CH24 Gastroesophageal Reflux Disease | PharmD Master Reference

30-Second Snapshot

What it is:Symptoms or tissue damage caused by stomach contents refluxing up into the esophagus (and sometimes the throat or lungs). Occasional heartburn after a big meal doesn't count. GERD means it's frequent enough or bad enough to matter, generally 2 or more episodes per week, or any episode severe enough to cause tissue injury.

The core problem:The lower esophageal sphincter (LES) is supposed to be a one-way valve. When it relaxes too often, stays too weak, or gets pushed around by a hiatal hernia, acidic gastric contents wash back up into an esophagus that has none of the stomach's protective defenses. Repeated exposure burns the lining.

What you do about it:Reduce the acidity and volume of what's refluxing (antacids, H2RAs, PPIs), reduce how often reflux happens (lifestyle changes, weight loss), and in select cases fix the mechanical problem (surgery). Most patients live on acid suppression, stepped down to the lowest dose that keeps them quiet.

Worth knowing

Think of GERD treatment as step-down, not step-up.You start aggressive with a PPI to get control and heal the mucosa, then taper to the lowest effective regimen. That's backwards from how a lot of other disease states work, and it's a common source of confusion.

Pathophysiology - Why the Drugs Work

Everything traces back to one structure failing to do its job: the LES.

The mechanical problem

Transient LES relaxationsare the most common mechanism. The sphincter opens spontaneously, outside of swallowing, letting acid reflux up.
A weak, atonic, or hypotensive LESfrom baseline low resting pressure does the same thing more chronically.
Hiatal herniaphysically displaces part of the stomach above the diaphragm, which drags the LES out of its normal high-pressure zone and makes it easier for acid to migrate upward, especially from the postprandial "acid pocket," a layer of unbuffered acid that sits in the proximal stomach after meals.
Increased intra-abdominal pressure(obesity, pregnancy) physically pushes contents against a sphincter that's already struggling.

Everything else that weakens the barrier

Beyond LES pressure, GERD needs a failure of the esophagus's backup defenses: poor esophageal clearance of refluxed fluid, delayed gastric emptying (more volume sitting around to reflux), reduced mucosal resistance to acid, inadequate epidermal growth factor, and reduced salivary buffering. Damage severity depends on whatrefluxes (acid, pepsin, bile acids, pancreatic enzymes all hurt the mucosa), how much, and how longit sits in contact with the esophagus.

The unlock

Every drug class in this chapter attacks one part of that chain. Antacids and acid suppressants (H2RAs, PPIs)reduce the acidity of the refluxate so it hurts less when it does come up. Alginic acidforms a physical raft over gastric contents. Prokinetics(metoclopramide, prucalopride) attack gastric emptying and LES tone directly. Nothing here permanently fixes the LES itself, that's what surgery is for.

Where chronic reflux ends up

Repeated acid exposure erodes the squamous epithelium, producing erosive esophagitis. Keep going and you get esophageal strictures (scarring narrows the lumen), Barrett esophagus(the squamous lining changes to intestinal-type columnar epithelium, a metaplastic response to chronic injury), and eventually esophageal adenocarcinomain a minority of Barrett's patients. This is why alarm symptoms and long-standing disease change your workup.

Clinical Presentation

GERD splits into two overlapping categories: symptom-based disease (with or without visible tissue injury) and tissue-injury disease (with or without symptoms). You can absolutely have significant esophagitis with minimal symptoms, and severe heartburn with a pristine-looking esophagus. Symptom severity does nottrack with the amount of tissue damage.

Category	Findings
Classic esophageal	Heartburn (substernal warmth/burning rising from the abdomen, may radiate to neck), regurgitation, water brash (hypersalivation), belching, chest pain
Aggravated by	Lying down, bending over, high-fat meals, spicy food, citrus, coffee
Extraesophageal	Chronic cough, laryngitis, hoarseness, sore throat, wheezing, asthma
Alarm symptoms	Dysphagia, odynophagia, GI bleeding, unintentional weight loss

Don't miss an MI

Substernal burning chest pain is exactly how some myocardial infarctions present, especially atypically in women (jaw pain, SOB, sweating, fatigue, lightheadedness, nausea, or just "heartburn" and altered mental status in the elderly). New or first-time "heartburn" in a patient with cardiac risk factors deserves a second look before you hand them an antacid.

