Ppi activation

Four class periods at the beginning of the fall course are devoted to a focused review of acid-base chemistry, functional group chemistry and drug receptor structure and common binding interactions. Another 3 lessons that provide an in-depth structure-based discussion of drug metabolism are covered before the chemical dissection and analysis of specific classes of therapeutic agents begin.

A practice-oriented approach that emphasizes the relevance of chemistry to the contemporary practice of pharmacy has long been a hallmark of the Chemical Basis courses.

However, the proton pump inhibitors are an exception to this usual topic layout as they are covered in the fall semester course as part of a 2-lesson series on anti-ulcer agents. This series also includes the relatively simple H2 antagonists, which are purposefully covered immediately after a discussion of the H1-antihistamines also a chemically straightforward lesson.

Nevertheless, proton pump inhibitor chemistry is the most mechanistically intricate of the compounds they have studied. The format of the Chemical Basis lessons prepared by the author has been previously described 1 and is briefly summarized here. Each topic is delivered to students as a conversational self-explanatory lesson handout organized to provide the following:. Students read these documents and the lesson handout prior to the class period in which the material will be formally presented and take an online open-book quiz on the key concepts and SAR discussed in the lesson handout.

Optional but strongly encouraged application exercises are made available to give students additional practice with the skills and abilities they will be expected to demonstrate on examinations. These optional exercises take the form of structure challenge exercises, study questions, problem worksheets, case studies, and practice examinations.

Faculty members encourage students to share their answers to these optional exercises with the faculty member so they can benefit from a one-on-one consultation on performance strengths and weaknesses.

The handout constructed for the proton pump inhibitors lesson is provided below. The handout is not referenced but students are made aware that lesson material comes from information found in widely utilized medicinal chemistry textbooks and from the scientific and clinical literature.

This pump is located in the canaliculus the acid-secreting network of the parietal cell and is stimulated to secrete acid by the cyclic adenosine monophosphate, produced through action of histamine on the Gs coupled H2 receptor. When H2 antagonists are administered, histamine is unable to stimulate the proton pump to release hydrochloric acid into the stomach. However, gastrin and ACh are still actively at work. In order to stop the secretion of all gastric acid, regardless of the original chemical stimulus, you must inhibit the pump itself because it is the very last step in the acid secretion process.

In addition to stopping acid stimulated by the mediators mentioned above, proton pump inhibitors PPIs also stop the basal secretion of gastric acid, making them very comprehensive and potent therapeutic agents in the treatment of gastroesophageal reflux disease GERD and gastric or duodenal ulcer.

While H2 antagonists might be sufficient in managing the symptoms of mild GERD, studies have shown superior esophageal healing with the use of PPIs, and they are the agents of choice in moderate-severe disease. Because PPIs stop gastrin-mediated acid secretion, gastrin secretion increases, leading to hypergastrinemia.

The excessively high gastrin levels can lead to hyperplasia of the histamine-containing ECL cells of the gastric fundus. Fortunately, progression of this hyperplasia to carcinoid tumors has not been noted in humans. The alpha subunit has 10 transmembrane- or membrane-inserted segments and contains a total of 28 cysteine CYS residues. Unlike H2 antagonist compounds that interact competitively and reversibly with the H2 receptor, PPIs form a covalent disulfide bond with the ATPase enzyme, leading to an irreversible inhibition of the pump.

Since the inactivation of the receptor site the ATPase in this case is irreversible and complete, the PPIs are very potent and long-acting therapeutic entities.

The ATPase is not able to recover from its irreversible interaction with the inhibitor structure the disulfide bond formed is non-reducible and the body must synthesize new enzyme de novo which takes time. Until new protein is made, gastric acid secretion is halted. The 5 PPI products currently on the market omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole all contain this basic structural framework and differ only in the nature of substituents placed on the pyridine and benzimidazole rings.

