Drug Interactions of H₂ Receptor Antagonists-  Ranitidine: A Review

 

Sarfaraz Ahmad¹*, Md. Sajid Ali¹, Nawazish Alam¹, Md. Intakhab Alam¹, Md. Sarfaraz Alam¹, Md. Daud Ali²

¹College of Pharmacy, Jazan University, Jazan,  KSA.

²Department of Pharmacy, Mohammad Al-Mana College for Health Sciences, Al Khobar, KSA.

 

ABSTRACT:

Ranitidine has OTC drug status as well as it is an essential drug by WHO, hence it is popularly selling drug from community and hospital pharmacy. Many prescription and nonprescription drugs were found having drug interaction with ranitidine which may lead to either drug toxicity or therapy failure. This review compiles potential drug interactions of ranitidine with several categories of drugs along with effective measures. Ranitidine is in a group of drugs called histamine-2 blockers. H₂ receptor antagonists continue to be prescribed usually for acid –peptic disease. Their safety record finally led to their availability as “Over the Counter” drugs. Histamine is a naturally-occurring chemical that stimulates cells in the stomach (parietal cells) to produce acid. H₂-blockers inhibit the action of histamine on the cells, thus reducing the production of acid by the stomach. Ranitidine hydrochloride is prescribed for conditions such as gastroesophageal reflux disease (GERD), ulcers, Zollinger-Ellison syndrome, erosive esophagitis, upper gastrointestinal bleeding, heartburn, and other conditions where reduction of gastric secretion and acid output is desirable.

 

INTRODUCTION:

Ranitidine was first prepared as AH19065 by John Bradshaw in the summer of 1977 in the Ware research laboratories of Allen and Hanburys Ltd, part of the Glaxo organization.¹ Ranitidine is in a group of drugs called histamine-2 blockers. H₂ receptor antagonists continue to be prescribed usually for acid –peptic disease². Their safety record finally led to their availability as “Over the Counter” drugs.³Chemically it is N[2-[[[5-[(dimethylamino)methyl] 2furanyl]methyl] thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following structure⁴:The empirical formula is C₁₃H₂₂N₄O₃S.HCl.

 

Figure 1. Structure of ranitidine hydrochloride.

 

Table 1: Important Descriptions: ^5-9

GERD (Acid Reflux, Heartburn)	A condition in which the acidified liquid contents of the stomach backs up in to the esophagus
Peptic Ulcer:	Is an ulcer in the lining of the stomach, duodenum, or esophagus. Ulcer formation is related to Helicobacter pylori bacteria in the stomach
Scleroderma:	Scleroderma is an autoimmune disease of the connective tissue. It is characterized by the formation of scar tissue (fibrosis) in the skin.
Hives:	Hives, also called urticaria, is a raised, itchy area of skin that is usually a sign of an allergic reaction. The allergy may be to food or medications,
Barrett's Esophagus:	Barrett's esophagus occurs as a complication of chronic gastroesophageal reflux disease.
Hiatal Hernia:	Hiatal hernia is a condition in which a thin membrane of tissue connects the esophagus with the diaphragm becomes week, and a portion of the stomach slides.
Esophagitis:	Esophagitis is caused by an infection or irritation of the esophagus. Infections that cause esophagitis include candida yeast infection of the esophagus
Heartburn (Acid Reflux):	Heartburn is a burning sensation experienced from acid reflux (GERD). Symptoms of heartburn include chest pain, burning in the throat, difficulty in swallowing,
Cyclic Vomiting Syndrome (CVS):	Cyclic vomiting syndrome is a condition in which affected individuals have severe nausea and vomiting that come in cycles. Researchers believe that cyclic

 

 

Drug Class and Mechanism: 

Ranitidine is an oral drug that blocks the production of acid by acid-producing cells in the stomach. It belongs to a class of drugs called H₂ (histamine-2) blockers that also includes cimetidine, nizatidine and famotidine.¹⁰

Histamine is a naturally-occurring chemical that stimulates cells in the stomach (parietal cells) to produce acid. H₂-blockers inhibit the action of histamine on the cells, thus reducing the production of acid by the stomach. Since excessive stomach acid can damage the esophagus, stomach, and duodenum and lead to inflammation and ulceration, reducing stomach acid prevents and heals acid-induced inflammation and ulcers. The FDA approved ranitidine in October 1984.¹¹

 

Figure 2. Secretion of HCl by gastric acid parietal cell and its regulation (Gastric Lumen)

 

Indications and Therapeutic Use:

Ranitidine hydrochloride is prescribed for conditions such as gastroesophageal reflux disease (GERD), ulcers, Zollinger-Ellison syndrome, erosive esophagitis, upper gastrointestinal bleeding, heartburn, and other conditions where reduction of gastric secretion and acid output is desirable⁹. These include the following:

1.    The treatment of nonsteroidal anti-inflammatory drug (NSAID)- induced lesions, both ulcers and erosions, and their gastrointestinal (GI) symptoms and the prevention of their recurrence;

2.    The prophylaxis of GI hemorrhage from stress ulceration in seriously ill patients;

3.    The prophylaxis of recurrent hemorrhage from bleeding ulcers;

4.    The prevention of Acid Aspiration Syndrome from general anaesthesia in patients considered to be at risk for this, including obstetrical patients in labour, and obese patients.