Terminology trap

NERD (nonerosive reflux disease)is symptomatic GERD with a normal-looking, non-eroded esophagus on endoscopy. It's not "mild" GERD, symptoms can be just as bad as erosive disease. The absence of visible injury doesn't mean the absence of disease.

Diagnosis

Most GERD is a clinical diagnosis. You don't need a scope to treat typical heartburn.

Typical symptoms, no alarm features:history alone is sufficient. Start empiric acid suppression, often trialed as an 8-week PPI course.
Not responding to empiric therapy, or alarm symptoms present:get an upper endoscopy. It's the preferred test for assessing mucosal injury and identifying strictures, Barrett esophagus, and other complications.
Other tools for select situations:ambulatory pH monitoring, combined impedance-pH monitoring, high-resolution esophageal pressure topography (manometry), and impedance manometry. Barium esophagram is not routine for GERD itself, it's reserved for severe dysphagia (looking for a stricture) or pre-op workup before hiatal hernia surgery.

Testing gotcha

If you're sending a patient for H. pyloritesting (a different disease, but the same GI unit often orders it in tandem), remember PPIs and bismuth can cause false-negative urea breath and stool antigen tests. That's a PUD issue, not a GERD one, but it's exactly the kind of cross-chapter trap that shows up on exams.

Treatment Approach

Goals:relieve symptoms, decrease frequency and duration of reflux, heal any injured mucosa, prevent complications, and improve quality of life.

Therapy works by decreasing refluxate acidity, decreasing the gastric volume available to reflux, improving gastric emptying, raising LES pressure, enhancing esophageal acid clearance, and protecting the mucosa directly. In practice, that means a tiered approach based on symptom frequency and severity, and it runs step-down: start with a PPI to gain control fast, then taper to the lowest dose of acid suppression that keeps symptoms away.

Severity tier	Approach
Intermittent, mild heartburn	Individualized lifestyle changes + patient-directed antacids and/or nonprescription H2RA or PPI
Symptomatic GERD, typical presentation	Lifestyle changes + prescription-strength H2RA (6–12 weeks) or PPI (4–8 weeks), empiric
Moderate-to-severe symptoms, erosive esophagitis, or complications	Lifestyle changes + PPI (up to twice daily, up to 8 weeks) or high-dose H2RA, or antireflux surgery

The 2-week rule

Patient-directed (OTC) therapy is fine for mild, intermittent symptoms. But if symptoms are unrelieved after 2 weeksof lifestyle changes plus OTC treatment, or symptoms are continuous for more than 2 weeks, that patient needs to see a provider, not just buy a bigger bottle of Tums. Alarm symptoms (dysphagia, bleeding, weight loss) skip straight to endoscopy regardless of duration.

PPI beats H2RA when it matters:PPIs give more rapid symptom relief and higher healing rates than H2RAs in moderate-to-severe GERD, and ACG guidelines recommend PPI over H2RA specifically for erosive esophagitis. Twice-daily PPI dosing is reserved for patients not responding to standard once-daily therapy, or those with extraesophageal symptoms like reflux chest syndrome.

Nonpharmacologic Therapy

Lifestyle modification is individualized, not a blanket checklist for every patient, but the menu of options is:

Elevate the head of the bed6–8 inches (blocks under the headposts, or a foam wedge), and consider sleeping on the left side.
Weight lossfor overweight or obese patients, since intra-abdominal pressure is a direct driver.
Avoid foods that drop LES pressure:fatty meals, chocolate, caffeine, alcohol, peppermint/spearmint.
Avoid direct mucosal irritants:citrus juices, tomato juice, coffee, spicy food.
Include protein-rich meals,which actually augment LES pressure.
Eat smaller meals; avoid eating within 2–3 hours of lying down.
Stop smoking. Avoid tight-fitting clothes.
For unavoidable esophagus-irritating medications(bisphosphonates, tetracycline, NSAIDs, iron, potassium chloride, quinidine), take upright with plenty of liquid or food if appropriate.

