Review of Gastroesophageal Reflux Pharmacotherapy Management

Abstract

Acid suppressive therapy (AST) has been the primary mechanism to provide gastroesophageal reflux disease (GERD) symptomatic relief and prevent complications in many individuals with GERD. Many AST options exist, but proton pump inhibitors (PPIs) have developed popularity in symptomatic relief for refractory GERD patients. To help reduce persistent symptoms, the use of AST therapy optimization is imperative and involves timing doses appropriately and increasing the dose and dosing frequency. Recently, more data has become available regarding the safety profile of AST, specifically PPI use. This data has raised awareness about its potential for toxicity with long-term use. This chapter focuses on the pharmacological management of GERD with a focus on the current updates regarding AST safety and efficacy.

1. Introduction

Gastroesophageal reflux disorder (GERD) is one of the most prevalent digestive disorders in the United States and affects almost 28% of the American population [1, 2]. GERD is a chronic condition that occurs when acid flows from the stomach back up into the esophagus, which causes the upper digestive tract mucosal lining to become irritated [3]. There are many common causes of GERD, including alcohol, obesity, spicy foods, medications, hiatal hernias, and pregnancy [4]. Heartburn, one of the most common symptoms of GERD, is a form of indigestion that typically produces a burning sensation in the chest region due to acid reflux [2]. Other less common symptoms of GERD include frequent burping, pain upon swallowing, a sore or hoarse throat, cough, a sensation of a lump in the throat, and asthma. GERD can lead to serious long-term complications such as Barrett’s esophagus, erosive esophagitis, or esophageal cancer if left untreated, which makes treating the condition important [5]. Once patients have an established clinical diagnosis of GERD, treatment options include medications, lifestyle modifications, and surgery. Therapy goals include eliminating symptoms, managing and preventing complications, and maintaining remission [6]. Lifestyle modifications are an essential treatment component, including dietary changes such as decreasing consumption of fatty and spicy foods and reducing caffeine intake. Others include exercising, reducing weight, avoiding smoking, and head elevation while resting or sleeping [7]. Acid-suppressive therapy (AST), such as proton pump inhibitors (PPIs), histamine two receptor antagonists (H2RA), and antacids, are the cornerstone of treatment for GERD. Since GERD is a chronic disease, lifelong treatment is typically necessary to reduce symptoms and prevent long-term complications [8].

2. Antacid therapy

Antacids are medications that neutralize stomach acid, thereby increasing gastric pH [9]. Common brands of antacids, which are available over-the-counter, include Maalox®, Rolaids®, Tums®, and Gaviscon® [9]. The various properties of these different products are listed in Table 1 [9]. Antacids are available in different formulations, which commonly include aluminum, calcium, or magnesium salts. Aluminum hydroxide and magnesium hydroxide salts neutralize gastric acid, forming aluminum or magnesium salts and water. The antacids increase gastric pH and inhibit pepsin activity [9]. Aluminum hydroxide’s therapeutic effect is 20–60 minutes when fasting or up to 3 hours, taking effect 1 hour after meals [9]. Magnesium hydroxide’s duration of action occurs from 30 minutes to 6 hours after administration [9]. Calcium salts work by inhibiting the proteolytic activity of pepsin and additionally increase the tone of the lower esophageal sphincter (LES) when pH is >4 [9]. Calcium carbonate absorbs primarily in the duodenum and changes with age (60% for infants, 28% for prepubertal children, 34% for pubertal children, and 25% for adults). It is important to note that absorption doubles during pregnancy [9]. Solubility of calcium carbonate increases with increasing acidity [9]. Constipation, diarrhea, nausea, vomiting, and hypophosphatemia are common side effects of antacid use [9]. Drug interactions with antacids are common and may involve interactions with medications such as levothyroxine, fluoroquinolones, tetracyclines, iron supplements, and salicylates. These interactions typically result in decreased absorption of the aforementioned medications and can affect therapy [9]. In order to minimize the effects of antacids on the absorption of other medications, the recommendation is to administer the medications 2 hours before or up to 6 hours after taking antacids [9]. Historically, antacids were the first-line medication for the treatment of peptic ulcer disease (PUD) prior to the introduction of PPIs [9]. Due to their familiarity and low cost, antacids are still very commonly used to treat heartburn. When used for the treatment of heartburn, patients are recommended to consult their physician if symptoms persist after 14 days of use. Antacids represent a low-cost, relatively safe option for patients with intermittent GERD symptoms but have the potential to mask more serious problems, which is why long-term unsupervised use is not recommended [9].