We will soon see that the electron donating or withdrawing nature of these substituents has a significant impact on chemical reactivity and onset of antisecretory action. The 2-pyridylmethylsulfinylbenzimidazole proton pump inhibitor pharmacophore with pKa 1 and pKa 2 sites identified.

The sulfinyl moiety found in the parent PPI structures is not sufficiently reactive to form the essential disulfide bond with the proton pump CYS residues and must first be activated through 2 protonations and a subsequent spontaneous rearrangement to form the active sulfenamide or sulfenic acid derivatives.

The need for activation means that the PPIs are inactive as administered. Let us take a closer look at these critical reactions in order to understand how the PPIs really work. Remember that the PPI activation pathway begins with 2 protonation reactions which occur readily in the highly acidic parietal cell.

Your knowledge of acid-base chemistry should tell you that only 2 of the PPI's 3 nitrogen atoms are capable of accepting proton: the pyridine nitrogen and the doubly bonded benzimidazole nitrogen N3. The pKa of the pyridine nitrogen referred to as the pKa1 runs between 3. These pKa1 values ensure that the pyridine nitrogen of all PPIs will be almost completely cationic at the low pH 1. Prove it to yourself with the Henderson-Hasselbalch equation!

Go on…. Even though there will be very little of the nucleophilic unionized pyridine conjugate available, it will be absolutely critical to the ability of the PPIs to irreversibly inhibit the proton pump.

More on that in a minute! Electron donating substituents on the pyridine ring especially at the R1 position will push electrons to the pyridine nitrogen and increase the percentage existing in cationic form at gastric pH. However and more importantly , this electronic enrichment will also increase the nucleophilic character of any PPI pyridine nitrogen atoms in the unionized conjugate base form. Electron withdrawing substituents would of course have the opposite effect.

The pKa value of the benzimidazole N3 designated as pKa2 is much lower than that of the pyridine nitrogen and ranges from 0. Lansoprazole and rabeprazole have identical pKa2 values of 0. These lower pKa values mean that the benzimidazole ring protonates after the pyridine ring and the extent of protonation will be significantly lower. None-the-less the higher the pKa2 value the more willingly the benzimidazole nitrogen accepts proton and becomes cationic.

Since this intramolecular nucleophilic attack generates the active form of the PPI, the rate at which it occurs will determine the rate at which the proton pump will be inactivated. Electron donating substituents on the C5 position of the benzimidazole ring will push electrons to N3 and increase the percentage existing in cationic form at gastric pH.

This in turn increases the electrophilic character of adjacent C2 due to negative induction loss of electron density from C2 to the cationic nitrogen. Only a few molecules of this essential monocation will be available at any given time. Eventually all or most of the PPI molecules will be activated and form disulfide bonds with the vulnerable proton pump CYS residues.

Now let us look at that all-important intramolecular nucleophilic attack. The lone pair of electrons of the unionized pyridine nitrogen attacks at the C2 of the benzimidazole ring, a position made highly electrophilic by protonation of the adjacent N3. When the pyridine attacks, a new bond is formed between the benzimidazole carbon and the pyridine nitrogen. When you make a new bond, you must break an old bond and the bond that breaks is the bond between the benzimidazole nitrogen and the sulfinyl sulfur atom.

Note that a new 5-member ring has formed. Note also that the benzimidazole is now partially reduced only 1 double bond remains. The spiro carbon is highly electron deficient because it is surrounded in all directions by strongly electron-withdrawing atoms or groups especially the cationic nitrogen atom and the sulfinyl. It is literally screaming for electrons. When this double bond forms, it forces the bond between the benzimidazole and the sulfinyl sulfur atom to break.

The oxygen atom of the sulfinyl group willingly takes the released proton, converting the sulfinyl to sulfenic acid R-S-OH. The sulfenic acid moiety can form a disulfide bond with the sulfhydryl SH group of proton pump CYS or CYS residues, releasing a molecule of water in the process. More commonly, however, the lone pair of electrons on the pyrrole-type nitrogen of the benzimidazole attacks the electron deficient sulfur atom of the sulfenic acid to generate a cyclic thiadiazine structure known as a sulfenamide.

