1. Emerging drugs for treatment
of GERD

2. Flow of presentation
• Introduction
• Epidemiology
• Risk factors
• Symptoms & complications
• Pathophysiology
• Management
• Emerging drugs

3. Introduction
• Def- A condition which
develops when the
reflux of gastric
contents into the
esophagus,
hypopharynx or
oropharynx causes
troublesome symptoms
(i.e., at least two
heartburn
episodes/week) and/or
complications

4. Epidemiology
• 44 % of the population reported monthly heartburn and
19.8 % suffered from heartburn or acid regurgitation at
least once a week.
• Prevalance 10 - 20%
• One of the most common digestive diseases
• Common in whites
• More common in women, however men & people over
the age of 60 develop more complications

5. Risk factors
Life style
•Smoking
•Certain exercising &
bending
•Wearing of tight
clothing
•Lying flat after a meal
Diet
•Fatty, greasy foods.
•Peppermint and chocolate
•Carbonated and alcoholic
beverages
•Large meals
•Citrus, onions, garlic and
tomatoes
•Spicy food

6. Medicines that relaxes LES
• Benzodiazepines
• Theophylline
• Narcotics containing
codeine.
• Calium channel
Blockers
• Nitroglycerine
• Potassium
supplements
• Iron supplements
• NSAIDS
• Erythromycin

7. Symptoms Complications
• Heartburn
• Epigastric pain
• Regurgitation
• Dysphagia
• Chest pain
• Nausea
• Odynophagia
• Supraesophageal
symptoms
• Inflammation of the
esophagus
• Bleeding or ulcers
• Strictures
• Barrett's esophagus and
adenocarcinoma
• Supraesphageal
manifestations
• Asthma
• chronic cough
• pulmonary fibrosis
• ENT manafestations

8. Pathophysiology
• The 3 mechanisms during swallowing that keep acid out
of the esophagus include:
– “Swallowed saliva which helps neutralize stomach
acid”.
– “Sweeping muscles contractions that act to cleanse
the lower esophagus of stomach acid”.
– Protective contracture of the LES & higher pressure
than lower esophagus (10-45 mmhg)
“Swallowed saliva which helps to neutralize
stomach acid”.
“Swallowed saliva which helps to neutralize
stomach acid”.
“Sweeping muscles contractions that act to
cleanse the lower esophagus of stomach acid”
“Sweeping muscles contractions that act to
cleanse the lower esophagus of stomach acid”
Protective contracture of the LES & higher
pressure than lower esophagus (10-45
mmhg)
Protective contracture of the LES & higher
pressure than lower esophagus (10-45
mmhg)

10. • Contraction phase-LES always remain in a tonic
contraction along with some transient relaxation in
between (TLESR)
• Relaxation phase- deglutition and distention are major
stimuli to induce relaxation (via- efferent vagus N at M1
receptor, releases NANC neurotransmitter)
• Pathway-
Afferent(vagal)NTS DMV/NA
Esophageal
peristalsis and LES
relaxation
Efferent(vagal)
Inhibitory(NO, VIP)
& excitatory(Ach,
tachykinin) neurons
in myenteric plexus
↵

12. Neurohormonal control of LES
tone and relaxation
• Ach- via parasympathetic pathway( M3 recep)- LES contraction
• Sympathetic pathway- α recep- contraction, β recep- relaxation
• Motilin- phasic LES contraction
• Glutamate – NT of sensory afferent
• DMV- contain NT- Ach,NO,DA,Epinephrin
• NO- main NT(synthesized by neuronal Nos) responsible for LES
relaxation
• At NTS & DMV- GABAB & CB1 inhibit TLESR

14. Management
• Lifestyle Changes- stop
smoking & alcohol,
reduce weight, eat small
meals, loose fitting
clothes, avoid lying down
for 3 hrs, raised head
end of bed to 6-8 inches.
• Medications
• Surgery- Nissen
Fundoplication
Lifestyle ChangesLifestyle Changes
MedicationsMedications
Surgery-Surgery-
Endoscopic optionsEndoscopic options

15. Medications
• Antacids:
• Sodium bicarbonate
• Aluminum hydroxide
• Magaldrate
• Calcium carbonate
• Magnisium hydroxide
• H2 blockers
• Cimetidine
• Famotidine
• Nizatidine
• Ranitidine
Proton pump inhibitors
• Omeprazole
• Lansoprazole
• Pantoprazole
• Rabeprazole
• Esomeprazole
Prokinetics
• Metoclopramide
• Domperidone

16. Seeking newer drugs
• Despite the best effective treatment (PPI) 22% pts
continue to experience symptoms
• Long term safety of PPI is questionable
• With PPIs, histamine H2 receptor antagonists (H2 RAs)
or prokinetic agents, almost three-quarters continued to
experience heartburn frequently.
• Associated side effects of other drugs

17. Emerging drugs & targets
Transient LES relaxation reducing agentsTransient LES relaxation reducing agents

19. GABAB RECEPTOR
AGONISTS
• Rationale
– GABAB receptors are expressed in LES-projecting neurons
of the motor nucleus of the vagal nerve, and in the
subnucleus centralis of the nucleus tractus solitarius , both
important nuclei in the control of TLESRs.
Activation of peripheral GABAB receptors
Inhibition of gastric vagal mechanoreceptors
impairs vagal motor outflow,
inhibitory effect on the triggering of TLESRs