Medication	Formulation	Dosage	Duration
Calcium carbonate	Tablet 1 g	1–4 tablets by mouth with a maximum of 8 g/day as calcium carbonate as symptoms occur.	14 days
Calcium carbonate and magnesium hydroxide	Chewable tablets: 700 mg/300 mg	Chew 2–4 tablets by mouth four times a day with a maximum of 8 tablets per 24 hours	14 days
Calcium carbonate and magnesium hydroxide	Liquid: 400 mg/135 mg per 5 ml	Take 10–20 ml by mouth four times a day with a maximum of 90 ml per 24 hours	14 days
Aluminum hydroxide, magnesium hydroxide, and simethicone	Tablets: 200 mg/200 mg/25 mg; Liquid: 200 mg/200 mg/20 mg per 5 ml; Liquid:400 mg/400 mg/200 mg per 5 ml	Take 1–4 tablets four times a day as needed with a maximum of 16 tablets in 24 hours; Take 10–20 ml between each meal and at bedtime, or as directed by your physician, with a maximum of 120 ml per 24 hours	14 days
Aluminum hydroxide and magnesium trisilicate	Chewable tablet: 80 mg/14.2 mg	Chew 2–4 tablets four times a day with a maximum of 16 tablets per 24 hours	14 days

Table 1.

Dosing and duration of available antacids [5, 6, 10, 11].

The use of antacids in renal dysfunction can lead to the accumulation of aluminum and magnesium. Accumulation begins when creatinine clearance (CrCl) is less than 25 ml/min, and use is not recommended when CrCl < 10 ml/min. No current dose adjustments are recommended to prevent accumulation for those with renal dysfunction [10]. For patients on hemodialysis, antacids should not be used unless patients can be reliably monitored, including signs and symptoms of toxicity and serum magnesium levels. Symptoms of hypermagnesemia include anorexia and nausea due to magnesium’s depressant effect on the central nervous system.

Additionally, hypermagnesemia can cause to skeletal muscle weakness and decreased deep tendon reflexes [11, 12]. Other signs of magnesium toxicity include electrocardiographic changes, muscle weakness, and hypotension [11, 12]. Aluminum accumulation can lead to ‘dialysis dementia’ (impaired cognition), dialysis osteomalacia, and dialysis encephalopathy [11, 12].

3. Histamine 2 receptor antagonists (H2RA)

H2RAs consist of famotidine, ranitidine, cimetidine, and nizatidine [13]. Famotidine and cimetidine, available over the counter, are the only H2RAs currently available in the United States. The dosing and duration of these H2RAs are summarized in Table 2 [13].

Drug	Formulation	Dosage	Duration
Famotidine	PO or IV	20–40 mg BID; 20 mg Q12H	14 days
Cimetidine	PO or IV	400 mg QID; 800 BID; 300 mg Q6H	14 days

Table 2.

Dosing and duration of available H2RA.

Ranitidine and nizatidine are no longer available in the United States. They were withdrawn from the market in April 2020 due to the detection of a carcinogenic agent N-nitrosodimethylamine (NDMA), in some available products [13]. NDMA is a probable human carcinogen and has been linked to multiple cancers, including kidney cancer, bladder cancer, and cancers of the digestive tract [14]. Higher concentrations of NDMA were found in older products and products stored above room temperature [14].

As food enters the stomach, the hormone gastrin is released, leading to histamine’s release. Histamine binds to H2 receptors on parietal cells, activating adenylate cyclase to increase cAMP within the cell [15]. Increase in intracellular cAMP leads to protein kinase A (PKA) activation, which phosphorylates proteins, leading to the H+/K+ ATPase releasing acid into the stomach [15]. H2RAs function by competitively inhibiting H2 receptors located on the outer surface of parietal cells in the stomach’s inner lining [15, 16]. By blocking the H2 receptor, H2RAs prevent the downstream effect of the release of gastric acid into the stomach [15]. This mechanism of action leads to a decrease in stomach acidity, which helps relieve the symptoms of GERD. The H2RAs are considered interchangeable as all have shown equivalent efficacy at approved doses in clinical trials [15].

