distention and fever. Treatment for this:
• Leukocytosis, elevated serum amylase and
lipase are indicators.
• Can be associated with chronic use of
medications, such as tetracyclines,
azathioprine, mesalamine, etc.
Acute pancreatitis (CT scan). Note
enlargement of pancreas and bile duct
(arrow). L, Liver, K, Kidneys, a, aorta, s,
superior mesenteric artery
1. Withhold food and liquids by mouth.
2. Nasogastric suction to remove stomach acid.
3. Give lactated Ringer solution.
4. Give opioid for severe pain.
If acute pancreatitis is due to
hypertriglyceridemia, then use of MTP
inhibitor Lomitapide is needed.
Zollinger-Ellison syndrome (gastrinomas)
• Peptic ulcer disease, abdominal pain, and
diarrhea are common presentations.
• Increased gastric acid secretion due to
gastrin-releasing tumor.
• Can also cause for dramatic increase in
histamine release from ECL cells.
• Peptic ulcers that appear in unusual
places, such as the jejunum or lower
duodenum can be indicators.
• A secretin stimulation test may be ordered
to see if gastrin response is exaggerated.
• Surgery to remove the gastrinoma is best. Octreotide can bind to these gastrinomas because
Depending on the extent of disease, they have the receptors, octreotide can be used as a
chronic PPI may be given. tumor imaging agent. Octerotide can also be used to
slow the progression of the tumor as well.
Esophageal cancers can develop due to
untreated chronic GERD
• Extremely lethal malignancy.
• Can present as a squamous cell carcinoma or adenocarcinoma (most common
presently).
• Is associated with smoking and alcohol consumption (factors can act synergistically).
• Dietary deficiencies of Vitamin A, selenium, and zinc have been linked to these
cancers. Patients with head and neck cancer are at an increased risk of esophageal
cancer.
• These tumors can arise with chronic gastric reflux and presence of Barrett’s
esophagus. Most esophageal cancers occur in the lower third of the esophagus (75%
of cases).
• Neoadjuvant chemotherapy (preparative) may be necessary before surgical removal.
Such chemotherapeutic agents like irinotecan, 5-FU, capecitabine, and vinorelbine
(taxanes) are used especially with metastatic esophageal cancers.
• Radiation therapy can also be combined with chemotherapy for treatment.
Gastroparesis (prokinetics)
• Gastroparesis is delayed gastric emptying.
• Etiologies include:
• Diabetes
• Obesity/GERD
• Post-gastric surgery
• Idiopathic
• Mild intermittent symptoms will cause
nausea with postprandial abdominal Drugs used to treat symptoms of gastroparesis include:
distention and pain.
1. Dopamine antagonists
• Severe symptoms will cause excessive 2. Macrolide antibiotic (erythromycin)
vomiting. 3. Cholinomimetics or acetylcholinesterase inhibitors
 Prokinetics are drugs that can help stimulate gut
motility and treat the symptoms of gastroparesis
• Erythromycin can act as a motilin mimetic.
• Can be used to induce antral contractions and used short term in patients with gastroparesis.
Typically used in moderate-to-severe gastroparesis
• Tolerance typically occurs over time.
• Standard dose for gastric stimulation is 1.5-3 mg/kg IV or 125 mg every 12 hours orally. Should be
given as a suspension.
• Can induce prolongation of QT interval so patients that have abnormal heart rhythms should be
monitored while given erythromycin.
• Bethanechol (cholinomimetic) and neostigmine (AchE inhibitor)
• Bethanechol increases smooth muscle tone in the GI tract (via M3 receptors) and is typically used
following abdominal surgery. Can also be used to treat urinary retention. Bethanechol does NOT
have any nicotinic action. Should not be used in patients that have a bowel obstruction or patient
with inflammatory bowel disease (IBD).
• Neostigmine is a reversible AchE inhibitor. Used for paralytic ileus and urinary bladder atony. Also,
Dopamine receptor 2 antagonists (domperidone,
metoclopramide) can stimulate upper GI motility.
• Dopamine inhibits motility in the upper Neural connections in upper GI
GI, however it will stimulate motility in Dopaminergic neuron
the colon.
• Can be used in patients with CINV. Has

Inhibition
central antiemetic action.
Cisapride
• Adverse effects include anxiety,
+
confusion, and may cause dystonia and
tardive dyskinesia. Could cause
5HT4R
Activate D2R - Domperidone
constipation, however tolerance Metoclopramide
develops to this.
• Domperidone has black box warning due Cholinergic neuron
to prolongation of QT interval in elderly
patients.
Bethanechol
• Can also elevate prolactin levels and
induce galactorrhea, gynecomastia, +
M3 receptor
amenorrhea, and impotence
(significantly affects patient Smooth muscle
Polling question #3
3. Ranitidine inhibits which of the following?
A. Gastrin binding to parietal cells
B. Histamine binding to parietal cells
C. H+,K+-ATPase
D. Parietal cell prostaglandin receptors
 Clinical case
4. Janet Swigel is a 68-year-old women with Type 2 diabetes who presents to the GI clinic with
complaints of heartburn 4-5 times a week over the past 5 months. She also reports some
regurgitation after meals that is often accompanied by an acidic taste in her mouth. She states
that her symptoms are worse at night, particularly when she goes to bed. She finds that her
heartburn worsens, and she coughs a lot at night which keeps her awake. She has had difficulty
sleeping over this time period and feels fatigued during the day. She reports no difficulty
swallowing foods or liquids. She has tried OTC Tagamet® 24HR as needed for the past 3 weeks.
This has reduced the frequency of her symptoms to 3-4 days per week, but they are still bothering
her. Patient is negative for H.pylori and has esophagitis after an endoscopy was performed last
week. Patient is currently taking ibuprofen for joint pain.
A. What subjective and objective information indicates the presence of GERD in
this patient?
B. What additional information is needed to fully assess this patient’s GERD?
C. What are other potential complications of long-standing untreated GERD?
The End
Any questions?