Ranitidine - Drug Monograph

Of course. Here is a comprehensive, evidence-based drug monograph for Ranitidine, formatted as a complete blog post.

Introduction

Ranitidine is a histamine H₂-receptor antagonist that was first approved in the early 1980s. For decades, it was a cornerstone therapy for the management of gastric acid-related disorders, celebrated for its efficacy and favorable safety profile. It worked by competitively inhibiting histamine at the H₂ receptors of the gastric parietal cells, leading to a significant reduction in both basal and stimulated gastric acid secretion. It was available in both prescription and over-the-counter (OTC) formulations. However, in April 2020, the U.S. Food and Drug Administration (FDA) requested the removal of all ranitidine products from the market due to the presence of unacceptable levels of N-Nitrosodimethylamine (NDMA), a probable human carcinogen.

Mechanism of Action

Ranitidine exerts its therapeutic effects by competitively blocking histamine at the H₂ receptors located on the basolateral membrane of gastric parietal cells. This blockade inhibits the activation of the proton pump (H⁺/K⁺ ATPase) via the cyclic adenosine monophosphate (cAMP) pathway. The primary result is a profound reduction in the volume and hydrogen ion concentration of both basal gastric acid secretion and acid secretion stimulated by food, histamine, pentagastrin, caffeine, and insulin.

Indications

* Duodenal Ulcer: Short-term treatment and maintenance therapy. * Gastric Ulcer: Short-term treatment of benign gastric ulcer. * Gastroesophageal Reflux Disease (GERD): Treatment of erosive esophagitis and associated heartburn. * Pathological Hypersecretory Conditions: Management of conditions like Zollinger-Ellison syndrome and systemic mastocytosis. * Erosive Esophagitis: Treatment and maintenance. * Over-the-Counter (OTC) Use: For the prevention and relief of heartburn, acid indigestion, and sour stomach.

Dosage and Administration

* Oral Administration: * Active Duodenal Ulcer: 150 mg twice daily or 300 mg once at bedtime. * Maintenance for Duodenal Ulcer: 150 mg once at bedtime. * GERD: 150 mg twice daily. * Erosive Esophagitis: 150 mg four times daily. * Hypersecretory Conditions: 150 mg twice daily (may be titrated up to 6 g/day in divided doses). * OTC Use: 75 mg to 150 mg taken 30-60 minutes before consuming food or beverages expected to cause heartburn.

* Parenteral Administration (IV/IM): * Used in hospitalized patients unable to take oral medication. * Typical dose: 50 mg (2 mL) every 6-8 hours via intermittent IV infusion or IM injection.

* Special Populations: * Renal Impairment: Dose adjustment is required. For patients with a creatinine clearance < 50 mL/min, the recommended dose is 150 mg orally every 24 hours or 50 mg parenterally every 18-24 hours. * Hepatic Impairment: Caution advised; dose adjustment may be necessary as metabolism is partially hepatic. * Geriatric Patients: Dosing should be cautious, often starting at the low end of the dosing range due to potential decreased renal function.

Pharmacokinetics

* Absorption: Rapidly absorbed from the GI tract. Oral bioavailability is approximately 50% due to first-pass metabolism. Peak plasma concentrations occur within 2-3 hours. Food may delay absorption but does not significantly affect overall bioavailability. * Distribution: Widely distributed throughout the body. Plasma protein binding is low (10-19%). It crosses the placenta and is excreted in breast milk. * Metabolism: Extensively metabolized in the liver via hepatic oxidation, reduction, and conjugation to form metabolites including ranitidine N-oxide, desmethyl ranitidine, and ranitidine S-oxide. * Elimination: Eliminated primarily via the kidneys through glomerular filtration and tubular secretion. Approximately 30% of an oral dose and 70% of an intravenous dose are recovered in the urine as unchanged drug. The elimination half-life is 2-3 hours.

Contraindications

* Known hypersensitivity to ranitidine or any component of the formulation. * History of acute porphyria (ranitidine may precipitate attacks).