All H2RAs are available as oral tablets [15]. Famotidine comes in other formulations, including a chewable tablet, a powder for oral suspension, and a solution for intravenous administration [15]. Famotidine is also available in combination with calcium carbonate, magnesium hydroxide, and ibuprofen [15]. H2RA’s therapeutic effect typically begins one hour after administration, and its effect can last between 4 and 10 hours [15].

H2RAs are metabolized in the liver and the kidneys, and dose adjustments are required for renal impairment [15]. Cimetidine dose adjustments are necessary for patients with a CrCl of less than 30 ml/min. For famotidine, a dose adjustment should be made for patients with a CrCl less than 50 ml/min, as QTc prolongation has been reported in patients with renal dysfunction [15].

H2RAs have a strong safety profile due to their wide therapeutic index [15]. Reported side effects of H2RAs include constipation, diarrhea, headache, dry mouth, and abdominal pain [15]. In patients over 50 and those with renal or hepatic dysfunction, central nervous system (CNS) side effects have been observed [15]. These include anxiety, depression, confusion, insomnia, disorientation, delirium, hallucinations, and agitation [17]. Compared to famotidine, cimetidine has shown to have more side effects which are attributed to its prolonged half-life. Additionally, it has been found to have weak anti-androgenic activity. Consequently, endocrine dysfunction has been reported with cimetidine use and includes symptoms such as decreased libido, gynecomastia, impotence, hyperprolactinemia, and galactorrhea [18]. These adverse effects are more likely to occur with high-dose therapy used in hypersecretory conditions and typically do not begin to appear until at least one month of treatment [18].

For patients in the hospital setting, those who are taking H2RAs and also recceing antibiotic therapy have been found to have an elevated risk for Clostridioides difficile infection [19]. Additionally, increasing evidence suggests a link between AST and community- and hospital-acquired pneumonia [20]. There have been several proposed mechanisms for this association [20]. A potential mechanism for this observation is that the stomach’s acidic environment, which typically serves as a barrier against pathogens, is no longer effective due to the increased pH from AST. This higher pH makes the stomach more hospitable for the pathogenic organisms to grow [20]. Additionally, some have proposed that since gastric acid usually may stimulate the cough reflex, allowing for the clearing of infectious agents from the respiratory tract, an increase in pH leads to a decrease in this mechanism of clearing pathogens [20]. Finally, another proposed mechanism is AST causing a decreased immune response due to the potential impairment of white blood cells [20].

As with other medications, there are several drug interactions with H2RAs [15]. Since H2RAs increase gastric pH, they may affect medications that require an acidic environment for proper absorption [15]. Some medications requiring an acidic environment for absorption include itraconazole, ketoconazole, ampicillin, cephalosporins, sulfonylureas, dasatinib, iron salts, gefitinib, enteric-coated budesonide, and cyanocobalamin. Additionally, cimetidine inhibits several CYP450 isoenzymes (CYP1A2, CYP3A4, CYP2C19, and CYP2D6) and thus should be avoided while taking other medications metabolized by these enzymes [15]. Examples of such drugs include warfarin, selective serotonin reuptake inhibitors (SSRIs), and theophylline [15]. Consequently, famotidine has become the preferred H2RA for GERD due to lesser side effects and lesser drug interactions compared with cimetidine [15].

While PPIs are preferred over H2RAs due to more robust evidence for their use, H2RAs can be added to PPI monotherapy in certain situations [4, 16, 21]. If there is objective evidence of night-time reflux, H2RA therapy can be added at bedtime to PPI monotherapy taken during the day in select patients. However, tachyphylaxis may develop after several weeks of use [4]. Since basal acid secretion is highest in the evening, H2RA administration in the evening may be beneficial. Additionally, H2RAs may also play a role in PPI step-down therapy. Finally, tachyphylaxis is a concern for H2Ras, if administered consecutively for 14 days or more and has also been linked to extended H2RA treatment [4].

