gastroesophageal%20reflux%20disease
GASTROESOPHAGEAL REFLUX DISEASE
Gastroesophageal reflux disease is a disorder in which gastric contents recurrently reflux into the esophagus, causing troublesome symptoms and/or complications.
It is produced by various mechanisms such as frequent occurrence of transient relaxation of the lower esophageal sphincter or pressure abnormalities in the lower esophageal sphincter (which can be caused by hormonal and neural mediators, food, drugs and patient lifestyle).
Typical symptoms are acid regurgitation and heartburn.
Regurgitation is the perception of flow of refluxed gastric contents into the mouth or hypopharynx.
Heartburn is defined as burning sensation in the retrosternal region.

Principles of Therapy

Treatment Goals:
  • Relief of symptoms
  • Healing of esophagitis
  • Prevention of recurrence and complications

Pharmacotherapy

Empiric Therapy
  • Current consensus is that for patients with uncomplicated reflux symptoms, empiric therapy is the appropriate initial management 
  • Patients presenting with typical symptoms of GERD in the absence of long-standing, frequently recurring, progressive alarm symptoms or complicated disease may be started on empiric treatment without further investigation
  • Acid suppressive therapy is currently the mainstay of treatment for symptom relief in GERD in both acute and long-term treatment
    • Proton pump inhibitor is the drug of choice and recommended as initial therapy because of its superior safety
    • Patients with chest pain or GERD-related NCCP should have a thorough initial cardiac evaluation prior to starting empiric therapy
  • Short course therapy is effective in GERD patients treated empirically and duration varies from 2-8 weeks
    • Should be tried for 2 weeks for patients with typical GERD symptoms
    • Patients who present with atypical or extraesophageal manifestations take a longer time to respond to empiric therapy and often require twice-daily dosing for at least 12 weeks

Proton Pump Inhibitors (PPIs)

  • Eg Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole
  • Most potent type of acid suppressants
    • Provide most rapid symptom relief and heal esophagitis in the highest proportion of patients
      • Rabeprazole's high pKa gives it a slightly faster onset of action and since it is metabolized to a lesser extent via CYP2C19, gene polymorphism does not influence its gastric acid suppression
    • Cornerstone of therapy for erosive esophagitis when given at standard dose once daily for 8 weeks
  • Recommended for both moderate and severe GERD and its complications
    • No clear advantage has been shown with the use of one PPI over another in GERD therapy
  • PPIs are substituted benzimidazoles that irreversibly bind the H+ K+ ATPase, the final step in gastric acid secretion
  • Should be given 30-60 minutes prior to meals to give PPIs time to interact with an activated pump
    • Dexlansoprazole, Pantoprazole and Rabeprazole can be taken with or without food
  • On-demand therapy with PPI is used where symptom control is the primary objective (eg patients with esophageal GERD syndrome without esophagitis or mild erosive GERD)
  • Continuous therapy with PPI is recommended to maintain a healed mucosa, preventing recurrence of symptoms (eg in patients with erosive esophagitis)
  • Generally well tolerated; side effects reported were minor such as diarrhea, abdominal pain, headache which resolve as treatment is discontinued
  • Superiority in the treatment of reflux esophagitis is supported by several reviews and trials
  • Initial management for patients with suspected extraesophageal reflux syndrome
    • Once- or twice-daily therapy for at least 12 weeks as empiric therapy
    • Patients with partial response to once-daily therapy, adjust dose timing and/or consider twice-daily dosing, especially in patient with nighttime symptoms, sleep disturbance, or variable schedules
    • A specialist referral should be considered if patient fails empiric therapy with PPI as non-GERD etiologies must be excluded
  • Pregnant patients with GERD may be given a short-term PPI in the last two trimesters of pregnancy if clinically indicated
    • Other options include H2RAs, eg Ranitidine, and antacids except for preparations containing sodium bicarbonate

Histamine2-Receptor Antagonists (H2RAs)

  • Eg Cimetidine, Famotidine, Nizatidine, Ranitidine, Roxatidine
  • Recommended in divided doses for symptomatic relief of milder forms of GERD
  • Have a role in inhibiting nocturnal acid secretion in mild erosive esophagitis or NERD
    • When given either after an evening meal or at bedtime, H2RAs often provide effective nighttime relief
    • When given as a supplement to PPI therapy, only a small dose of H2RAs at bedtime is recommended and given at a well-separated time from PPI evening dose
    • Can be used on a short-term basis as tachyphylaxis can occur with long-term therapy 
  • Decrease gastric acid production, particularly in the postprandial state, without affecting esophagogastric barrier dysfunction
  • Associated with a low incidence of adverse effects (4%)
  • May be given intermittently to patients intolerant of PPIs
  • Numerous, randomized, controlled trials have shown that standard dose of H2RAs is more effective than placebo in the treatment of reflux symptoms and healing of esophagitis
Maintenance Therapy
  • Goal is to have a symptom-free patient without esophagitis
  • Use the lowest dose and least potent medication that can obtain a complete and sustained symptomatic response
  • The need for maintenance therapy is determined by the impact of the residual symptoms on the patient’s quality of life
  • Type of maintenance therapy based on duration of treatment:
    • Continuous maintenance therapy refers to daily administration of treatment for months or even years to prevent relapse of GERD symptoms
      • Given mainly for those with moderate to severe erosive reflux disease
    • Discontinuous therapy is either intermittent or on-demand
      • Intermittent therapy is patient-initiated short courses of therapy with a fixed duration taken even after symptoms have resolved
      • On-demand therapy is when patient starts treatment when symptoms occur and continues until these are gone
      • Both intermittent and on-demand therapy are recommended for long-term maintenance of acid suppression and in patients with mild symptoms and with PPI-responsive NERD