Warnings and Precautions

* NDMA Impurity: The primary reason for its withdrawal. NDMA is a known environmental contaminant and suspected human carcinogen found in unacceptable levels in ranitidine products, which appears to increase over time, especially when stored at higher temperatures. * QTc Prolongation: Dose-dependent QT interval prolongation has been reported with intravenous formulations, particularly in patients with renal impairment or those receiving high doses. Avoid in patients with known QT prolongation or those taking other drugs known to prolong the QT interval. * Liver Dysfunction: Cases of hepatitis, hepatocellular, hepatocanalicular, and mixed hepatitis have been reported. Monitor LFTs. * Phenylketonuria: Some orally disintegrating tablets may contain aspartame, a source of phenylalanine. * Central Nervous System (CNS) Effects: Confusion, agitation, depression, and hallucinations have been reported, primarily in elderly and severely ill patients. * Risk of Pneumonia: Some studies suggest an increased risk of community-acquired and hospital-acquired pneumonia due to the reduction of gastric acidity, which allows for bacterial colonization of the stomach.

Drug Interactions

* Drugs Dependent on Gastric pH for Absorption: Ranitidine increases gastric pH, which can alter the absorption of other drugs. * Decreased Absorption: Ketoconazole, itraconazole, dasatinib, erlotinib, atazanavir. Administer these drugs at least 2 hours before ranitidine. * Increased Absorption: Midazolam, triazolam. * Warfarin: Conflicting data exists; some reports suggest potential for increased INR and risk of bleeding. Close monitoring of INR is recommended. * Procainamide: Ranitidine may reduce renal clearance of procainamide, increasing its plasma levels and risk of toxicity. * High-Dose Methotrexate: Ranitidine may reduce the renal tubular secretion of methotrexate, potentially increasing methotrexate levels and toxicity.

Adverse Effects

* Common (>1%): Headache, constipation, diarrhea, nausea, vomiting, abdominal discomfort. * Serious (≤1%): * Hepatobiliary: Hepatitis, hepatocellular necrosis, jaundice. * Hematologic: Thrombocytopenia, agranulocytosis, aplastic anemia. * Cardiovascular: Bradycardia, AV block, QT prolongation (IV form). * CNS: Mental confusion, agitation, depression, hallucinations (especially in elderly/ill patients). * Endocrine: Reversible gynecomastia has been reported with prolonged use. * Hypersensitivity: Rash, anaphylaxis, angioedema.

Monitoring Parameters

* Efficacy: Resolution of symptoms (e.g., pain, heartburn), healing of ulcers/erosions confirmed via endoscopy if clinically indicated. * Safety: * Renal Function: Serum creatinine/BUN at baseline and periodically in patients with or at risk for renal impairment. * Hepatic Function: Liver function tests (LFTs) if symptoms of hepatitis appear (e.g., jaundice, fatigue). * Hematologic: Complete blood count (CBC) in patients presenting with signs of infection or bleeding. * Cardiac: ECG monitoring in patients receiving high-dose IV therapy, especially those with renal impairment or underlying cardiac disease.

Patient Education

* Market Withdrawal: Patients should be informed that all ranitidine products have been removed from the market and they should discontinue use. They should not purchase or use any remaining stock. * Alternative Therapies: Patients should consult their healthcare provider or pharmacist for safe and effective alternatives, such as other H₂ blockers (e.g., famotidine) or proton pump inhibitors (e.g., omeprazole, pantoprazole). * Proper Disposal: Patients should be advised on how to safely dispose of any unused ranitidine medication following FDA recommendations. * Historical Context: If taken in the past, patients should be aware of the potential long-term risk related to NDMA exposure and discuss any concerns with their healthcare provider.

References

1. U.S. Food and Drug Administration (FDA). (2020). FDA Requests Removal of All Ranitidine Products (Zantac) from the Market. [https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market](https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market) 2. Lexicomp Online®, Ranitidine: Drug Information. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2023. 3. McQuaid, K. R. (2023). Drugs Used in the Treatment of Gastrointestinal Diseases. In Katzung & Trevor's Basic & Clinical Pharmacology (16th ed.). McGraw Hill. 4. National Center for Biotechnology Information. PubChem Compound Summary for CID 5039, Ranitidine. [https://pubchem.ncbi.nlm.nih.gov/compound/Ranitidine](https://pubchem.ncbi.nlm.nih.gov/compound/Ranitidine) 5. Shin, J. M., Kim, N. (2013). Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. Journal of Neurogastroenterology and Motility, 19(1), 25–35. 6. Merck & Co., Inc. (2018). Zantac® (ranitidine) [prescribing information]. Whitehouse Station, NJ.