5.    In addition, ranitidine is indicated for the prophylaxis and maintenance treatment of duodenal or benign gastric ulcer in patients with a history of recurrent ulceration

 

Heartburn is often confused with symptoms of a heart attack. If patient is experiencing chest pain, pain spreading to the arm or shoulder, a heavy feeling in the chest, nausea, sweating, or any other signs of heart trouble then seek emergency medical care.¹²

 

Before taking ranitidine, patients should tell their doctor if they have or have ever had: Porphyria (a group of disorders that can cause nerve or skin problems), Phenylketonuria (a metabolic genetic disorder), Kidney disease, Liver disease. Patient should discuss to medical practitioners and laboratory personnel if they are taking ranitidine before having any lab work, as this medicine can impact the results of certain tests.¹³

 

Unless directed by doctor, patient shouldn't take OTC ranitidine for longer than two weeks. If patient is taking ranitidine for stomach ulcers, it might take up to eight weeks before an ulcer heals. So patients should keep using the medication as their doctor prescribes and patients should tell to doctor if their symptoms don't improve after six weeks.¹⁴

Table 2:FDA Pregnancy Categories

Category	Description
Category A	Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Example drugs or substances: levothyroxine, folic acid, magnesium sulfate, liothyronine.
Category B	Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.  Example drugs: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole.
Category C	Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.  Example drugs: tramadol, gabapentine, trazodone, and prednisone.
Category D	There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Example drug: Lisinopril, alprazolam, losartan, clonazepam, lorazepam.
Category X	Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Example drugs: atorvastatin, simvastatin, warfarin, methotrexate, finasteride
Category N	FDA has not classified the drug. Example drugs: aspirin, oxycodone, hydroxyzine, acetaminophen, diazepam.

 

Table 3 Dosage range of ranitidine:

Condition	Doses
GERD	150 milligrams (mg) twice daily or 300 mg at bedtime. The maintenance dose is usually 150 mg a day.
Gastrointestinal ulcers	150 milligrams (mg) twice daily or 300 mg at bedtime. The maintenance dose is usually 150 mg a day.
Heartburn	75 to 150 mg once daily or twice daily, taken 30 to 60 minutes before a meal or beverage that can cause heartburn
Erosive esophagitis	The typical dose is 150 mg, four times a day.
Zollinger-Ellison syndrome	The typical dose can be as high as 6 grams (g) a day.

 

FDA Pregnancy Categories:

The FDA has established five categories to indicate the potential of a drug to cause birth defects if used during pregnancy. The categories are determined by the reliability of documentation and the risk to benefit ratio. They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk. The pregnancy categories are:¹⁵ (Table-2).

 

Pregnancy and Ranitidine:

Ranitidine is an FDA Pregnancy Category B drug, which means it is not expected to harm an unborn baby. Patient should take opinion from doctor if they are pregnant or plan to become pregnant while taking this medicine. Don't breastfeed while taking ranitidine without first talking to your doctor. The drug can pass into breast milk.¹²

 

Ranitidine Side Effects:

Less serious (Common) Side Effects:

Constipation, diarrhea, nausea, vomiting, or stomach pain, Headache Insomnia Decreased sex drive or difficulty having an orgasm, Swollen or tender breasts.

 

Serious Side Effects:

Coughing up green or yellow mucus, Easy bruising or bleeding, Unusual weakness, Fast or slow heartbeat, Vision problems, Headache with a severe blistering, peeling, and red skin rash, Yellowing of the eyes or skin, Dark urine, Clay-colored stools, Loss of appetite.

 

 

Preparations: Tablets or Capsules: 25, 75, 150 and 300 mg; Syrup: 15 mg/ml; Injection: 1 mg/ml or 25 mg/ml.¹³ (Table-3).

 

Ranitidine Dosage:

Ranitidine comes as a tablet, syrup, effervescent tablet, and effervescent granules to take by mouth. It's usually taken once daily at bedtime or two to four times daily.