Interventional options

Antireflux surgery(laparoscopic Nissen fundoplication): consider when long-term pharmacotherapy is undesirable or complications are present.
Bariatric surgery(Roux-en-Y gastric bypass): consider in obese patients (BMI >35 kg/m²) already contemplating surgery.
Magnetic sphincter augmentation:can improve LES resistance and cut symptoms; long-term durability still uncertain.
Endoscopic therapies:radiofrequency ablation (mainly for Barrett esophagus with dysplasia) and transoral incisionless fundoplication (select chronic GERD patients).

Dosing Table

Drug	Brand	OTC/Rx Dose
Antacids (patient-directed, ≥12 y/o)
Magnesium/aluminum hydroxide + simethicone	Maalox	10–20 mL PRN or after meals and at bedtime; max 16 tsp/24h
Antacid/alginic acid	Gaviscon	2–4 tabs or 10–20 mL after meals and at bedtime
Calcium carbonate	Tums	500 mg, 2–4 tabs PRN
Nonprescription H2RAs (patient-directed, up to BID, ≥12 y/o)
Cimetidine	Tagamet HB	200 mg
Famotidine	Pepcid AC	10–20 mg
Nizatidine	Axid AR	75 mg
Nonprescription PPIs (patient-directed, once daily, >18 y/o)
Esomeprazole	Nexium 24HR	20 mg
Lansoprazole	Prevacid 24HR	15 mg
Omeprazole	Prilosec OTC	20 mg
Omeprazole/sodium bicarbonate	Zegerid OTC	20 mg/1100 mg
Prescription-strength H2RAs (6–12 weeks)
Cimetidine (off-label)	Tagamet	400 mg QID or 800 mg BID
Famotidine	Pepcid	20 mg BID
Nizatidine	Axid	150 mg BID
Prescription-strength PPIs (4–8 weeks)
Dexlansoprazole	Dexilant	30 mg once daily
Esomeprazole	Nexium	20–40 mg once daily
Lansoprazole	Prevacid	15 mg once daily
Omeprazole	Prilosec	20 mg once daily
Omeprazole/sodium bicarbonate	Zegerid	20 mg/1100 mg once daily
Pantoprazole (off-label)	Protonix	40 mg once daily
Rabeprazole	Aciphex	20 mg once daily
Erosive esophagitis / moderate–severe (up to BID, up to 8 weeks)
Dexlansoprazole	Dexilant	60 mg daily
Esomeprazole	Nexium	20–40 mg daily
Lansoprazole	Prevacid	30 mg once or twice daily
Omeprazole	Prilosec	20 mg once or twice daily
Rabeprazole	Aciphex	20 mg once or twice daily
Pantoprazole	Protonix	40 mg once or twice daily
High-dose H2RAs (8–12 weeks, for hypersecretors)
Cimetidine	Tagamet	400 mg QID or 800 mg BID
Famotidine	Pepcid	20–40 mg BID
Nizatidine	-	150 mg 2–4x daily (QID is off-label)
Maintenance (usual once-daily doses)
Omeprazole / Lansoprazole / Rabeprazole / Esomeprazole	-	20 mg / 30 mg / 20 mg / 20 mg once daily

Class-by-Class Detail

Antacids and antacid-alginic acid products

Antacids neutralizegastric acid directly (target pH >4), giving immediate but short-lived relief. They're the go-to for mild, intermittent symptoms, and are often layered on top of scheduled acid suppression for breakthrough symptoms. If a patient needs them daily for chronic symptoms, that's your cue they need prescription-strength acid suppression instead, not a bigger antacid bottle.

Alginic acid(in combination products like Gaviscon) isn't a real acid neutralizer and doesn't boost LES pressure. What it does is form a viscous raft that floats on top of gastric contents, physically blocking reflux and protecting the esophagus. The combo may outperform antacids alone for symptom relief, though there's no good evidence it helps with endoscopic healing. Content of alginic acid varies a lot between products, more is better, look for at least 500 mg.

Duration math

Antacids given on an empty stomach last about 1 hour. Taken after meals, food slows gastric emptying and stretches that out to roughly 3 hours. Even so, a bedtime dose alone cannot maintain acid suppression through the night, that's a job for H2RAs or PPIs.