Again, a molecule of water is lost in the process. The sulfenamide sulfur atom is electron deficient because of its proximity to so many electron-withdrawing nitrogen atoms. This electron-deficient sulfur is equally capable of forming a disulfide bond with the nucleophilic SH group on the critical proton pump CYS residues.

When it does, the thiadiazine ring breaks and the proton-pump adduct that forms is identical to that formed by the sulfenic acid product. Regardless of how it forms, the disulfide bond between the proton pump and the PPI is extremely stable and non-reducible. That means that the disulfide bond cannot break to regenerate the free SH group on the proton pump CYS residues.

The inhibition is therefore irreversible. It should be noted that the sulfur atom on both the sulfenamide and the sulfenic acid analog is perfectly positioned to accept the attacking CYS-SH because the molecule is being held in place by bonds formed between the PPI and the 2 anionic proton pump residues found at positions GLU and either GLU or ASP.

Brain Teaser: Since the site of action of PPIs is the gastric parietal cell, why are all PPI products marketed as enteric coated delayed release tablets or capsules? This Brain Teaser is a tough one, so I'm going to help you out. To reach this site intact the drug must be systemically absorbed and then distribute back into the stomach in its unionized form from the general circulation.

If the PPI structures encountered gastric acid in the stomach lumen immediately after oral administration, they would be activated too soon and would react non-selectively with CYS residues found on proteins in the stomach lining. However, when protected by enteric coating, the drug will not be released from the formulation until it reaches the intestine.

The higher pH of intestinal fluid 5. Did you really think I was going to let you get away without this important discussion? Proton pump inhibitors bind strongly to serum proteins and are extensively metabolized by the CYP family of enzymes. The 2C19 isoform is particularly important in converting parent structures to inactive metabolites, although CYP3A4 also plays a role in PPI biotransformation. Some agents, most notably omeprazole and its pure S isomer esomeprazole and are not only metabolized by CYP isoforms…they inhibit them, too.

This of course leads to the potential for significant drug-drug interactions. Fortunately, despite the hypothetical risk, few metabolism-based drug-drug interactions involving the PPIs are of clinical significance.

A significant fraction of the dose is biotransformed in the gut and via first-pass metabolism. In addition to the oxidative metabolites generated by CYP isoforms, the sulfinyl group can be non-enzymatically reduced to the sulfide also called a thioether.

Omeprazole, esomeprazole, pantoprazole, and lansoprazole undergo extensive CYP-mediated metabolism. While the metabolic pathway of enantiomerically pure esomeprazole mimics its racemate omeprazole, it has a lower dependency on CYP2Cmediated metabolism and a greater reliance on CYP3A4-catalyzed biotransformation.

Still, CYP2C19 is the major isoform involved in the metabolism of both omeprazole and esomeprazole although esomeprazole is metabolized at only one third the rate of the R isomer. In contrast, CYP plays a relatively minor role in rabeprazaole metabolism. This activity will highlight the mechanism of action, adverse event profile, and other key factors e. Objectives: Identify the mechanism of action of proton pump inhibitors. Describe the potential adverse effects of proton pump inhibitors.

Review the appropriate monitoring for patients on proton pump inhibitors. Outline interprofessional team strategies for improving care coordination and communication to advance proton pump inhibitor outcomes.

Access free multiple choice questions on this topic. Proton-pump inhibitors PPIs represent a class of drugs most prominently known for their use in acid-related disorders. Omeprazole, a drug belonging to this class, is among the top 10 most prescribed drugs in the United States. PPIs are derivatives of the heterocyclic organic molecule benzimidazole.

They are often the first-line agents amongst gastroenterologists for the following [1] :. PPIs also have utility in treating pediatric diseases.