Options for Chronic Acid Suppression:

  • Step-up therapy involves starting treatment with the less potent agents and moving up for treatment response
    • If patient does not respond to an H2RA within 2 weeks, switch to PPI
    • If patient does not respond to the standard once-daily treatment for 8 weeks, double the dose of the same PPI (30 minutes prior to breakfast and 30 minutes prior to dinner)
      • Other options to consider include switching to a different PPI, changing medication time, or adding a prokinetic agent, an alginate or an H2RA at night 
    • If patient still does not respond to above regimens, patient’s symptoms are likely not secondary to reflux and warrant diagnostic testing
  • Step-down therapy makes use initially of a potent acid suppressant, then decreasing dose or switching to less-potent agents
    • Begins with the patient taking PPI for 8 weeks, followed by an H2RA if GERD symptoms were adequately controlled with a PPI
    • This is followed by stepping down further to on-demand use of antacids if patient was asymptomatic while taking an H2RA
    • Majority of patients who experienced symptom relief after being placed on more than a single daily dose of PPI can be successfully stepped down to single-dose therapy without recurrence of reflux symptoms
  • Maintenance treatment for GERD is recommended at the lowest effective dose
    • Step-down therapy should be attempted
  • Chronic PPI therapy for adequate symptom control
    • Even with adequate symptom control and PPI tolerability, the likelihood of long-term spontaneous remission of the disease is low
    • Though PPIs are generally safe with long-term use, careful consideration is required in patients at risk for complications, eg iron deficiency, vitamin B12 deficiency, increased susceptibility to enteric infections, microscopic colitis, fractures and pneumonia
  • For patients with suspected extraesophageal GERD syndrome with a concomitant esophageal GERD syndrome, maintenance therapy with once- or twice-daily PPIs
Adjunctive Pharmacotherapy

Antacids and Alginates
  • Effective in short-term or intermittent symptom relief; antacid-alginate combination is recommended for episodic and postprandial reflux symptoms
  • Usually taken after each meal and at bedtime
  • Alginate reacts with gastric acid creating a viscous gel or raft above the gastric contents that acts as a mechanical barrier to reduce reflux into the esophagus
    • Mode of action is physical and does not depend on systemic absorption

Propulsives/Prokinetic Agents

  • Eg Domperidone, Metoclopramide, Itopride, Mosapride
  • Effective in patients with mild symptoms
  • Domperidone has the advantage of having less pyramidal effects
  • Oral Metoclopramide may be given to patients unresponsive to conventional therapy
  • Combination of Mosapride with a PPI may have additional benefit when PPI monotherapy does not have satisfactory results, particularly in PPI resistance 
    • Studies show that Mosapride does not have any significant cardiovascular effects even with concomitant administration of Ketoconazole and Erythromycin; Mosapride does not block D2 receptor hence does not cause extrapyramidal effects   
  • Long-term use is not recommended because of risk of neurological, cardiac and other adverse effects◦
    • Treatment should be at the lowest effective dose and kept as short as possible

Refractory GERD

  • It is the persistence of troublesome GERD symptoms in compliant patients despite standard treatment or twice-daily dosing of PPI for at least 8 weeks  
    • Troublesome symptoms impair patient's quality of life and may cause sleep disturbance and affect work 
  • Patients with NERD commonly have PPI-resistant GERD symptoms
  • Causes included inadequate acid suppression, weakly acidic/non-acidic reflux, reflux sensitivity or other non-reflux causes such as functional heartburn, dysmotility, eosinophilic esophagitis or overlap syndrome with IBS and visceral hypersensitivity  
  • Impaired PPI treatment response may also be related to increased body weight and P450 system genotypes which affect PPI metabolism
  • Further evaluation may be considered in PPI therapy non-responders and may include an upper GI endoscopy with or without enhanced imaging and function testing (ambulatory pH monitoring and 24-hour combined impedance-pH studies/esophageal manometry  
    • Patients with suspected extraesophageal symptoms and have failed PPI therapy should be evaluated for non-GERD causes prior to starting GI evaluation with endoscopy or function testing   
  • Therapeutic options to consider include increasing the PPI dose, switching to a different PPI, changing medication time, or adding a prokinetic agent, an alginate or an H2RA at night 
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