H2 Blockers With PPIThere a minor drug interaction between H2 blockers and PPIs (proton pump inhibitors), but only in terms of their conflicting mechanisms of action. Due to how these medications work, using them at the same time could make them less effective (which is discussed below). However, using both together won't increase the risk of adverse effects.

There are certain situations where the combination of the two medications may provide extra benefit, but they need to be administered at appropriate times. We discuss this and more below.

PPI Use With H2 Blockers

H2 Blockers and PPIs are two distinct classes of medication that are used the treat excess stomach acid. Excess stomach acid is associated with a variety of conditions including heartburn, esophageal reflex disease (i.e. GERD) and stomach ulcers. Over the counter H2 blockers include:

  • Pepcid (famotidine)
  • Zantac (ranitidine)
  • Tagamet (cimetidine)

Over the counter and prescription PPI medications include:

  • Prilosec (omeprazole)
  • Nexium (esomeprazole)
  • Prevacid (lansoprazole)
  • Zegerid (omeprazole/sodium bicarbonate)
  • Protonix (pantoprazole)
  • Aciphex (rabeprazole)
  • Dexilant (dexlansoprazole)

H2 blockers, also known as "histamine 2 receptor blockers", work by blocking (i.e. antagonizing) the H2 receptor on gastric parietal cells (i.e. acid producing cells). When H2 blockers bind to the H2 receptor, parietal cells are inhibited from receiving signals (from histamine) that tell them to produce acid.

PPIs work at a later step in the acid production process. They inhibit the "proton pumps" located in parietal cells. More specifically, they inhibit the (H+,K+) ATPase enzyme system. Proton pumps are activated after parietal cells receive the signal from histamine. 

An interesting, and clinically important characteristic of PPI medication is that the acid producing cells (i.e. parietal cells) must be active in order for them to take effect and inhibit the proton pump. In other words, the parietal cells must be producing acid (e.g. in response to food consumption) for them to inactivate the proton pump.

Due to the mechanism of action of H2 blockers and PPIs, you should not take a H2 blocker before taking a PPI medication. As discussed above, the proton pumps in parietal cells need to be active in order for PPIs to work. Using a H2 blocker beforehand (which inhibits parietal cells from receiving signals to activate) will reduce or nearly eliminate the effect of PPI medication.

If you want to use both a H2 blocker and a PPI together, you ideally want to separate doses. It is important to allow enough time for the H2 blocker medicine to be metabolized out of the body, about 4 to 12 hours, depending on which medication is being used.

Having said all of the above, there are studies that show beneficial effects of using H2 blockers and PPIs together. One study found that utilizing a H2 blocker in the evening, in addition to taking a PPI medication earlier in the day, suppresses acid and improves symptoms of acid reflux more so than a PPI alone. 

If you are new to PPI therapy, know that it often takes 2 to 3 days of continuous use to notice an effect. In the first few days of PPI therapy, it may be helpful to add on a H2 blocker in the afternoon or evening until the PPI medication beings to take effect.


It is important to remember that if you do combine these two medications classes, they are not to be taken at the same time. This will greatly reduce the effect of the PPI medication. The most appropriate recommendation would be to take the PPI in the morning, about 60 minutes before food, and use a H2 blocker later in the day as needed. As always, be sure to speak with your doctor regarding the best course of action for your symptoms.