Currently, these drugs are FDA approved to treat symptomatic GERD in the short term and for healing eosinophilic esophagitis in the pediatric population. As for non-FDA-approved uses, PPIs have been used as an add-on therapy for patients on antiplatelet therapy before or after endoscopic procedures with a high risk of bleeding sequelae, functional dyspepsia, and eosinophilic esophagitis.

Furthermore, new research is exploring the potential anti-tumor effects of PPIs in the treatment of melanomas, multiple myeloma, colorectal cancer, lymphomas, metastatic breast cancer, and other cancer pathologies. Ultimately, PPIs function to decrease acid secretion in the stomach. The proximal small bowel absorbs these drugs, and once in circulation, affect the parietal cells of the stomach.

This enzyme serves as the final step of acid secretion into the stomach. Interestingly, PPIs are prodrugs activated only after undergoing an acid-catalyzed cleavage in the acidic secretory canaliculi of the parietal cells. Hepatic P enzymes degrade PPIs. While there are slight variations in the exact P enzymes that are dominant in the degradation of the variety of PPIs, most dominantly degrade by the action of CYP2C Understanding the metabolism of PPIs allows us to understand why some PPIs work better for some individuals than others.

For example, those of Asian ethnicity tend to have increased bioavailability of PPIs and thus should be managed initially with lower dosages. Furthermore, as we age, the bioavailability of PPIs increases, and thus dosages in the elderly should also be closely monitored and adjusted accordingly.

While other drugs can reduce acid secretion in the stomach, PPIs represent the most potent drugs for acid reduction.

The formulations of PPIs are often specifically designed to prevent premature activation by gastric acid. The delivery methods include:. For immediate acid suppression, there are intravenous formulations for lansoprazole, pantoprazole, and esomeprazole. As proton pumps recycle periodically in the stomach, it may take a few days for PPIs to achieve a full effect - and of note, their duration of action is slower than some other medications that affect acid production, such as histamine-receptor blockers.

These medications are best administered before food intake as proton pumps become activated during meals, and administration of PPIs prior to food intake will enhance the drug's efficacy. For this reason, most practitioners recommend that the patient take the PPI first thing in the morning when taken once daily.

If twice-daily dosing is employed, then a second dose is usually added approximately 30 minutes before dinner. For some select patients with nighttime predominance of symptoms, the timing of once-daily administration may change to 30 minutes pre-dinner. As the usage of PPIs continues to rise, it becomes extremely important to understand the extent of their adverse effects.

As the use of these medications is common, potential adverse effects have received significant media attention; however, it is essential to note that most of these associations have as their basis on low-grade evidence and observational associations rather than clear causation. The following is a description of the variety of adverse effects described in the literature.

Albeit a rare side-effect, PPIs may lower magnesium to a level not easily replenished by supplementation and only corrected with removal of PPI.

Hypomagnesemia is a serious complication that predisposes the patient to tetany, seizure, muscle weakness, delirium, and cardiac arrhythmias.

While the acidic environment of the stomach serves as an environment in which proteins become activated to perform certain functions, so too does it serve as a chemical barrier against bacterial infection. PPIs have correlations with an increased amount of Clostridium difficile infections, other enteric foodborne infections, and potentially increased risk of community-acquired pneumonia.

While it is still unclear as to the exact mechanism for this increased infection risk, one hypothesis proposed that the decreased acidic environment of the stomach leads to bacterial overgrowth and increased risk of bacterial aspiration.

PPIs can increase the levels of gastrin, which in turn leads to increased proliferation of ECL cells. However, the problem lies in the discontinuation of PPIs after prolonged use, which has been shown in some cases to result in acid levels higher than before the initiation of PPIs. This effect has been referred to as rebound acid secretion. The relationship was linear.

