NSAID-Associated Gastritis

GROUP 7 YL1B; SY 2017-2018

SANCHEZ, Eric Meynard P. SARTE, Cervin Benjamin G.

SANDOVAL, Marian Rose M. SEBASTIAN, Gem N.
SANTIAGO, Rozette D. SEFUENTES, Roland M.
SANTOS, Gio Adrian I. SEVILLA, Ansherina Joi M.
SANTOS, Lynelle Ruth M. SIBAL, Deanne Devonney R.

CASE PRESENTATION

 A 63-year-old female presents to the clinic with recurrent midepigastric pain over the last 3
months. She reports some relief shortly after eating, but then the discomfort returns. She has
tried various over-the-counter medications without relief. She also reports feeling tired and has
had to increase the amount of ibuprofen needed for relief of her arthritis. She denies nausea,
vomiting, and diarrhea. On exam she is found to have mild midepigastric tenderness and guaiac
positive stool. A CBC revealed a microcytic anemia and normal white blood cell count, consistent
with iron deficiency. The patient was referred to a gastroenterologist who performed an upper GI
endoscopy that identified gastric ulcers. He stated that he suspected that the ibuprofen, a
nonsteroidal anti-inflammatory drug (NSAID) was the causative agent and suggested switching
from ibuprofen to a coxib, such as celecoxib

CASE QUESTIONS:
1. What is the likely biochemical etiology of disorder?
2. Why do coxibs has a general lower incidence of upper GI problems than other NSAIDS?
3. What is the major difference between Aspirin and other NSAIDS with regards to platelet function?

SIGNS AND SYMPTOMS:

 Recurrent midepigastric pain
 Mild midepigastric tenderness
 Guaiac positive stool
 Microcytic anemia
 Iron deficiency

DIAGNOSIS:
 63-year-old female
 Arthritis taking NSAID (Ibuprofen)
 Recent onset of epigastric pain relieved with food
 Guiac positive stools
 Anemia and iron deficiency
 Endoscopic examination – Gastric ulcers
DEFINITION OF TERMS:
 Eicosanoids: Oxygenated lipid signaling molecules containing 20 carbons derived from
polyunsaturated fatty acids released from membrane phospholipids by the action of
phospholipase A2. These include the prostanoids produced by the cyclooxygenase pathway and
the leukotrienes produced by the lipoxygenase pathway.
 Prostanoids: Oxygenated lipid signaling molecules derived from polyunsaturated fatty acids
released from membrane phospholipids by the action of phospholipase A2. Prostanoids include
prostaglandins, prostacyclin, and thromboxanes.
 Prostaglandin: An oxygenated lipid signaling molecule that has a five-member ring system that is
derived from arachidonic acid and other 20-carbon polyunsaturated fatty acids. The
prostaglandins are hormone-like molecules that regulate cellular events near the area in which
they are synthesized.
 Thromboxane: An oxygenated lipid signaling molecule that has a six-member ring system derived
from arachidonic acid and other 20-carbon polyunsaturated fatty acids. Thromboxanes are
involved in platelet aggregation as well as vaso- and bronchoconstriction and lymphocyte
proliferation.
 PGH synthase: Prostaglandin H synthase; the enzyme that catalyzes the formation of
prostaglandin H from C20 polyunsaturated acids. PGH synthase has two activities; the
cyclooxygenase activity introduces the five-membered ring into the polyunsaturated fatty acid
while also introducing an endoperoxide between carbons 9 and 10 and a hydroperoxide at carbon
15. The peroxidase activity reduces the hydroperoxide to a hydroxyl group using glutathione as
the source of reducing equivalents. PGH synthase exists in two isoforms, PGHS-1 and PGHS-2.
PGHS-1 is the “basal” isoform and is expressed constitutively, whereas PGHS-2 is the inducible
isoform and has been implicated in cell proliferation and inflammation.
 NSAIDs: Nonsteroidal antiinflammatory drugs; NSAIDs inhibit the cyclooxygenase activity of PGH
synthase, thus inhibiting the production of prostaglandins and thromboxanes.
 Coxibs: A class of NSAIDs that is selective for inhibition of the cyclooxygenase activity of PGHS-2,
with weaker action against the PGHS-1 cyclooxygenase.
PATHOPHYSIOLOGY AND BIOCHEMICAL PROCESSES INVOLVED:

Prostaglandin Synthesis

 Prostanoids are oxygenated lipid-signaling molecules derived from polyunsaturated fatty

acids.
 Conversion of arachidonate to PGH2 is a key regulatory step in prostanoid biosynthesis.
 The first reaction (arachidonate à PGG2) involves insertion of two molecules of oxygen and
cyclization of FA backbone, which is catalyzed by COX-1 or COX-2. It is this step that is inhibited
by your NSAIDs
 The next step involves reduction of hydroperoxide on C15 to an alcohol and is catalyzed by
the peroxidase activity of COX-1 or COX-2
COX-1 vs COX-2
 COX can also be called prostaglandin H synthase complex (PGHS)
 Both isoforms of COX have cyclooxygenase and peroxidase activities and are structurally similar
proteins, they have very distinct pathophysiologic functions.
 COX-1 – regulation of hemostasis and vascular tone, renal function, and maintaining gastric
mucosal integrity
 COX-2 – an inducible enzyme typically expressed in response to cytokines and mitogens at sites
of inflammation or cell proliferation

 Are competitive inhibitors and

therefore:
 Are reversible if you increase the
concentration of the substrate or decrease
the concentration of the inhibitors
 Show decreased Km in Michaelis-
Menten kinetics
 Intersect at the Y-axis in the Lineweaver-
Burk plot

ASPIRIN
 The only exception to this competitive inhibition is aspirin.
 Aspirin has emerged as a very useful antithrombotic agent because of its activity against platelet
cyclooxygenase activity.
 Shows both archetypal modes of COX inhibition:
o First Mode – rapid reversible binding of inhibitor (I) at the cyclooxygenase site of the
enzyme (E) to form an EI complex;
o Second mode – a slower conversion of EI to a higher affinity complex, EI’
 PATHOPHYSIOLOGY & BIOCHEMICAL PROCESSES:
 E + I ↔ EI -> EI’
 EI and EI’ cannot bind fatty acid and thus neither can catalyze the COX reaction.
 For aspirin, conversion of EI to EI’ is accompanied by covalent modification of the protein, making
the transition irreversible.
 Formation of the EI’ complex produces a more powerful cyclooxygenase inhibition because the
inhibitor is not readily displaced by substrate and because inhibition persists even when free
inhibitor is removed.
GASTRITIS

 Gastric mucosa is resistant to highly acidic secretions that it produces.

 Prostaglandin E2 (after binding to its receptor) inhibits acid secretion and stimulates mucus
production. Hence it is an important factor in the maintenance of the gastric mucosal barrier.
 NSAIDs, such as ibuprofen and aspirin, damage the gastric mucosa by inhibiting prostaglandin
synthesis.
 When H+ ions accumulate in the mucosal cells, intracellular pH decreases, enzymatic
reactions become impaired, and cellular structures are disrupted (gastritis).
 The mucosal surface is protected by prostaglandins.
 For every hydrogen ion (H+) that is secreted, an HCO3- is produced, and as long as HCO3
production is equal to H+ secretion, mucosal injury does not occur.
 Aspirin and NSAIDs impair HCO3 secretion by the inhibiting gastric COX-1, which mediates
bicarbonate secretion.
 Prostaglandins play an important role in protecting gastric mucosa from injury. Improved
mucosal blood flow, decreased acid secretion, increase HCO3 secretion, and enhanced mucus
production.
 Patient may develop metabolic acidosis at some point.
 NSAIDs cause type C gastritis. (Can lead to stomach lining erosion, like the one seen in bile
acid reflux.
 GASTRITIS:
 For every hydrogen ion (H+) that is secreted, an HCO3- is produced, and as long as HCO3-
production is equal to H+ secretion, mucosal injury does not occur.
 Aspirin and NSAIDs impair HCO3- secretion by way of inhibiting gastric COX-1, which mediates
bicarbonate secretion

