If lifestyle changes do not effectively reduce symptoms, pharmacologic therapy is warranted. Pharmacologic therapy is designed to decrease the amount of acid that refluxes from the stomach back into the esophagus, increase gastrointestinal motility, or make the refluxed material less irritating to the lining of the esophagus by neutralizing the pH of the gastric acid.
In young, otherwise healthy patients presenting with heartburn and no esophagitis, a therapeutic trial of an acid-suppressing agent such as an antacid or a nonprescription H2 receptor antagonist can be used initially.
Antacids
Antacids have been successful in neutralizing gastric acid and relieving symptoms of gastroesophageal reflux disease (GERD). They work by increasing the pH of the stomach contents and increasing LES pressure, thereby decreasing the amount of refluxed material from the stomach. Patients need to be educated about the mechanism of action of antacids and their proper use. In order for antacids to be effective in relieving GERD symptoms, they must be administered every 2–4 hours. Counseling about potential drug interactions and adverse effects are of great importance, especially in renally impaired patients. Antacids in combination with alginic acid therapy may provide additional symptomatic relief. If symptoms persist or if the patient deteriorates, evaluation by a physician is necessary. All patients with alarm symptoms, irrespective of age, should be referred to a physician for further evaluation.
H2 Receptor Antagonists
If lifestyle changes or antacids do not provide relief, H2 receptor antagonists may be used. The four histamine receptor antagonists (cimetidine, nizatidine, famotidine, ranitidine) currently FDA-approved have been shown to be equally effective in alleviating symptoms of gastroesophageal reflux disease and healing mild to moderate esophagitis. These agents have limited effect on postprandial gastric acid secretion; in addition, tolerance to their acid-inhibitory effects has been seen within 30 days of initiation of therapy and disappears shortly after cessation of the medication. The tolerance is more pronounced with higher doses and shorter dosing intervals. Consequently, on-demand therapy, which provides lower consumption of drugs, may reduce this problem and be useful for patients with mild symptoms and no esophagitis.
Studies evaluating standard doses of the H2 receptor antagonists have found an overall mean esophageal healing rate of 48% and a 60% mean relief in symptoms. However, there is variability in many of the studies due to differences in dosing schedules and degree of esophagitis. Patients with erosive esophagitis may require more intensive pharmacologic therapy with higher doses of H2 receptor antagonists, proton pump inhibitors or surgery. In a meta-analysis of comparative trials, high-dose therapy with H2 receptors was associated with significantly higher rates of healing (52%) compared to standard doses (44%) after 4 weeks in patients with grade II esophagitis. However, even with high doses of H2 receptor antagonists, the healing rate does not exceed 30% in patients with grade III–IV esophagitis.
Kahrilas et al. recently published a study comparing standard and high-dose H2 receptor blocker therapy (ranitidine 300 mg bid) in patients who were symptomatic after 6 weeks of therapy with ranitidine 150 mg bid. The findings of this study demonstrated that higher doses did not provide improved symptomatic relief of heartburn. Only a minority of these patients (<20%) had complete resolution at 8 weeks of therapy. However, because the duration of effective acid suppression with an H2 receptor antagonist may be less than 6 hours, trials have shown more effective control of symptoms and healing with more frequent dosing. Jansen and associates found that the median healing time of patients with reflux esophagitis was decreased in those receiving ranitidine four times a day (5.4%) compared to the same dose twice a day (10.2%) and placebo (26.4%). In another study, upright daytime reflux was significantly reduced when famotidine was administered twice a day compared to once daily.
Because the efficacy of the H2 receptors are equal when used in equipotent doses, the selection of one over the other will depend upon the adverse effect profile, concurrent medications, and cost. When comparing the cost of agents, not only the drug cost but the daily cost individualized for that patient should be taken into account. Serious adverse effects are uncommon with H2 receptor antagonists, but thrombocytopenia and central nervous system changes — which include headache, confusion, and depression — can occur. The H2 receptor antagonist cimetidine inhibits several enzymes of the microsomal CYP system, thereby decreasing the hepatic clearance of a number of drugs (e.g., warfarin, diazepam, theophylline, phenytoin, and carbamazepine). Ranitidine, famotidine and nizatidine are less likely to interfere with hepatic metabolism of P-450 metabolized drugs.
Proton Pump Inhibitors
The goal of therapy for patients suffering with gastroesophageal reflux disease is complete relief of symptoms and healing. However, this is not achieved with H2 receptor antagonists alone. Proton pump inhibitors are the most effective agents to heal erosions and eliminate symptoms associated with GERD. They produce more profound suppression of acid and consistently achieve healing rates of over 90%. The greater the severity of esophagitis, the lower the healing rate. The substituted benzimidazoles (omeprazole, lansoprazole, rabeprazole and pantoprazole) are drugs which, once trapped and activated in the acid milieu, potently suppress gastric secretion of acid and pepsin. Their long duration of action allows once daily administration in many patients.