Adverse effects:magnesium-containing antacids cause diarrhea; aluminum and calcium-containing ones cause constipation. Significant drug interactions with tetracycline, ferrous sulfate, isoniazid, sulfonylureas, and quinolone antibiotics (antacids chelate or raise gastric pH and block absorption), so separate dosing times.

H2-receptor antagonists

Cimetidine, famotidine, and nizatidine reversibly block H2 receptors on parietal cells, reducing acid secretion. They work well for mild-to-moderate GERD, and low-dose OTC or standard BID prescription dosing is often enough for symptomatic relief. Duration of action beats antacids, but efficacy is highly variableand frequently underwhelms, especially compared to PPIs.

The switch rule

If standard-dose H2RA isn't cutting it, the move is to switch to a PPI, not escalate the H2RA dose. Switching is both more cost-effective and more clinically effective. Patients who truly need higher doses may be acid hypersecretors, which is a distinct category from "just needs more of the same drug."

Adverse effects:headache, fatigue, dizziness, constipation or diarrhea, and with chronic use, tachyphylaxis (tolerance builds), plus delirium and dementia risk especially in older adults. Cimetidine specificallycan cause gynecomastia and carries the most drug interactions of the class, inhibiting metabolism of theophylline, warfarin, phenytoin, nifedipine, and propranolol via CYP enzymes. Since all H2RAs are roughly equally effective, pick the specific agent based on pharmacokinetics, safety profile, and cost, not efficacy.

Note: ranitidine was withdrawn from the US market over NDMA contamination concerns and isn't a current option, even though it's still mentioned in some coursework as a class example.

Proton pump inhibitors

Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole are all prodrugs that irreversibly inhibit the H⁺/K⁺-ATPase (the "proton pump") in gastric parietal cells, the final common step of acid secretion. That irreversible block is why they're more potent and longer-lasting than H2RAs, and why they're first-line for erosive esophagitis and moderate-to-severe symptoms.

Timing is not optional

PPIs only inhibit actively pumpingproton pumps, and pumps are recruited to the cell surface by eating. Take them 30–60 minutes before breakfast(or the largest meal of the day) so peak drug levels line up with peak pump activity. Take it at bedtime or with no meal nearby and you lose a big chunk of efficacy. Dexlansoprazole is the exception, its dual delayed-release formulation means it can be taken without regard to meals. If dosing BID, the second dose goes about 10–12 hours after the first, before a meal or snack.

Formulation quirks:most PPIs are acid-labile and come as enteric-coated granules in delayed-release capsules or tablets. For patients who can't swallow capsules, contents can be mixed in applesauce or orange juice; for NG tubes, mix in 8.4% sodium bicarbonate solution. Esomeprazole granules disperse in water. Pantoprazole and rabeprazole delayed-release tablets must not be crushed, chewed, or split. Zegerid(omeprazole/sodium bicarbonate) is different, it's immediate-release, must be taken on an empty stomach at least 1 hour before a meal, and the capsule must be swallowed whole (never opened or sprinkled on food), though the powder-for-suspension form works for NG tubes. IV esomeprazole and pantoprazole exist for patients who can't take oral meds but aren't more effective and cost significantly more.

Short and long-term risks

Short-term:headache, diarrhea, nausea, abdominal pain, and increased risk of community-acquired pneumonia and enteric infections including C. difficile(less acid means less of the stomach's natural antimicrobial barrier). Long-term:vitamin B12 deficiency, iron deficiency, hypomagnesemia, hypocalcemia, and osteoporosis/bone fractures (impaired calcium absorption in a low-acid environment). This is why indefinite PPI use isn't harmless and step-down to the lowest effective dose matters.

Drug interactions:reduced absorption of ketoconazole and itraconazole (both need an acidic stomach to dissolve). Omeprazolein particular inhibits CYP2C19, which can blunt the conversion of clopidogrel to its active metabolite and reduce its antiplatelet effect, an interaction that shows up constantly on boards and in practice with cardiology patients.

Promotility agents and mucosal protectants

Metoclopramide, a dopamine antagonist, raises LES pressure in a dose-related way and speeds gastric emptying, but doesn't improve esophageal clearance and lacks evidence for endoscopic healing. It's an adjunct for patients with a documented motility defect (LES incompetence, delayed gastric emptying), not a GERD monotherapy, and current ACG guidance doesn't recommend using it for GERD alone. Its adverse effect list is the reason it's not used more: somnolence, nervousness, fatigue, depression, diarrhea, and importantly extrapyramidal symptoms and tardive dyskinesia with longer use.

