Treating GERD with PPIs
How Stomach Acid Is Produced
Acid is produced by cells in the stomach lining called parietal cells. Inside these cells, the actual production of acid is done by little chemical pumps known as proton pumps. These proton pumps do the work of producing hydrochloric acid. These proton pumps have two states – active (producing acid) and inactive (not producing acid). The pumps are activated when special sensors in the stomach detect that the pH of the stomach fluids have risen to a higher level (less acidic). The main way that this happens is when you eat a meal. They can also be activated by other means, which I will mention later.
Proton Pump Inhibitors
Proton Pump Inhibitors are potent blockers of production of stomach acid. They are truly remarkable medications and have provided hundreds of millions of people relief from heartburn and ulcers. PPIs have had a major impact in prevention of cancer of the stomach and esophagus.*
PPIs (proton pump inhibitors) are currently the safest and most effective drugs available for treating gastroesophageal reflux disease (GERD). They work by permanently bonding to and blocking the active proton pumps in the parietal cell, thus preventing them from producing any more acid. Eventually these blocked pumps are sloughed off and new pumps are produced, but while the majority of pumps are blocked, very little acid is produced in the stomach. It is important to remember that PPIs can only block those proton pumps that are in an active state, and any pumps that were not in an active state during the exposure to a PPI will still be able to produce acid later if they are activated.
Although you swallow the pill and it goes into your stomach, it does not work there. The PPI has to leave the stomach, go into the small intestine, be absorbed into the bloodstream, go to the liver, go back to the circulation, through the heart, the aorta, and back to the stomach. There it goes into the acid producing parietal cell where it can block the activated proton pump. A long winded route to help you with your heartburn.*
PPIs are what are known as pro-drugs, which means that when they are taken they are not in an active or working state – they require certain conditions to be activated, specifically they require a very highly acidic environment to be activated. This specific environment is only found right at the site of acid production in the parietal cell, so they do not get activated until they reach the parietal cell. After they are activated they are eliminated from the body very quickly. For these reasons, PPIs do not really affect any other area of the body or produce “side effects” and they are very safe, even in high doses.
Not only do Proton Pump Inhibitors not work in the stomach directly, they are inactivated and destroyed by acid. Drug manufacturers have made two delivery methods to bypass the intensely acidic stomach juices. Almost all the PPIs (all except Zegerid) are enteric coated and delayed release (DR) to be absorbed in the intestine and not released (and destroyed) in the stomach. This protects the drug but delays the effect. Also PPIs must be activated by food stimulating the parietal cell to make acid. Therefore to get the best effect of your medication, you should take it on an empty stomach half an hour to an hour before eating.*
The most recent research has shown that infants and young children metabolize PPIs at a rate 3 times faster than adults. As a result, larger and more frequent doses are usually required in order to achieve therapeutic results in infants and young children. TID (three times daily) is recommended dosing for any children under the age of 2.
There are two types of PPIs: DR (delayed release) PPIs and IR (immediate release) PPIs. Prevacid (capsules, Solutabs, powder packets), Prilosec (tablets and capsules), Nexium (tablets, capsules and packet), Aciphex (capsules) and Protonix (capsules) are all DR PPIs. Currently, Zegerid is the only FDA approved IR PPI on the market.
Zegerid (omeprazole-bicarbonate) has the same active ingredient as Prilosec (omeprazole DR) but should not be confused with Prilosec. I have heard from pharmacies that they could give Prilosec with bicarbonate in place of Zegerid. They ignored that Zegerid has immediate release omeprazole and Prilosec is delayed release. The bicarbonate does two things. It neutralizes the acid so that the omeprazole is not destroyed in the stomach. It turns on the parietal cells allowing an easy target for the Zegerid to stop the acid production. For this reason Zegerid is the fastest and longest acting of the PPI medications.*
H2RA drugs such as Zantac, Pepcid, Tagamet or Axid should not be administered within 4 hours of a PPI, as they will interfere with the PPI and make it less effective.
How Delayed Release PPIs Work
In their pure and unprotected form, PPIs are very vulnerable to degradation when exposed directly to the acid in the stomach. For this reason, DR PPIs are given an enteric coating. This protective coating is specifically designed not to dissolve while the drug is in the acidic fluids in the stomach, but instead it dissolves when the tablet or granules reach the higher pH (less acidic) environment of the duodenum (the first section of the small intestine). Here the coating dissolves and the drug is absorbed into the blood stream, where it is carried to the parietal cells, where it does its job of blocking proton pumps. This whole process takes 30 minutes to 1 hour.
DR PPIs should be given on an empty stomach (about 2 hours after finishing the last feeding) because food in the stomach can both lower the level of absorption and raise the pH in the stomach, causing the enteric coating on the drug to dissolve, which then leaves the drug vulnerable to exposure to pockets of acid in the stomach which could destroy the drug.
