Ranitidine

Article Author:
Katie Morgan
Article Editor:
Rajni Ahlawat
Updated:
1/13/2019 10:38:21 PM
PubMed Link:
Ranitidine

Indications

Ranitidine is FDA-approved for both adults and children aged 1 month to 16 years. Ranitidine, over-the-counter for self-care use without a prescription, is only FDA-approved in children older than 12 years.

FDA-Approved Ranitidine Indications

  • Benign gastric ulcer disease, short-term, and maintenance
  • Duodenal ulcer disease, short-term, and maintenance
  • Erosive esophagitis
  • Hypersecretory conditions (e.g., Zollinger-Ellison, systemic mastocytosis, multiple endocrine adenoma syndrome)  
  • Gastroesophageal reflux disease (GERD)
  • Non-ulcer dyspepsia, indigestion, heartburn, and sour stomach

Non-FDA-Approved Ranitidine Indications

  • Anaphylaxis[1][2]
  • NSAID-induced ulcer prophylaxis[3]
  • Stress ulcer prophylaxis[4]
  • Taxane-related urticaria prophylaxis[5]
  • Aspiration prophylaxis during obstetric anesthesia[6]

Mechanism of Action

Mechanism

Ranitidine is a competitive inhibitor of histamine H2-receptors. The reversible inhibition of H2-receptors in gastric parietal cells results in a reduction in both gastric acid volume and concentration. Ranitidine’s acid-lowering effect is more pronounced for basal and nocturnal acid secretion than it is for food-stimulated acid secretion. Additional indirect effects of ranitidine are decreased pepsin secretion and increased nitrate-reducing bacterial flora.

Pharmacokinetics and Pharmacodynamics

When dosed orally, ranitidine has a bioavailability of 50%, which is relatively unaffected by food. The peak levels occur 2 to 3 hours post-administration for oral administration and occur 15 minutes after intramuscular administration. Ranitidine is primarily excreted unchanged in the urine, with a half-life ranging from 2.5 to 3 hours, and because of the renal elimination, the half-life may increase to 4 to 5 hours in patients with kidney dysfunction.

Administration

Oral

Ranitidine is available as tablets, capsules, or oral syrup. Ranitidine solution or the dissolved tablet may be mixed with select enteral tube feeding solutions. [7] 

Intramuscular (IM)

Administer as an undiluted solution.  

Intravenous (IV)  

Intermittent IV bolus: Dilute with a compatible IV solution prior to use to a maximum concentration of 2.5 mg/mL. Then the solution may be administered at a maximum rate of 10 mg per minute.

Intermittent IV infusion: Dilute with a compatible IV solution prior to use to a maximum concentration of 0.5 mg/mL. Then the solution may be administered at a maximum rate of 2.5 to 3.5 mg per minute.

Continuous IV infusion: Dilute 150 mg ranitidine in 250 mL of a compatible IV solution. This solution then may be administered at a rate of 6.25 mg per hour. For patients with Zollinger-Ellison disease, a faster infusion rate may be required.  Dilute prior to use to a maximum concentration of 2.5 mg/mL. Then the infusion may be started at a rate of 1 mg/kg per hour to a maximum dose of 2.5 mg/kg per hour. Ranitidine may be added to total parenteral nutrition. However, its stability varies greatly depending on the specific ingredients, concentrations, and packaging of the final product.[8]

Adverse Effects

The initial clinical trials for ranitidine reported the following adverse effects following oral or parenteral administration (frequency not defined):

  • Central nervous system (CNS): Malaise, dizziness, somnolence, insomnia, vertigo, mental confusion, agitation, and hallucinations.
  • Cardiovascular: Tachycardia, bradycardia, asystole, atrioventricular block, and premature ventricular beats. Bradycardia may be more frequent with rapid intravenous administration and in patients with cardiac rhythm disturbances.
  • Gastrointestinal (GI): Constipation, diarrhea, nausea, vomiting, abdominal discomfort, pancreatitis.
  • Hepatic: Hepatocellular, cholestatic, or mixed hepatitis; hepatic failure
  • Musculoskeletal: Myalgia, arthralgia
  • Hematologic: Leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, agranulocytosis
  • Endocrine: Decreased libido, impotence, galactorrhea, gynecomastia
  • Integumentary: Rash, alopecia, vasculitis
  • Respiratory: Pneumonia
  • Renal: Increased serum creatinine, acute interstitial nephritis
  • Other: Hypersensitivity reactions, anaphylaxis

Transient pain at the site of intramuscular (IM) injection has been reported. Transient local burning or itching has been reported with intravenous (IV) administration of ranitidine.  