4. Proton pump inhibitors (PPIs)

PPIs, currently available on the market, include omeprazole (Prilosec®), esomeprazole (Nexium®), lansoprazole (Prevacid®), dexlansoprazole (Dexilant®), pantoprazole (Protonix®), and rabeprazole (Aciphex®). PPIs are available both over-the-counter or via a prescription and are widely used to manage GERD, treatment/prevention of PUD, dyspepsia, pyrosis, H. pylori eradication, NSAID-induced ulcers, and erosive esophagitis [22].

PPIs irreversibly bind to the (H+, K+)-ATPase enzyme in the stomach’s parietal cells, preventing gastric acid (H+) release [23]. PPIs are prodrugs converted to the active form (sulphenamide) of the drug via protonation by hydrogen ions in the gastric acid [24]. Dexlansoprazole (Dexilant®), the R-enantiomer of lansoprazole, is available as a unique dual delayed-release formulation. Dexlansoprazole is currently the only dual delayed-release formulation of a PPI commercially available in the United States [25]. Dexlansoprazole capsules contain two sets of enteric-coated granules designed to disintegrate at different pH levels [25]. The first set of granules begins to disintegrate in the proximal small intestine and the second set disintegrates at a higher pH further down the intestinal tract [25].

PPIs are the recommended first-line agents for pharmacological management of GERD. An 8-week course of therapy is recommended to provide symptomatic relief and allows healing of erosive esophagitis [4]. All PPIs are considered clinically equivalent; therefore, any agent is acceptable as a first-line option [4]. Once a day, dosing before the first meal of the day is recommended initially for most PPIs [25]. Administering traditional delayed-release PPIs 30–60 minutes prior to meals is preferred in order to obtain optimal pH control. Administration of PPIs before meals allow the prodrug to be converted to the active sulphenamide form via gastric acid [26]. In contrast, newer formulations such as Dexilant® do not have to be administered regarding meals, allowing for dosing flexibility [4]. If a patient only has a partial response to PPI therapy, it is recommended to either change the timing of the dose or switch to a different PPI [4]. If neither of these changes is effective, further options include increasing the PPI from once to twice daily, primarily if the patient reports night-time symptoms or sleep disturbances [4]. Alternatively, a trial of dexlansoprazole can be considered due to its unique release mechanism, which may help reduce breakthrough symptoms [25]. Maintenance therapy beyond the initial 8 weeks can be considered if the patient continues to be symptomatic after completion of therapy or has complications such as Barrett’s esophagus or erosive esophagitis [4]. The lowest effective dose possible should always be used to avoid complications and long-term side effects [4].

Typical side-effects include headache, diarrhea, nausea, vomiting, and abdominal pain. PPIs’ potentially more severe side effects include hypomagnesemia, B12 deficiency, increased risk of osteoporosis-related fractures, and C. difficile infections. PPIs should not be used long-term unless instructed by the patient’s provider to minimize the risk of the severe side effects mentioned above. Other potential risks include reduced nutrient absorption, dementia, and an increased risk of pneumonia [27].

The reduction of gastric acid due to PPI use may result in decreased absorption of vitamin B12 (cyanocobalamin), iron, and calcium salts [28]. It is recommended for patients to be monitored for pernicious anemia while on PPI therapy [28].

As mentioned above, PPI therapy use can potentially increase the risk of developing a C. difficile infection. Therefore, it should be used cautiously in high-risk patients for C. difficile [4]. Additionally, increasing evidence suggests a link between acid-suppression therapy and community- and hospital-acquired pneumonia [27]. Short-term PPI usage may increase the risk of community-acquired pneumonia compared to long-term users [4]. Several theories have been proposed to rationalize this association discussed previously. Initiating a PPI after the first case of pneumonia is associated with an increased risk of recurrent pneumonia. The risk seems to be elevated during the first 30 days of PPI use [27, 29].

Another potential side-effect of long-term PPI use is osteoporosis [4]. It is not recommended to discontinue a PPI in patients diagnosed with osteoporosis [4]. Additionally, concern for hip fractures and osteoporosis should not affect the decision to initiate PPIs for long-term use as long as other risk factors for osteoporosis are not present [4]. Patients treated with bisphosphonates such as alendronate should consider using H2RA for GERD as PPIs can potentially increase the risk of fracture for patients with osteoporosis by 38% [30]. While, all PPIs have similar safety profiles if a patient does experience a side effect with a particular PPI, switching to another PPI can potentially reduce adverse drug reactions [4].

