Emerging drugs for treatment of GERD

Flow of presentation

• Introduction

• Epidemiology

• Risk factors

• Symptoms & complications

• Pathophysiology

• Management

• Emerging drugs

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

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

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

Medicines that relaxes LES

• Benzodiazepines• Theophylline• Narcotics containing

codeine.• Calium channel

Blockers• Nitroglycerine

• Potassium supplements

• Iron supplements• NSAIDS• Erythromycin

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

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)

• 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

↵

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

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

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

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

Emerging drugs & targets

Transient LES relaxation reducing agentsTransient LES relaxation reducing agents

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

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

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

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

• 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

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

.

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

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

• 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

• 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

• 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

Summary

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

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.

Classification

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

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.