The pharmacokinetic profiles of the various proton pump inhibitors appear to be relatively equal (Table 5). All proton pump inhibitors are rapidly absorbed, with peak plasma concentrations occurring at 2–4 hours.
| Table 5. Pharmacokinetic Comparison of Proton Pump Inhibitors | ||||
| Parameters | Omeprazole (Prilosec) | Lansoprazole (Prevacid) | Rabeprazole (Aciphex) | Pantoprazole (Protonix) |
| Tmax | 2.5 hr | 1.5–3 hr | 3–3.5 hr | 2.8 hr |
| Half-life | 0.5–0.7 | 1.4 hr | 1.02 hr | 1.9 hr |
| Protein binding | 95% | 99% | 96% | 98% |
| Clearance | Liver | Liver | Liver | Liver |
| Bioavailability | 35%–60% | 85% | > or = 30% | 77% |
| Dosage form | Oral | Oral | Oral | Oral/IV |
In clinical trials, proton pump inhibitors have been shown to have higher and faster healing rates of esophagitis and symptom relief than H2 receptor antagonists. Proton pump inhibitors have been shown to heal all grades of esophagitis in at least 70% to 95% of cases at 4 to 8 weeks (Table 6), which is substantially more than that seen with2 receptor antagonists. Overall, there do not appear to be any significant differences in healing rates or in symptom relief between the four proton pump inhibitors when equivalent doses are used.
Studies have demonstrated a strong correlation between esophageal healing and maintaining symptom relief with severity of illness and acid suppression. With severe disease, larger doses of proton pump inhibitors (i.e., lansoprazole 30 mg vs. 15 mg per day) are generally required for adequate healing and symptom relief.
Omeprazole, lansoprazole, rabeprazole and pantoprazole are all metabolized by the P-450 enzyme system, lending to potential drug interactions. Omeprazole has been shown to decrease the clearance of diazepam (27%) and phenytoin (19%). However, doses of 20 mg of omeprazole have not been shown to alter steady state plasma concentrations of phenytoin.
A clinically significant case report of an interaction between warfarin and omeprazole (20 mg daily) was reported in one patient who developed widespread bruises and hematuria, with a prothrombin time of 48 seconds. Lansoprazole may slightly increase the clearance (6%) of theophylline, which probably is not clinically significant. Rabeprazole has not been shown to interact with theophylline, warfarin or phenytoin, possibly due to low affinity to the 2C19 isoenzyme. However, rabeprazole may increase digoxin serum concentrations. Pantoprazole, in contrast to omeprazole and lansoprazole, is also metabolized by a cystosolic sulphotransferase which appears to interact less with drugs that are in competition for the same P-450 system. This may explain a lower potential for drug interactions. However, to date pantoprazole’s use has been limited.
Proton pump inhibitors are generally well tolerated and associated with few adverse effects, namely nausea, headache, and diarrhea.
Early animal studies with omeprazole produced hypergastrinemia, which was associated with gastric enterochromaffin-like cell hyperplasia. However, with more than 17 years of worldwide use, despite the fact that omeprazole increases serum gastrin levels to approximately 1.5 times that of normal, no clinically significant increase in endocrine or parietal cell density has been found.
| Table 6. Comparison of Proton Pump Inhibitors for the Treatment of Reflux Esophagitis | |||||
| Drug | Dose (mg/day) | Healing Rate (% Patients) | Symptom Relief (%) | Reference | |
| 4 wks | 8 wks | ||||
| Omeprazole Pantoprazole |
20 40 |
78 74 |
94 90 |
94 90 |
30 |
| Omeprazole Rabeprazole |
20 20 |
81 81 |
92 94 |
83 86 |
45 |
| Omeprazole Lansoprazole Lansoprazole |
20 30 15 |
82 83 75 |
91 90 79 |
L = O | 31 |
Prokinetic Drugs
The pathogenesis of gastroesophageal reflux disease can be related to defects in esophagogastric motility, poor esophageal clearance and delayed gastric emptying time. Therefore, it may be possible to promote healing with the use of a prokinetic drug, such as cisapride or metoclopramide, to strengthen the force of the contraction of the lower esophageal sphincter (LES) and esophageal body or to increase gastric emptying. Studies have shown that cisapride provides symptomatic relief and healing of esophagitis.
Meta-analysis of the efficacy for the treatment of mild GERD with cisapride, omeprazole and ranitidine were cure rates of 58%, 75% vs. 38%, respectively. In the treatment of severe gastroesophageal reflux disease, the cure rates were 43% for cisapride 80 mg/day, 87% for omeprazole 20 mg/day and 50% for ranitidine 300 mg/day. In addition, cisapride, 10 mg four times a day, has been shown to provide symptomatic relief and healing of mild esophagitis with comparable results with cimetidine, 400 mg four times a day. The use of either metoclopramide or cisapride is, however, limited by their adverse effect profile. Metoclopramide has a 20% to 50% incidence of fatigue, restlessness, tremor or parkinsonism. Cisapride has many drug interactions and is associated with prolonging the QT interval, thereby limiting its use in cardiac patients.
Combination therapy with an H2 receptor antagonist has demonstrated improved healing of esophagitis compared to2 receptor antagonist alone. Therefore, cisapride is comparable to standard H2 receptor antagonist therapy.
Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.