The 2015 Beers Criteria list identifies ranitidine as a therapy that may potentially trigger or exacerbate delirium in adults older than 65 years of age. Caution should be used when treating the elderly with ranitidine. [9]

Long-term use of ranitidine for greater than 2 years may also be associated with vitamin B12 deficiency. [10]

Pregnancy

Ranitidine is known to cross the placenta; however, it is still commonly used when pregnant patients require acid-suppressing therapy. Of note, increasing studies are revealing a correlation between acid-suppressing therapy use during pregnancy and the development of childhood asthma. [11] Likewise, ranitidine is excreted into breastmilk, and the risks and benefits of use should be discussed prior to initiating therapy.

Contraindications

Ranitidine is contraindicated in patients who have previously experienced a hypersensitivity reaction to ranitidine or any of the product components. Small case series and analyses demonstrate conflicting results regarding cross-sensitivity among H2-receptor antagonists; caution is advised.  Due to differences and similarities between the chemical structures, there is speculation that some H2 blockers have less risk of cross-reactivity than others. [12][13][14]

Furthermore, patients with any history of acute porphyria should avoid ranitidine because it may trigger porphyric events.

Clinicians urge patients to seek professional medical care and contraindicate the over-the-counter product when they have difficulty or pain when swallowing food or have blood in vomit or stool. Concurrent use is contraindicated with other acid reducers, kidney disease, or in patients younger than 12 years old.

Monitoring

Efficacy Parameters

Patients should notice an improvement in symptoms. Laboratory signs of improvement would include an increase in gastric pH. For GI bleeding, the goal gastric pH is typically greater than 4. The goal gastric acid secretion in Zollinger-Ellison disease is less than 10 mEq per hour.

Additional Monitoring

For patients receiving ranitidine IV at total daily doses greater than 400 mg, daily monitoring of liver function tests (aspartate aminotransferase and alanine aminotransferase) may be warranted. For acutely ill patients, serum creatinine may also be measured to provide information for renal dose adjustments as well as to monitor for potential nephrotoxicity. When there is a concern of GI bleeding, further monitoring may include occult blood tests, hemoglobin, and hematocrit.

Toxicity

Severe toxicity to ranitidine is rare, and there currently is no antidote for ranitidine overdose. Patients may present with CNS depression or severe hypotension. Supportive treatment and monitoring based on the presenting symptoms may be warranted.

Enhancing Healthcare Team Outcomes

Guidelines and Recommendations

The 2015 American Academy of Allergy, Asthma, and Immunology (AAAAI), and American College of Allergy, Asthma, and Immunology (ACAAI) anaphylaxis practice parameter describe inadequate evidence for the use of H2-blockers in the treatment of anaphylaxis; however, H2-blockers can be considered adjunct therapy after the administration of epinephrine.[1][2] (Level II)

The 2009 American College of Gastroenterology guideline for the prevention of NSAID-related ulcer complications conclude that double-strength H2-blockers may reduce the risk of NSAID-induced endoscopic peptic ulcers. However, this guideline also concludes that H2 blockers are inferior to proton pump inhibitors for this indication.[3] (Level II)

The 2016 Surviving Sepsis Campaign guidelines recommend H2-blockers or proton pump inhibitors be used in patients with risk factors for stress ulcer prophylaxis.[4] (Level II)

The 2016 American Society of Anesthesiologists guideline for obstetric anesthesia suggest consideration of non-particulate antacids, H2 blockers and/or metoclopramide to prevent aspiration.[6] (Level II)