DR PPIs should be given 30 minutes to 1 hour before a full meal (2 oz or more for infants). As already mentioned, in order for PPIs to work their best you want as many proton pumps to be in an active state as possible, and the primary way of achieving this is by eating a full meal. The timing is important because you want the meal to be activating lots of proton pumps right at the same time that the drug is reaching peak levels in the blood stream.
Some DR PPIs, such as the beads inside of capsules, should be taken with a small amount of acidic food such as diluted apple or pear juice, or one of those in puree form.
You should never break or crumble a tablet form of DR PPI, as this will compromise the protective enteric coating. (Prevacid Solutabs contain enteric-coated granules within the tablet, and it is ok to break a Solutab in half, as this should not harm the individual granules.)
You should never give a DR with a non-acidic food (such as milk, formula or cereal), as this will dissolve the enteric coating and leave the drug unprotected.
DR PPIs should never be chewed or crushed, as this will compromise the protective enteric coating.
How Immediate Release PPIs Work
Rather than use an enteric coating to protect the drug from stomach acid, IR PPI Zegerid accompanies the PPI (omeprazole) with the necessary quantity of buffer (sodium bicarbonate) required to neutralize the acid that is present in the stomach, raising the pH to a level that is safe for the drug. This gives Zegerid several advantages over DR PPIs.
The drug can be absorbed directly and immediately into the blood stream, both in the stomach and in the duodenum, and start blocking proton pumps much more quickly.
The buffer provides immediate relief from the reflux, acting as an antacid and neutralizing the acid in the stomach and esophagus.
The buffer works even more effectively than a meal, turning on more proton pumps in the stomach, which are then blocked by the drug.
All of these things combine to make an immediate release PPI work much faster and more effectively than its enteric coated counterparts. Most doctors think that a compound is just a liquid PPI and that all forms of PPIs work the same way. Although it is true that the actual drug, the PPIs, are the same in their various forms, the way in which the drug is delivered makes a very big difference, both in speed of delivery and in effectiveness.
Dr. Jeffrey Phillips (PharmD) wrote: I did the original studies on Zegerid (which I had called SOS, for simplified omeprazole suspension). My original work was in critically ill adults who were in the ICU and had high risk of stomach bleeding from something known as “stress ulcers”. Anyway, needless to say, these patients are on the mechanical ventilator and have other risk factors for stress ulcer bleeding (e.g. head injury, burns, major surgery, and others). They have a tube (nasogastric) in their stomachs since they have no ability to swallow on their own. So, my initial goal was to make a liquid formulation of omeprazole (since the small granules in the capsule would cause the nasogastric tube to clog. Anyway, in the process of doing the research I found that the acid control was much faster and better (higher pH was obtained) with the SOS. So I worked on flavorings for SOS and started research in infants who had reflux. We found that once again the acid control was immediate and the pH obtained was higher than with the pellets (or granules) of omeprazole. This was then repeated in clinical trials in adults. Here is an excerpt from a recent review of Treatments for GERD. First a few abbreviations: drPPI = delayed release PPI (this is any form other than Zegerid) and irPPI = immediate release PPI (Zegerid). Recent developments in gastroesophageal reflux disease and Barrett’s esophagus. Author: Tytgat GN. Published 2012 Journal of Digestive Diseases 2012; 13; 291–295. All drPPIs have a relatively slow onset of pharmacological action and may require several doses to achieve maximum acid suppression. The time of dosing and ingestion of meals may also influence the pharmaco- kinetics of drPPIs. Moreover, they fail to provide full 24-h suppression of gastric acid production because they all allow nocturnal acid recovery, defined as a drop of intragastric pH under 4 for more than 1 h even with twice-daily dose. IR omeprazole consists of pure, non-enteric-coated omeprazole powder along with sodium bicarbonate. The antisecretory effect of IR omeprazole is quicker than that of drPPI. The rapid increase of intragastric pH is likely due to the neutralizing effect of sodium bicarbonate, which may also accelerate and enhance the absorption of omeprazole, whose increased bio-availability may translate in more profound acid sup- pression. The rapid rise of intragastric pH may also facilitate gastrin release, enhancing the activation of proton pumps available for inhibition. This new formulation provides sustained control of intragastric pH at steady state, and dosed at bedtime may be effective in improving the control of nocturnal pH and, therefore, useful in treating night-time acid reflux.
Since the buffer does the work of a meal in turning on the proton pumps and no enteric coating is involved, Zegerid can be given without regard to mealtime (in-between, before, during, or after meals). The dose can even mixed with a small amount of breastmilk, formula, or non-acidic solids, provided that the child can finish the dose in one sitting. (Zegerid should not be mixed with acidic foods such as applesauce, yogurt or juice)
The liquid form of Zegerid – Zegerid Powder for Oral Suspension – is a stable, true homogeneous liquid suspension, which is very easy to split up into exact individual doses and administer to infants and children.