LABORATORY DIAGNOSIS:
 Complete blood count (CBC) - The complete blood count, or CBC, lists a number of many
important values. This test can detect anemias respectively of the case. Typically, it includes the
following:
o White blood cell count (WBC or leukocyte count)
o WBC differential count
 o Red blood cell count (RBC or erythrocyte count)
o Hematocrit (Hct)
o Hemoglobin (Hbg)
o Mean corpuscular volume (MCV)
o Mean corpuscular hemoglobin (MCH)
o Mean corpuscular hemoglobin concentration (MCHC)
o Red cell distribution width (RDW)
o Platelet count
o Mean Platelet Volume (MPV)
 Peripheral blood smear - A blood smear is a blood test used to look for abnormalities in blood
cells. The test provides information on the number and shape of these cells, which can help
doctors diagnose certain blood disorders or other medical conditions. Irregularities in the number
or shape of your red blood cells can affect how oxygen travels in your blood. For example
(microcytic anemia that may indicate Iron deficiency anemia)
 Serum ferritin - A ferritin test measures the amount of ferritin in your blood. Ferritin is a blood
cell protein that contains iron. A ferritin test helps your doctor understand how much iron your
body is storing.
 Fecal Occult Blood Test (FOBT) - The fecal occult blood test (FOBT) is a lab test used to check
stool samples for hidden (occult) blood. A positive test is indicative of bleeding along the
Gastrointestinal Tract.

DIFFERENTIAL DIAGNOSIS:
 Helicobacter pylori infection - H. pylori is a common type of bacteria that grows in the digestive
tract and has a tendency to attack the stomach lining. This bacteria can lead to diseases in some
people, including peptic ulcers, and an inflammatory condition inside your stomach known
as gastritis.
 H. pylori gastritis can be differentiated to NSAIDs-associated gastritis by a positive H. pylori blood
kit test, breath test and stool antigen test.

TREATMENT:
 Treatment for NSAID gastritis
 NSAID-induced gastritis may be managed using drugs approved for ulcer disease.
 It is preferred to stop NSAID therapy when ulcer disease occurs.
 If NSAID therapy is to be continued, proton pump inhibitor is the drug of choice in the presence
of ulcer disease.
 Drugs:
o PGE1 Analogue (Misoprostol)
 MOA: A prostaglandin E1 analogue that inhibits acid secretion and stimulates
mucus and bicarbonate production.
o Proton Pump Inhibitors (Omeprazole)
 MOA: Blocks H+/K+ ATPase or the proton pump. It is the terminal stage in gastric
acid secretion, being directly responsible for secreting H+ ions into the gastric
lumen, making it an ideal target for inhibiting acid secretion.
o H2 Receptor Antagonists (Ranitidine)
  MOA: Blocks histamine from stimulating the cAMP of the gastric parietal cell
leading to the inhibition of acid secretion.

ANSWERS TO CASE QUESTIONS:

1. What is the likely biochemical etiology of the disorder?
 Primarily, NSAID inhibition of a gastric enzyme
 (COX-1) required for synthesis of prostaglandins that have a protective
 effect on the gastric mucosa. A contributory factor is direct mucosal
 damage due to the acidic chemistry of NSAIDs

2. Why do coxibs generally have a lower incidence of upper GI problems than other NSAIDS?
 Traditional NSAIDs, such as ibuprofen and aspirin, inhibit both COX-1 and COX-2.
 The coxibs- are selective inhibitors of COX-2, allowing continued production of protective
prostaglandins by gastric COX-1.
 3. What is the major difference between aspirin and other NSAIDs with regard to platelet function?
 Aspirin covalently modifies platelet COX-1, thus irreversibly blocking thromboxane formation and
reducing platelet function for the lifespan of the affected platelet (platelets cannot synthesize
new proteins). The inhibitory action of other NSAIDs on platelet COX-1 is not covalent and is
eventually reversed when the agents’ blood levels decline.
4. How are the stomach cells protected from HCl?
 HCl, strong acid pH between 0.3-3.0
 Gastric lining is surrounded by Mucous which is filled by Bicarbonate that counteracts the acidity
of the HCl.

CONCEPT MAP:

REFERENCES:
 Guideline for the Treatment and Prevention of NSAID-Induced Ulcers Frank L. Lanza, M.D.,
F.A.C.G.; THE AMERICAN JOURNAL OF GASTROENTEROLOGY
 Lippincott’s Illustrated Reviews Pharmacology 5th Edition and 6th Edition
 BRS: Pharmacology 6th Edition
 Katzung Basic and Clinical Pharmacology 17th Edition
 Goldfrank’s Toxicologic Emergencies 10th Edition
 First Aid Cases for the USMLE Step 13rd Edition
 Various Internet Website