Plasma level of the drug was not correlated with the inhibition or binding amounts except administration beginning time. Drug concentration in the blood abolished fast with the elimination half-life about minutes in rats, while the inhibition prolonged since the inhibition was achieved by covalent binding of activated omeprazole. This clearly shows that measuring the plasma level of the drug cannot reveal the inhibition of the drug. Then, the pump enzyme was isolated from each stomach.

Radioactive OMP bound to the enzyme was measured together with quantity of the enzyme. Maximum binding stoichiometry was 2. Several factors must be considered to understand the pharmacodynamics of PPIs: accumulation of PPI in the parietal cell, proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell and the stability of PPI binding.

If covalent binding of PPI to the enzyme is inert, only de novo biosynthesis was responsible for restoration of ATPase activity. The half-life of PPI binding will be same as the half-life of the pump enzyme. Half-life of the rat pump enzyme was about 54 hours 33 but restoration of the enzyme activity after PPI administration was about 15 hours of half-life. Activated PPI binding to the pump enzyme is achieved through the disulfide forming between the activated PPI and cysteines of the enzyme.

Disulfide bond is pretty weak on reductive cleavage. In the parietal cell, there are mM of glutathione, which can cleave the disulfide. If glutathione can access the disulfide of PPI bound enzyme, glutathione can cleave the PPI, resulting in restoration of the enzyme activity. Since omeprazole binds at Cys and Cys, different accessibility of glutathione to each cysteine may result in faster cleavage. Only Cys bound omeprazole is responsible for the inhibition, in other words, restoration of the enzyme activity depends on the cleavage of disulfide of PPI at Cys Different restoration of the pump enzyme activity was observed among PPIs.

Restoration of the pump activity was much slower in pantoprazole treated rats with biphasic mode. Incubation of the inhibited ATPase with glutathione resulted in a different rate of loss in the binding of omeprazole and pantoprazole.

These observations showed that removal of the drug's binding to Cys accounts for the fast phase of recovery of acid secretion, while the slow recovery occurs because of the delay in removal of the drug from Cys Thus the stability of PPI binding is one of the factors affecting the duration of the inhibitory activity. The PPIs are inactive in their native form and are rapidly metabolized by the liver.

Since PPI is an acid-activated prodrug, it is important to keep the PPI plasma level high until the gastric acid secretes. Maintaining high plasma level of the drug is significantly affected by the character of the metabolism. Metabolism of PPIs is dependent on the cytochrome P system. Omeprazole is a racemic mixture of 2 enantiomers, R-omeprazole and S-omeprazole. Each enantiomer showed different affinity to the CYP enzyme. Major metabolites of lansoprazole are 5-hydroxy lansoprazole and the sulfone.

Similar patterns of metabolism were observed in pantoprazole and rabeprazole. It is clear that the quantity of PPI bound to the enzyme is directly linked to the inhibition of gastric acid secretion. However, it is very difficult to measure the quantity of PPI binding in vivo, so we need another parameter substituting the quantity of PPI binding. As discussed above, the plasma level of the drug was not linear to the inhibitory activity.

It was, however, observed that the gastric antisecretory effect was related to the total dose and AUC, whereas the peak level or the shape of the curve was of minor importance. However, this relationship is only acceptable up to a certain level such as the ED50 level of dosage. Linear relationship between the inhibitory activity and AUC was not shown at higher dosage of the drug. Though the relationship between AUC and the inhibition was not linear at higher dosage of the drug due to the short half-life of the drug and the limited exposure of the enzyme to the drug, at least AUC showed the efficacy of the drug with good reliability.

Unlike the animal model, the measurement of inhibition of acid output in human is not easy, so measuring intragastric pH is used to present the inhibition due to drug activity. Actually, control of the intragastric pH is very important in healing acid-related diseases and eradicating Helicobacter pylori.