Immediate release can be absorbed in the stomach, as well as duodenum, ileum, jejunum and large intestines. PPI medicines require that acid pumps (called proton pumps) be in the mode of trying to make acid. When they are in this mode (and only when they are in this mode) the pumps can be shut down. If the pumps are not “on” they cannot be turned off, kind of like lights in your house. (Try to turn off a light if it is already off – it doesn’t work). Anyway, in real life – food is the major stimulator of the acid pumps coming on. So for example throughout the day there is a meal or formula or milk stimulus from early in the day till later in the afternoon till around 6pm or so. Then typically, the feeding stops and hence the acid secretion goes way down (because the pumps are not “on”). So if you try to give a dose of PPI during this period evening thru to 5am there will be little effect. However, antacids are good stimulators of acid pumps coming on, especially sodium bicarb, calcium carbonate and magnesium hydroxide. Things are further complicated because the enteric coated PPIs are absorbed only when they get into the duodenum (which of course takes time) – this is why the enteric coated PPIs must be given 1/2 hr before feeding so that the drug (PPI) will be in the blood as the meal stimulates the pumps to come “on.” (Dr. Jeffrey Phillips, PharmD).
Some Important Notes About Zegerid:
There are currently two forms of Zegerid available: Zegerid capsules (20 mg and 40 mg) and Zegerid Powder for Oral Suspension (20 mg and 40 mg). When giving Zegerid to infants and children, we definitely recommend the use of Zegerid Powder for Oral Suspension (usually the 20 mg strength packets).[SEE LINK ^^ABOVE^^ FOR UP TO DATE INFORMATION ON THE PACKETS AND OTC]
When mixing Zegerid Powder for Oral Suspension for infants and children, we highly recommend that you mix it at a concentration of 2 milligrams per milliliter (2mg/mL) according to the instructions found here on infantreflux, rather than according to the package instructions, which are designed for adults and result in you having to give a much higher volume of liquid per dose.
A minimum amount of buffer is required per dose of Zegerid to neutralize the acid in the stomach and protect the drug from degradation. As a result, a minimum volume of Zegerid must be administered per dose in order to provide the minimum amount of buffer needed. When using the 20 mg packets of Zegerid, mixed at a concentration of 2 mg/mL, a minimum volume of 3.5 mL (7 mg) should be administered per dose. The 40 mg packets of Zegerid contain proportionally half the amount of buffer as the 20 mg packets, so when using the 40 mg packets, mixed at a concentration of 2 mg/mL, a minimum volume of 7 mL (14 mg) should be administered per dose.
After Zegerid is mixed at a concentration of 2 mg/mL, it will remain stable for up to 21 days in refrigeration or up to 24 hours at room temperature.
Zegerid contains omeprazole, a PPI that has been approved by the FDA for pediatric use. It is not a new drug, only a new and better formulation of a drug that has already been proven to be safe and effective, both for children and adults.
Zegerid contains no proteins or allergens of any kind.
A Word About Pharmacy Compounded PPIs
Most PPIs can be compounded extemporaneously by a pharmacy into a buffered liquid suspension, and many pediatricians prescribe and recommend such suspensions.
However the use of these suspensions is not recommend, as research has shown that the vast majority of such suspensions become unstable within a very short period of time (usually a week or less). This loss of stability is related to the use of flavorings and other agents in the suspension.
In addition, most pharmacies do not add enough buffer to their suspensions to adequately protect the drug from degradation by the stomach acid. This is particularly a problem if a child is receiving a very low dose.
How Long to See Results of the PPI?
You may find that you are told that PPIs can take up to two weeks for you to see their full effects. This is KIND OF right… PPIs do not take two weeks to be effective. It is a drug that has an effect in the body right away; when given correctly, the acid production is suppressed. A time-frame of 48 hours for the PPI to work efficiently is a reasonable amount of time. So, the PPI works right away, more or less, BUT it can take up to two full weeks in some infants, before we see improvement, and that depends on how irritated or inflamed the esophagus already is. For this period of time, it is a good idea to keep the H2 Blocker, too (such as: Zantac, Axid, Pepcid, Tagamet), making sure to space the doses of the H2 Blockers four hours apart from the PPI dose. Some infants suffer so much, that they need both medications even for a longer period of time. Once improvement is seen, then the H2 Blocker may be stopped. “PPI take two weeks to be effective” is a saying, which is popular in infantreflux.org/forum and the FB Group (Infant Reflux: Support for Gerdlings), is somewhat correct because some babies need that time to improve, but, generally speaking, it is NOT correct, since the drugs are effective right away. It also may take two weeks for a baby’s little system to get used to the new medication, but the PPI works, no matter what, if it is administered correctly of course.
“Proper Usage of Proton Pump Inhibitor | PPI.” Reflux Care of New York How Should I Take My Proton Pump Inhibitor PPI Comments. N.p., 08 Nov. 2012. Web. 10 Nov. 2015. <http://refluxny.com/ppi-treatment/>