Bethanecholhas limited value due to side effects (urinary retention, abdominal discomfort, nausea, flushing) and isn't routinely recommended.

Prucalopride, a 5-HT4 agonist FDA-approved for constipation, has an off-label niche for improving gastric emptying and reducing esophageal acid exposure.

Baclofen, a GABA-B agonist, reduces the frequency of transient LES relaxations directly and can cut post-prandial and nocturnal acid reflux. ACG guidance supports a trial (5–20 mg TID) in patients with symptomatic GERD despite optimal PPI therapy.

Sucralfate, a nonabsorbable aluminum-sucrose salt, coats and protects the mucosa. It has limited value for typical GERD (not enough evidence for a strong recommendation) but is more useful for radiation esophagitis or bile/nonacid reflux, situations where acid suppression alone won't help since the offending agent isn't acid.

Vonoprazan (Voquenza) - the new acid blocker class

Vonoprazan is a potassium-competitive acid blocker (PCAB), a newer mechanism distinct from PPIs. It still inhibits the H⁺/K⁺-ATPase, but competitively and reversibly by blocking the potassium-binding site, rather than covalently and irreversibly like PPIs. FDA-approved for GERD and as part of H. pylori regimens.

	PPIs	Vonoprazan (PCAB)
Binding	Irreversible, covalent	Reversible, competitive
Needs active pump/meal timing	Yes, take 30–60 min before a meal	No, can be taken fed or fasted
Onset	Slower, needs pump recruitment	More rapid, prolonged, and robust antisecretory effect

Vonoprazan-specific adverse effects

Acute tubulointerstitial nephritis, C. diffinfection, bone fractures, vitamin B12 deficiency, hypomagnesemia, and severe skin reactions (SJS/TEN). Many of these overlap with PPI long-term risks, but the nephritis and severe skin reaction signals are worth flagging specifically for this drug.

Vonoprazan also shows up in H. pylori eradication as Voquenza DualPak(vonoprazan 20 mg BID + amoxicillin 1000 mg TID) and Voquenza TriplePak(vonoprazan 20 mg BID + clarithromycin 500 mg BID + amoxicillin 1000 mg BID), both FDA-approved for H. pylori since 2022. That's PUD territory, not GERD, but it's the same drug and the same lecture, so expect it to get tested together.

Barrett Esophagus and Complications

Barrett esophagus is a metaplastic change where chronic acid exposure converts the normal squamous esophageal lining to intestinal-type columnar epithelium. It's diagnosed by endoscopy (with biopsy) and matters because it raises the risk of esophageal adenocarcinoma.

Who gets screened

Screen patients with >5 years of chronic GERDwho have 3 or more risk factors: age >50, truncal obesity, smoking history, male sex, or a first-degree family history of Barrett's or esophageal adenocarcinoma. Management is long-term PPI therapy plus surveillance; radiofrequency ablation is reserved for cases with confirmed dysplasia.

Other long-term complications of unmanaged reflux: esophagitis(erosion of the squamous lining), esophageal strictures(scarring narrows the lumen, presents as progressive dysphagia to solids), and bleeding. Any of these alarm-type presentations warrant endoscopy rather than empiric escalation of OTC therapy.

Maintenance Therapy

Plenty of patients relapse once acid suppression is stopped, so don't assume an 8-week course is a cure. Consider long-term therapy in anyone with symptomatic relapse after stopping or de-escalating treatment, to prevent both symptom recurrence and progressive esophageal damage.

PPIs are the maintenance drug of choicefor moderate-to-severe esophagitis or symptoms, and are the most effective option for patients with extraesophageal symptoms, complications, or erosive disease. Usual once-daily maintenance doses: omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, or esomeprazole 20 mg.
Lower doses or alternate-day PPI dosingcan work for milder disease.
H2RAscan maintain remission in patients with mild disease.
On-demand therapy(taking a PPI only when symptomatic) is a reasonable option specifically for endoscopy-negative GERD (i.e., NERD).

