Ranitidine - friend or cancerous foe
Updated: May 28, 2020
Ranitidine (or Zantac - one of its more popular trade names around the world) is a fairly commonly used drug in small animal internal medicine, particularly in gastroenterology (management of gastroesophageal reflux disease (GERD)). It even has its place as an adjunctive therapeutic in oncology cases (mast cells tumors; gastrinomas causing Zollinger-Ellison syndrome).
Currently, ranitidine is in the spotlight because of detection of an impurity called N-nitrosodimethylamine (or NDMA - not to be confused with NMDA (N-methyl-D-aspartate) receptors that are the target of drugs such as ketamine). I know, another mouthful to try swallow. Getting to the pointy end - NDMA is an environmental contaminant that has been found in water, meat, dairy products, and vegetables. It has been classified as a B2 carcinogen, which means it is considered a probable human carcinogen. Currently, exposure to high amounts of NDMA is though to cause gastric or colorectal cancer. In addition, it is known to be toxic to the liver.
That being said, the amount of NDMA present in products such as Zantac and the like, is considered to be comparable to how much a person would be exposed to if they for instance ate a piece of grilled or smoked meat. Interestingly, and perhaps some more food for thought, this compound or contaminant has also been identified in several blood pressure medications, including valsartan, losartan, and irbesartan [same drug class as that of telmisartan (Semintra), an angiotensin II receptor blocker (ARBs) - currently FDA approved for use in cats for the management of proteinuria and hypertension].
So what does this all mean when it comes to managing our patients - well, firstly let’s take a closer look at ranitidine and what it does. Ranitidine is a H2 histamine receptor antagonist (or blocker) (H2RAs). These H2 histamine receptors are found in the gastric parietal cells, along with other peripheral tissue sites (including vascular smooth muscle, heart, uterus, and of course mast cells, and neutrophils), and then also in the central nervous system. One major disadvantage of ranitidine, which particularly limits long-term use is the development of what is termed tachyphylaxis. This is defined as an acute, sudden decrease in response to a drug, in other words, a drug tolerance.
If we look at the recent ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats (Marks et al. 2018), the consensus reached by the panel regarding the use and/or effectiveness of H2RAs for the management of gastroduodenal ulceration or reflux esophagitis, is as follows:
“There is a lack of benefit for administration of H2RAs on a once-daily basis in dogs and cats to treat GUE and reflux esophagitis. Monotherapy with an H2RA given twice daily is inferior to PPI treatment given twice daily in dogs and cats. There is no evidence of benefit of administration of an H2RA with a PPI for ulcer healing, and this combination may diminish the effectiveness of the PPI.”
From the above it is clear that ranitidine, and/or other H2RAs should not be first-line choices in the management of gastroduodenal ulceration and/or reflux esophagitis.
It is important to note that, while contaminants such as NDMA have been identified as (probable) carcinogens in humans, the current knowledge on carcinogens in veterinary medicine is very limited. This to some degree probably stems from, or is in some way related, to the shorter life span of our patients when compared with human counterparts. As such, extrapolation of such risk/s to our patients may in fact not be accurate, however, it does seem prudent to not only acknowledge it but also limit all unnecessary exposure, at least until more is known on the topic.
So, in summary, if you are currently managing one of your patients with ranitidine or a client approaches you to discuss the topic (or even regarding treatment with telmisartan), explain to the owner the current limitations regarding our understanding of carcinogens in veterinary medicine, and the fact that in human medicine, the FDA is currently not advising that patients taking this medication discontinue it. A voluntary recall is underway.
However, taking into consideration that, based on expert opinion/consensus, H2RAs are not considered the optimal treatment for diseases such as gastroduodenal ulceration and/or reflux esophagitis, it seems prudent to switch patients currently being treated with H2RAs to the more effective proton-pump inhibitors such as omeprazole or esomeprazole, from a mechanistic and clinical point-of-view. Similar justification can be proposed when it comes to the management of oncology cases (mast cell tumors; gastrinomas).
Some useful links and further reading:
Marks SL, Kook PH, Papich MG, et al. (2018), ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats. J Vet Intern Med, 32:1823-1840. Available online: https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.15337