Similar to H2RAs, drug interactions, while taking a PPI, can occur due to increasing the pH of the stomach [15]. Medications that require an acidic environment for absorption include itraconazole, ketoconazole, ampicillin, cephalosporins, sulfonylureas, dasatinib, iron salts, gefitinib, enteric-coated budesonide, and cyanocobalamin [31]. PPIs with specific antiretroviral agents such as atazanavir, delavirdine, and nelfinavir can decrease their bioavailability. Therefore, the coadministration of PPIs with these medications should be avoided [32].

In 2009, the FDA issued warnings regarding concomitant PPI therapy and clopidogrel use. Clopidogrel is a prodrug activated to its active metabolite through the CYP 450 mechanism [4, 33]. All PPIs apart from dexlansoprazole have been found to exert some degree of CYP2C19 inhibition. Furthermore, all PPIs, including dexlansoprazole, are CYP2C19 substrates [33]. For a patient taking clopidogrel, PPIs can potentially reduce their antiplatelet effects due to CYP2C19 inhibition [4, 33]. Consider the use of a PPI with minimal or no impact on CYP2C19, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole if a PPI is necessary for a patient receiving clopidogrel as these did not result in a clinically significant reduction in exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [4, 33]. The use of omeprazole and esomeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart [4, 33]. Pantoprazole is the preferred PPI in the hospital setting to minimize drug interactions as it is a weak CYP2C19 inhibitor (Table 3) [4, 33].

Drug	Available formulation	Oral dose and frequency	Duration of use
Dexlansoprazole	Dual delayed-release oral capsule [34]	30 mg QD or 30 mg twice daily	4–8 weeks
Esomeprazole	Delayed-release oral capsule, delayed-release oral suspension, parenteral [37]	20 mg QD or 20 mg twice daily	4–8 weeks
Lansoprazole	Delayed-release oral capsule, delayed-release orally disintegrating tablets, oral powder [35]	15 mg QD or 15 mg twice daily	4–8 weeks
Omeprazole	Delayed-release capsules, delayed-release oral suspension, delayed-release orally disintegrating tablets, oral powder [38]	20 mg QD or 20 mg twice daily	4–8 weeks
Pantoprazole	delayed-release oral tablets, delayed-release oral suspension, parenteral [36]	20 mg QD or 20 mg twice daily	4–8 weeks
Rabeprazole	Delayed-release oral tablets [39]	20 mg QD or 20 mg twice daily	4–8 weeks

Table 3.

PPI dose, frequency, and duration of use recommended for GERD [34, 35, 36, 37, 38, 39].

5. Non-acid suppressive therapy alternatives

5.1 Metoclopramide

The most commonly used prokinetic agent, metoclopramide, can be used to treat gastrointestinal motility disorders [40, 41]. Not only is metoclopramide a central dopamine D₂ receptor antagonist, but the medication also blocks the dopamine D₂ receptor in peripheral nerve endings and promotes the release of acetylcholine. This leads to increasing gastrointestinal motility, gastric emptying, and LES tone [40, 41].

Metoclopramide comes in oral and parenteral formulations for GERD use, with the dosing frequency summarized in Table 4. The onset of action for the oral formulation is 30–60 minutes, 1–3 minutes for intravenous, and 10–15 minutes for intramuscular injections [42, 43]. All formulations have a 1–2 hour duration with rapid absorption [42, 43]. It is hepatically metabolized through oxidation, glucuronide, and sulfate conjugation [42, 43]. This results in the formation of monomethyl metoclopramide, which is an oxidative metabolite formed through CYP2D6 [42, 43].

Formulation	Dosing	Duration
Oral	10–15 mg PO up to four times per day, 30 minutes before meals and at bedtime	Up to 12 weeks
Intravenous (IV)/intramuscular (IM)	10 mg IV or IM up to four times per day, 30 minutes before meals and at bedtime	Up to 12 weeks

Table 4.