This medicine may be taken with or without food. Follow the directions on your prescription or package labeling carefully. Patient should dissolve the effervescent tablets and granules in a full glass of water before drinking. Measure the liquid form of ranitidine with a special dose-measuring spoon, not a kitchen spoon.

 

Ranitidine hydrochloride is sometimes used in addition to one or two antibiotics to treat gastrointestinal ulcers caused by H pylori bacteria. This is known as dual therapy when one antibiotic is used and triple therapy when two antibiotics are used. This combination of medicines kills the bacteria and prevents ulcers from recurring. Patients should not share medicine with other people. It may not be suitable for them and may harm them. The pharmacy label on patient’s medicine tells how much medicine should take. It also tells patient how often he/she should take their medicine. This is the dose that patient and their prescriber have agreed. Patients should not change the dose of their medicine unless they are told to do so by their prescriber. If they feel that the medicine is making them unwell or they do not think it is working, then they should talk to their prescriber.^16,17

 

Figure 3. Drug interaction classifications

 

Ranitidine Overdose:

If patients suspect an overdose, contact a poison control center or emergency room immediately.

 

Missed Dose of Ranitidine:

If patient miss a dose of ranitidine, take it as soon as remember. However, if it's almost time for your next dose, skip the missed dose and continue on your regular dosing schedule. Don't take extra doses to make up for a missed one.

 

Ranitidine Interactions: (Figure-3)

Ranitidine has the potential to affect the absorption, metabolism or renal excretion of other drugs. The altered pharmacokinetics may require dosage adjustment of the affected drug or discontinuation of treatment. Interactions occur by several mechanisms including:

 

1) Inhibition of cytochrome P450-linked mixed function oxygenase system: Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system such as diazepam, lidocaine, phenytoin, propranolol and theophylline. There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine.

 

2) Competition for renal tubular secretion: Since ranitidine is partially eliminated by the cationic system, it may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g such as those used in the treatment of Zollinger-Ellison syndrome) may reduce the excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs.

 

3) Alteration of gastric pH: The bioavailability of certain drugs may be affected. This can result in either an increase in absorption (e.g. triazolam, midazolam) or a decrease in absorption (e.g. ketoconazole, atazanavir, delaviridine, gefitnib). Sporadic cases of drug interactions have been reported in elderly patients involving both hypoglycaemic drugs and theophylline.

Special Populations In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired pneumonia.

 

Elderly patients may be at increased risk for confusional states and depression.^12,13

 

 

Table 3 Major interaction of ranitidine with other drugs: ^12-14,18-22

 

Table 4Disease interactions:^23-28

 

Tips for Patients to Avoid OTC Drug Interactions:

Patients should thoroughly read the labels of all over-the-counter and prescription medicines.

Patients should make sure that they know the benefits as well as the potential risks of both prescription and over-the-counter medications they are taking.

They should look specifically for the section called "Warnings" on the labels of over-the-counter medicines.

Patients should talk to their doctor or pharmacist before taking any new prescription or over the counter medication.

Patients should maintain a record containing the list of prescription or over the counter medications and share it with their doctors and their pharmacist.

Patients should use one pharmacy for all of their family's prescription and over-the-counter medication needs. By filling all prescriptions at one pharmacy, all the important information about (what and when the patients take) could be found in a central location. The pharmacist can help the patients by retrieving all the information about possible drug interactions from any OTC, prescription or herbal medications.

Learning about interactions with commonly used OTC remedies can also assure smart choices.

Talk to doctor or pharmacist if you have any medical conditions or take other medications. They can help explain what risks you may have and what precautions to take.

 

CONCLUSION:

Physicians should be aware of potential drug interactions with H₂ receptor antagonist medicines when prescribing new medications. Pharmacists can be instrumental in assisting patients with using H₂ receptor antagonists safely and effectively. To achieve maximum efficacy of a medication, drug-drug interactions, drug-disease interactions, and the timing of administration with respect to food should be examined thoroughly before co administration of multiple medications. Physicians and Pharmacists should make patients aware of the potential for toxicity and adverse drug interactions associated with the long-term and inappropriate use of ranitidine. They should advise Patients to use ranitidine not in higher-than-recommended doses or not in combinations that magnify the risk of adverse interactions. Pharmacists may provide educational materials to patients so that they may learn to recognize the generic names of medications. Pharmacists should warn consumers of the risks of misuse of medicines. Because many patients self-medicate with OTC medicines and are unaware of potentially dangerous drug interactions, proper counseling on the appropriate use of these agents can help minimize adverse effects and ensure positive clinical outcomes.

 

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Received on 28.09.2015          Modified on 15.10.2015

Accepted on 04.11.2015        © RJPT All right reserved