References

[1] Lieberman P,Nicklas RA,Oppenheimer J,Kemp SF,Lang DM,Bernstein DI,Bernstein JA,Burks AW,Feldweg AM,Fink JN,Greenberger PA,Golden DB,James JM,Kemp SF,Ledford DK,Lieberman P,Sheffer AL,Bernstein DI,Blessing-Moore J,Cox L,Khan DA,Lang D,Nicklas RA,Oppenheimer J,Portnoy JM,Randolph C,Schuller DE,Spector SL,Tilles S,Wallace D, The diagnosis and management of anaphylaxis practice parameter: 2010 update. The Journal of allergy and clinical immunology. 2010 Sep     [PubMed PMID: 20692689]
[2] The diagnosis and management of anaphylaxis: an updated practice parameter. The Journal of allergy and clinical immunology. 2005 Mar     [PubMed PMID: 15753926]
[3] Lanza FL,Chan FK,Quigley EM, Guidelines for prevention of NSAID-related ulcer complications. The American journal of gastroenterology. 2009 Mar     [PubMed PMID: 19240698]
[4] Rhodes A,Evans LE,Alhazzani W,Levy MM,Antonelli M,Ferrer R,Kumar A,Sevransky JE,Sprung CL,Nunnally ME,Rochwerg B,Rubenfeld GD,Angus DC,Annane D,Beale RJ,Bellinghan GJ,Bernard GR,Chiche JD,Coopersmith C,De Backer DP,French CJ,Fujishima S,Gerlach H,Hidalgo JL,Hollenberg SM,Jones AE,Karnad DR,Kleinpell RM,Koh Y,Lisboa TC,Machado FR,Marini JJ,Marshall JC,Mazuski JE,McIntyre LA,McLean AS,Mehta S,Moreno RP,Myburgh J,Navalesi P,Nishida O,Osborn TM,Perner A,Plunkett CM,Ranieri M,Schorr CA,Seckel MA,Seymour CW,Shieh L,Shukri KA,Simpson SQ,Singer M,Thompson BT,Townsend SR,Van der Poll T,Vincent JL,Wiersinga WJ,Zimmerman JL,Dellinger RP, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive care medicine. 2017 Mar     [PubMed PMID: 28101605]
[5] Bookman MA,Kloth DD,Kover PE,Smolinski S,Ozols RF, Intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. Seminars in oncology. 1997 Dec     [PubMed PMID: 9427258]
[6] Practice Guidelines for Obstetric Anesthesia: An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. Anesthesiology. 2016 Feb     [PubMed PMID: 26580836]
[7] Crowther RS,Bellanger R,Szauter KE, In vitro stability of ranitidine hydrochloride in enteral nutrient formulas. The Annals of pharmacotherapy. 1995 Sep     [PubMed PMID: 8547732]
[8] Allwood MC,H M, Factors influencing the stability of ranitidine in TPN mixtures. Clinical nutrition (Edinburgh, Scotland). 1995 Jun     [PubMed PMID: 16843929]
[9] American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2015 Nov     [PubMed PMID: 26446832]
[10] Lam JR,Schneider JL,Zhao W,Corley DA, Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013 Dec 11     [PubMed PMID: 24327038]
[11] Lai T,Wu M,Liu J,Luo M,He L,Wang X,Wu B,Ying S,Chen Z,Li W,Shen H, Acid-Suppressive Drug Use During Pregnancy and the Risk of Childhood Asthma: A Meta-analysis. Pediatrics. 2018 Feb     [PubMed PMID: 29326337]
[12] Song WJ,Kim MH,Lee SM,Kwon YE,Kim SH,Cho SH,Min KU,Kim YY,Chang YS, Two cases of h(2)-receptor antagonist hypersensitivity and cross-reactivity. Allergy, asthma     [PubMed PMID: 21461253]
[13] Demirkan K,Bozkurt B,Karakaya G,Kalyoncu AF, Anaphylactic reaction to drugs commonly used for gastrointestinal system diseases: 3 case reports and review of the literature. Journal of investigational allergology     [PubMed PMID: 16784015]
[14] Park KH,Pai J,Song DG,Sim DW,Park HJ,Lee JH,Jeong KY,Pan CH,Shin I,Park JW, Ranitidine-induced anaphylaxis: clinical features, cross-reactivity, and skin testing. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2016 Apr     [PubMed PMID: 26764898]