The duration time of intragastric pH over 3 is crucial for healing duodenal ulcers. Therefore, duration time of intragastric pH over 3 or 4 and mean or median intragastric pH become powerful tools in evaluating the drug's efficacy. Mean intragastric pH was shown to have some linearity with AUC, 44 however, the degree of acid suppression shown by intragastric pH profile would be the best in vivo parameter with which to compare the potency of PPIs.

Pharmacokinetic properties are summarized in Table. Pharmacokinetic Property of Proton Pump Inhibitors 49 , 62 - After the clinical efficacy of omeprazole 20 mg was well studied, other PPIs were compared to omeprazole. For example, lansoprazole 30 mg was compared to omeprazole 20 mg. One study showed slightly improved acid suppression by lansoprazole 30 mg 45 while another study showed no significant difference.

Generally speaking, omeprazole, lansoprazole, pantoprazole and rabeprazole have similar efficacy for healing the acid-related diseases. S-omeprazole has an advantage on metabolism as its plasma concentration is higher than that of omeprazole. AUC of S-omeprazole was much higher than that of omeprazole. Thus, S-omeprazole, named as esomeprazole, gave improved intragastric pH profile as expected.

Since esomeprazole was superior to other PPIs for acid suppression, better healing rates on acid-related diseases were achieved. Clinical studies demonstrated that esomeprazole 40 mg od for up to 8 weeks provided higher rates of healing of erosive GERD, along with a greater proportion of patients with sustained resolution of heartburn, than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od.

The metabolic advantage of esomeprazole increases the plasma concentration, resulting in higher AUC, however its short half-life minutes is still the key issue in drug efficacy.

There is no drug present at night. In order to keep reasonable plasma level of the drug, twice-daily dosing was designed and provided significantly greater acid suppression than once-daily dosing. Esomeprazole 40 mg bd has also been shown to be superior to pantoprazole 40 mg bd and lansoprazole 30 mg bd in maintaining intragastric pH at 4.

Twice-daily dosing of esomeprazole provides significantly greater acid suppression than once-daily dosing and may, therefore, be a reasonable consideration for patients requiring greater acid-suppression for GERD. Recently a novel formulation of the R-enantiomer of lansoprazole has been introduced.

This is a dual release formulation of 60 mg of PPI with normal enteric coating release at around pH 5. Dexlansoprazole delayed-release DR 60 mg gave better control of intragastric pH than esomeprazole 40 mg Fig. Mean gastric pH values for dexlansoprazole DR and esomeprazole were 4. Night time pH control was significantly improved with dexlansoprazole.

Comparison of dexlansoprazole modified-release MR and esomeprazole delayed-release DR. A Mean plasma concentration-time curves of dexlansoprazole and esomeprazole after single oral doses of dexlansoprazole MR 60 mg and esomeprazole 40 mg DR capsule in healthy subjects. B Mean intragastric pH from 0 to 24 hours postdose after single oral doses of dexlansoprazole MR 60 mg open square and esomeprazole 40 mg DR capsule closed circle.

Adapted from Kukulka et al. Rabeprazole extended-release ER 50 mg formulation was developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. One study shows that Rabeprazole ER groups provided mean durations of There have been some concerns about the safety of PPIs. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole.

Since PPIs were introduced, considerable progress has been achieved in the management of acid-related diseases. Metabolism of PPI was different among individuals. This difference was from the variation of CYP2C19 phenotype. Better control of the intragastric pH was achieved by this specific enantiomer. Though the shape of the plasma concentration curve or the peak level was of minor importance, AUC was relatively linear-fit with the antisecretory inhibition.

Good linearity was observed between the amounts of PPI binding and the inhibition. Measuring the intragastric pH and AUC is enough to judge the drug efficacy. DR or ER of the drug enabled the night time pH control due to prolonged time of effective plasma concentration.

In patients with GERD, standard doses of esomeprazole and dexlansoprazole maintain intragastric pH above 4 for significantly longer periods compared with standard doses of other PPIs after 5 days of treatment. Authors appreciate Dr.

George Sachs and Dr.