Dosing and duration of metoclopramide [42, 43, 44].

Metoclopramide use is limited due to the central nervous system side effects such as agitation, irritability, depression, drowsiness, dystonic reactions, and tardive dyskinesia [45]. The most common side effects reported are dysgeusia, fatigue, restlessness, and drowsiness in more than 10% of patients taking metoclopramide. Severe side effects that may occur with metoclopramide are visual impairment, tardive dyskinesia, suicidal ideation, serotonin syndrome, seizures, porphyria, angioedema, and agranulocytosis [42, 43].

Metoclopramide should not be administered with atypical antipsychotics due to the increased risk of tardive dyskinesia, other extrapyramidal symptoms, and neuroleptic malignant syndrome [42, 43]. If atypical antipsychotics have to be used with this medication, patients must be monitored closely for movement disorders and CNS effects [42, 43]. Atypical antipsychotics should be discontinued upon first signs of dyskinesia [42, 43]. Due to the increased risk of tardive dyskinesia, treatment is not recommended beyond 12 weeks with metoclopramide use [44]. Populations with characteristics such as diabetes, geriatric, female, renal dysfunction, pediatric, or more than 12 weeks of metoclopramide use have all been associated with an increased risk of tardive dyskinesia and symptoms are often irreversible [42, 43, 44].

According to guidelines for the management of GERD, metoclopramide does not have a role in therapy unless gastroparesis is present [4]. Metoclopramide monotherapy is generally considered in patients refractory to conventional, acid-suppressive therapy [4]. Although PPIs are regarded as first-line, using a PPI alone is insufficient in approximately 30% of GERD patients [46, 47]. Prokinetic drugs have been used in clinical settings as a second-line option despite the fact that their benefits for GERD management are not well established [46, 47].

Although insufficient evidence is available regarding combination therapy with PPIs, the evidence for metoclopramide and H2RA combination therapy use did not show a clear benefit compared to monotherapy [4].

5.2 Baclofen

Baclofen is currently used off-label for GERD management. It works by stimulating the GABA-B receptor leading to reduced release of glutamate and aspartate and also reduces input into the alpha motor neurons [4]. Baclofen has been shown to reduce transient LES relaxation, reflux episodes, the number of postprandial acids and non-acid reflux events, nocturnal reflux activity, and belching attacks in two short-term randomized controlled trials [4]. Its use in GERD treatment is limited to patients refractory to PPI therapy and has no symptomatic relief [4].

Baclofen oral formulation onset of action is almost instantaneous; the medication is rapidly absorbed following administration [48, 49]. Dosing recommendations for refractory GERD patients is a trial of 5–20 mg given three times a day and must be dose-adjusted in CrCL < 80 ml/min since the kidney excretes 70–85% of baclofen as unchanged drug and metabolites [4, 48, 49].

Some limitations to baclofen use are the lack of long-term data as well as the side effects profile of the medication. Common side effects of baclofen include confusion, dizziness, drowsiness, headache, hypotonia, nausea, vomiting, and weakness [48, 49]. Severe side effects that may occur with baclofen are pulmonary embolism, renal failure, rhabdomyolysis, seizures, stroke, thrombosis, and ventricular tachycardia [48, 49].

Concurrent use of baclofen with opioid medications increases the risk of sedation and somnolence [48, 49]. Opioid medications for pain should be limited to patients who cannot tolerate alternative treatment options [48, 49]. Cough medications containing opioid medication should be avoided as well [48, 49].