Monitoring

Parameter	When	Watching for
Symptom frequency/severity	Every follow-up, and 2 weeks into any OTC self-treatment	Failure to respond, need to escalate or refer
Alarm symptoms	Every visit, ask directly	Dysphagia, odynophagia, bleeding, weight loss, need for endoscopy
Extraesophageal symptoms	Ongoing, especially in poor responders	Laryngitis, chronic cough, asthma exacerbation, chest pain needing further workup
B12, magnesium, calcium	Periodically with long-term PPI use	Deficiency from chronic acid suppression
Bone health	Long-term PPI use, especially older adults	Fracture risk, consider calcium/vitamin D counseling
Renal function	If on vonoprazan or long-term PPI	Acute interstitial nephritis (rare but described)

Patient Counseling

PPI timing:"Take this 30 to 60 minutes before your first meal of the day. It only works on acid pumps that are actively turned on, and eating is what turns them on, so timing really matters here."
Don't stop and restart on your own:"These need a few days of consistent use to build full effect. Taking it only on bad days won't control things the way daily dosing will, unless your doctor specifically set you up for on-demand dosing."
The 2-week rule:"If you're still needing this every day after two weeks, or you're having trouble swallowing, losing weight without trying, or seeing blood, stop self-treating and get seen."
Antacid interaction spacing:"Take your antacid at least 2 hours apart from your antibiotic or thyroid medication, it can block absorption."
Lifestyle framing that actually lands:"The biggest wins are eating your last meal earlier, not lying down right after eating, and if weight's an issue, even modest weight loss helps a lot. Fatty and spicy foods, chocolate, and caffeine are the classic triggers, but everyone's a little different, pay attention to your own pattern."
Don't chew/crush certain PPIs:"Swallow this one whole, don't crush or chew it, it's coated so it survives your stomach acid and dissolves further down."
Long-term use isn't risk-free:"Taking this for years is linked to lower B12, magnesium, and bone density, so we don't want you on the highest dose forever if a lower one keeps you controlled. That's not a reason to panic, it's a reason we'll periodically check if you can step down."

High-Yield Recall Sheet

GERD treatment is step-down, not step-up:start with a PPI, taper to the lowest effective regimen.
PPI > H2RAfor erosive esophagitis and moderate-to-severe symptoms, per ACG.
PPIs must be taken 30–60 min before a mealto hit actively pumping proton pumps. Dexlansoprazole is the exception (any time, food or no food).
Zegerid (omeprazole/bicarb)is immediate-release, empty stomach, capsule swallowed whole, never opened.
Pantoprazole and rabeprazole tablets:never crush, chew, or split.
H2RA not working? Switch to a PPI, don't just raise the H2RA dose.
Cimetidine= gynecomastia + the most drug interactions (CYP-mediated: warfarin, phenytoin, theophylline, propranolol, nifedipine).
Alginic acidforms a physical raft, doesn't neutralize acid or raise LES pressure.
Antacid AE pattern:magnesium = diarrhea, aluminum/calcium = constipation.
PPI long-term risks:B12 deficiency, hypomagnesemia, osteoporosis/fractures, C. diff, community-acquired pneumonia.
Omeprazole + clopidogrel:CYP2C19 inhibition blunts clopidogrel's antiplatelet effect.
Vonoprazan (Voquenza)is a PCAB, reversible/competitive H+/K+-ATPase block, no meal-timing requirement, faster and more robust than PPIs.
Metoclopramideraises LES pressure and speeds gastric emptying, but ACG doesn't recommend it as GERD monotherapy given EPS/tardive dyskinesia risk.
Baclofenhas ACG support as an add-on for reflux breaking through optimal PPI therapy.
Barrett esophagus screening:>5 years GERD + 3 or more risk factors (age >50, truncal obesity, smoking, male, +FH).
Symptom severity does not correlate with tissue damage severity, NERD can hurt just as much as erosive disease.
Alarm symptoms(dysphagia, odynophagia, bleeding, weight loss) mean endoscopy, not another OTC trial.
Antireflux surgery= laparoscopic Nissen fundoplication; bariatric surgery (Roux-en-Y) considered if BMI >35 and already planning surgery.