20. Baclofen
• A GABAB receptor agonist.
• Advantages
– It not only reduces acid reflux, but has a similar inhibitory effect
on non-acid reflux
– It effectively reduces duodenal reflux
• Disadvantages
– Has got a short half-life necessitating three – four doses/day
– Central action -central side effects such as dizziness and
somnolence- compromising its clinical use.
• Arbaclofen placarbil- sustained release formulation
• Lesogaberan- does not cross BBB, act peripherally

21. AZD3355
• New GABAB agonist preferentially acting in the periphery
at lower doses.
• It results in almost similar degree of inhibition of TLESR
as baclofen in healthy subjects.
• AZD3355 is well tolerated and significantly improves
symptoms of heartburn and regurgitation during PPI
treatment (add on therapy)
• Status –phase II

22. Metabotropic glutamate
receptor(mGluR5) antagonists
• It is the N.T released by vagal afferents to neurons in the
brain stem involved in the triggering of TLESRs.
• Metabotropic glutamate receptors (mGluR 1 and 5) mediate
excitatory actions of glutamate
• ADX10059- significantly reduce the number and duration of
symptomatic reflux episodes.
• Dizziness and nausea was reported in 9/12 and 4/12 patients
at the highest dose
• Status –phase II

23. • Mainstay of GERD treatment
• Potassium competitive acid blockers (P-CABs)-
AZD0865,CS-526, Revaprazan, soraprazan
• H3 agonists- R-α methyl histamine
• Newer PPIs- Ilaprazole (IY-81149), Tenatoprazole (TU-
199) (longer t1/2, nocturnal acid secretion inhibition)
Acid suppressantsAcid suppressants

24. potassium-competitive acid
blockers ( P-CABs)
• These agents bind ionically to the proton pump at or
near the potassium-binding site in a K+ -competitive
manner, blocking acid secretion through a direct,
reversible mechanism
.

25. P-CABS
• Very rapid onset of effect, achieved within 30 min
• Get concentrated 100,000-fold in the canaliculus of the
parietal cell compared to plasma levels.
• YH-1885(Revaprazan), AZD0865(linaprazan),
soraprazan and PF-03716556
• S/E- increase liver transaminase levels
• Status –linaprazan was terminated in Phase II development
because
– it showed signals of hepatotoxicity
– failed to show clinical superiority over esomeprazole

26. H3 agonists- R-α methyl histamine
• H3 receptors- located presynaptically on brain, and in the
gastrointestinal tract on cholinergic neurons on the myenteric plexus,
in endocrine cells of the gastric mucosa and, at least in some
species, on parietal cells
• play a role in regulating gastric acid secretion and maintaining gastric
mucosal integrity
• An acid inhibitory effect of H3 agonists has been provided by dog
studies, where dose-dependent inhibition of pentagastrin-stimulated
acid output has been observed.
• Status- preclinical phase

27. • Somewhat effective but only in patients with mild symptoms
• Serotonergic agents 5-HT4 agonist- Tegaserod, Cisapride, Itopride
• Increase gastric motility- more esophageal and stomach clearance
• Cisapride has been shown to reduce significantly the incidence of
TLESRs during sleep, and to increase lower oesophageal sphincter
pressure
• Itopride a D2 antagonist with anticholinesterase activity
• Rikkunshito- along with PPIs give good results
Prokinetic agentsProkinetic agents

28. • Sucralfate
• Increase the ability of the oesophageal lining to resist
injury from gastric reflux
• Acts by binding to the matrix proteins of the ulcer crater,
thus coating the ulcer against acid–pepsin
• Usefull in pregnant women, for whom acid-suppressive
therapy may not be the best option
Mucosal protectantsMucosal protectants

29. • Antigastrin vaccine- stimulates the production of high
affinity, gastrin 17-neutralizing antibodies
• CCK 2 antagonists-Itriglumid, Z-360
• CCK2 receptors recognize both gastrin and CCK, and
have been identified as primary mediators of gastrin
activity.
• Gastrin has an important role in both acid secretion and
control of gastric motility
• Status- phase I
Anti gastrin agentsAnti gastrin agents

30. Summary

31. Conclusion
• In addition to PPI, TLESR reducers have been
considered as the most promising strategies in the
management of GERD
• Prokinetics have potential role as add-on therapy to PPIs
and may provide additional benefit in special groups
• Anti gastrin vaccine may have future role as an acid-
reducing agent
• Further studies are clearly required to investigate the
promising utility of such agents

32. References
• Novel treatments of GERD: focus on the lower
esophageal sphincter. European Review for Medical and
Pharmacological Sciences. 2008; 12(Suppl 1): 103-110
• Guidelines for the Diagnosis and Management of
Gastroesophageal Reflux Disease.Am J Gastroenterol
2013; 108:308 – 328
• Current Trends in theManagement of Gastroesophageal
Reflux Disease: A Review. ISRN Gastroenterology
Volume 2012, Article ID 391631, 11 pages
• Review article: new pharmacological agents for the
treatment of gastro-oesophageal reflux disease. Aliment
Pharmacol Ther 2004; 19: 1041–1049.

34. Classification

35. Release of Gastric acid
• Histamine stimulates
acid release by
interacting with the
histamine receptor, H2
• Acetylcholine
activates the
cholinergic receptors
• Gastrin is released
when food is present
in the stomach

36. The 3 mechanisms of the lower
esophageal sphincter (LES) which
prevent backflow are:
• Pressure in the LES is greater than that of
the stomach.(10-45 mm Hg)
• High levels of Acetylcholine, a
neurotransmitter increases constriction of
the LES.
• Gastrin, a hormone also increases
constriction of the LES.