5.3 Potassium-competitive acid blockers (P-CABs)

P-CABs have been developing for over the past 30 years [50]. Unlike PPIs, P-CABs directly inhibit gastric H⁺/K⁺-ATPase in a K⁺-competitive, reversible manner and can bind to both the active and inactive forms of the ATPase pump resulting in a faster and longer duration of anti-secretory effect [26, 50]. Side effects of P-CABs include increased risk for gastric infection, obstruction of nutrient absorption, and increased levels of gastrin in the blood [50]. Advantages of P-CABs over PPIs have a faster onset of action with the maximum therapeutic effect observed in less than 2 hours post-administration [50]. P-CABs have a longer half-life compared to PPIs [50]. P-CABs have a better acid inhibitory effect than PPIs, and certain P-CABs have an effect that promotes gastric motility [50]. There are only three P-CABs available in Asia, with only one pending approval in the USA and Europe [50]. Revaprazan was the first-approved P-CAB in 2007 [50]. In South Korea and India, revaprazan is used to treat gastric ulcers, gastritis, and duodenal ulcers [50]. Revaprazan increases the percentage of time of pH > 4 in a dose-dependent manner [50]. In addition to suppressing acid, revaprazan has two more pharmacological effects: increased prostaglandin E2 and reduction in the production of leukotriene B4, which leads to gastroprotection [50]. However, the acid suppression ability and gastric pH > 4.0 holding time of revaprazan is not superior to conventional PPIs [26].

Vonoprazan fumarate has been approved in Japan since 2015 for treating gastroduodenal ulcers, healing and preventing erosive esophagitis, gastric protection in patients taking aspirin or NSAIDs, and eradicating H. pylori infection [50]. Vonoprazan can inhibit gastric proton pumps in neutral pH, unlike PPIs that need to be activated by an acidic environment [50]. It can be taken without regard to meals [50]. Vonoprazan is currently under phase III trial in the USA and Europe [50]. In healing erosive esophagitis, vonoprazan 20 mg compared to lansoprazole 30 mg showed similar results in healing when compared to lansoprazole [50]. In patients with non-erosive reflux disease, vonoprazan was studied at doses of 10 and 20 mg compared to placebo. Patients experienced less severe GERD symptoms with vonoprazan compared to placebo [50]. Safety concerns about the long-term use of vonoprazan have been raised because of the significant elevation of serum gastrin levels compared with conventional PPI therapy [26]. Increased incidence of gastric endocrine cell tumors in a nonclinical carcinogenicity study has been correlated with the increased serum gastrin level, but the impact on humans is still unknown [26].

Tegoprazan has been approved and available since July 2018 in South Korea for treating erosive esophagitis and non-erosive reflux disease [50]. In patients with erosive esophagitis, tegoprazan (50 or 100 mg) was compared to esomeprazole 40 mg for 8 weeks [50]. Results showed that both doses of tegoprazan were non-inferior [50]. Although not currently available in the United States, P-CABs may play a role in GERD management soon after FDA approval.

6. GERD treatment in special populations: Pregnancy

Pregnancy is considered a likely risk factor in GERD, with approximately 80% of pregnant women, in their third-trimester experiencing what is known as gestational reflux [51, 52]. This increased prevalence of gestational reflux is likely due to decreased LES pressure [51]. Heartburn and nausea may be expected in a healthy pregnancy, but there are concerns over specific agents used in treatment [51]. Treatment for gestational reflux calls for “step-up” therapy, starting with lifestyle modifications or alternative medicines such as acupuncture [51]. If that fails to provide enough relief, the following options would be antacids, sucralfate, or metoclopramide [51]. A step up from these regimens, if deemed ineffective, would be H2RAs, and a step up from that would be PPIs [51]. The American College of Gastroenterology (ACG) GERD guidelines do not have an extensive algorithm for gestational reflux [4]. The guidelines mention that sucralfate does not have a role in non-pregnant GERD patients, and PPIs are safe in pregnant patients if clinically indicated [4].

The FDA classified drugs for pregnancy in categories that help define a drug’s potential risk of fetal harm [51]. Category A of the FDA’s classification means that there are well-controlled studies in humans, and the drug shows no fetal risk [51]. None of the pharmacological options of therapy for gestational reflux are considered Category A [51]. Category B means that animal studies show no risks, but human studies do now show adequate evidence expressing safety [51]. All H2RA’s, sucralfate, metoclopramide, and most PPIs except for omeprazole are Category B [51]. Category C shows that animal studies show risk, but human studies lack the evidence to support safety [51]. Omeprazole and cisapride are considered Category C drugs [51]. As for all of the antacids that are aluminum, calcium, or magnesium-containing, those fall under Category N by the FDA [51]. Category N is defined as no classification [51].

Following the step-up treatment guideline, lifestyle modifications such as eating smaller meals, not eating at night, elevating the head of the bed, and avoiding postural changes and dietary triggers are considered the first line [51]. Next on the step-up is antacids, sucralfate, or metoclopramide which are mostly considered safe with a few exceptions [51]. One exception is magnesium trisilicate which is not recommended long term [51]. Long-term use of magnesium trisilicate has been associated with nephrolithiasis, hypotonia, cardiovascular impairment, and respiratory disease in the fetus [51]. It is also recommended that pregnant women avoid sodium bicarbonate as it can cause fluid overload and metabolic alkalosis [51]. Sucralfate is Category B and is generally regarded as acceptable for use [51]. Metoclopramide is a promotility agent that is part of the step-up therapy for pregnant women. Another promotility agent is cisapride which has shown evidence of being embryotoxic and fetotoxic in animals, and the FDA has removed this drug for causing fatal cardiac arrhythmias [51]. H2RAs are generally safe for pregnancy, except for nizatidine [51]. Nizatidine has been known to cause spontaneous abortion, congenital malformations, low birth weight, and fewer live births have been reported in animal studies [51]. Ranitidine was the only H2RA whose efficacy during pregnancy has been established, but it has recently been removed from the market for having a carcinogenic metabolite NDMA [51]. Next on the step-up therapy is PPIs which are generally safe for use in pregnancy except for omeprazole [51]. Omeprazole is embryotoxic and fetotoxic in animals, and case reports in humans show similar concerns [51].

7. Special populations: Elderly

Management of GERD in the elderly is generally similar to the adult population. However, there are specific concerns regarding treatments in the geriatric population. Most elderly patients have co-morbid conditions such as cardiovascular disease, hypertension, depression, and osteoporosis that require multiple medications [53]. Many medicines to treat these conditions can lead to decreased LES pressure, esophageal motility, and direct esophageal injury [53]. Examples include calcium channel blockers, benzodiazepines, nitrates, nonsteroidal anti-inflammatory drugs, and anticholinergic agents [53]. Aggressive, individualized treatments may be warranted due to the high risk of complications from GERD and co-morbid illnesses in this patient population [54]. Motility agents may improve LES tone, although success is limited in patients with severe disease [53]. Higher doses, up to four times daily, of H2RA may be required in some elderly patients for adequate acid suppression and symptom relief; however, proper dose adjustment is needed if patients have renal insufficiency [53]. As with most medications, the side effect, and drug interaction profile could be more pronounced in the geriatric population. No evidence-based guidelines support specific treatment options in those over 65. However, PPIs are usually first-line medical therapy in patients with GERD [54]. PPIs provide excellent acid suppression. Capsules may be opened and sprinkled in water, juice, or applesauce. Besides, lansoprazole and omeprazole are available in powder formulation for those that have difficulty or are unable to swallow [53]. Maintenance therapy is usually required in this population as long-term treatment is necessary to prevent relapse. Of note, unless the patient is high-risk (e.g., Barrett esophagitis, erosive esophagitis, chronic NSAID use, etc.), the Beers criteria advises against using PPIs continuously for > 8 weeks for patients ≥65 due to the risk of Clostridium difficile infection and bone loss [55]. Beers criteria also suggests avoiding H2RA use in patients who have delirium [55].

Effects of prolonged acid suppression can include: reduced absorption of nutrients, osteoporosis, and drug metabolism interference [53]. Although these effects are controversial, monitoring patients on long-term acid-suppressive therapy is still important. Surgery may be warranted in those with dysplasia, esophageal adenocarcinoma, and Barrett’s esophagus [54]. There are important factors to consider regarding the treatment and management of the elderly compared to the younger population. However, with appropriate direction, GERD can be treated in most elderly patients with successful outcomes.

8. Conclusion

GERD can be managed with pharmacological and non-pharmacological options. Treatment options should be individualized based on presenting factors. If poorly or not treated, it can lead to complications such as esophageal cancer, erosive esophagitis, Barrett’s esophagus, and possible bleeding and scarring. Routine follow-ups should be completed to ensure adherence and medication effectiveness. PPIs should be used as first-line therapy for treating and managing GERD, along with patient education on lifestyle modifications. Other pharmacotherapy regimens should be explored if shown ineffective, or surgical interventions may be required.