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Introduction of The Proton Pump inhibitors
Introduction of The Proton Pump inhibitors
Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitors of acid secretion available
Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitors of acid secretion available
Proton pump inhibitors (PPIs) block the gastric H,K-ATPase, inhibiting gastric acid secretion. This effect enables healing of peptic ulcers, gastroesophageal reflux disease (GERD), Barrett's esophagus, and Zollinger-Ellison syndrome, as well as the eradication of Helicobacter pylori as part of combination regimens
History of The Proton Pump inhibitors
History of The Proton Pump inhibitors
PPIs were developed in the 1980s, with omeprazole being launched in 1988. Most of these medications are benzimidazole derivatives, related to omeprazole, but imidazopyridine derivatives such as tenatoprazole have also been developed. Potassium-competitive inhibitors such as revaprazan reversibly block the potassium-binding site of the proton pump, acting more quickly, but are not available in most countries.
Medications
PPIs include lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), rabeprazole (AcipHex), and esomeprazole (Nexium). They are prescribed to both prevent and treat ulcers in the duodenum (where most ulcers develop) and the stomach
Mechanism of Action
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. The parietal cells contain the H+/K+ ATPase enzyme, the proton pump, that PPIs block. 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 P450 enzymes degrade PPIs. While there are slight variations in the exact P450 enzymes that are dominant in the degradation of the variety of PPIs, most dominantly degrade by the action of CYP2C19. 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.
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. The parietal cells contain the H+/K+ ATPase enzyme, the proton pump, that PPIs block. 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 P450 enzymes degrade PPIs. While there are slight variations in the exact P450 enzymes that are dominant in the degradation of the variety of PPIs, most dominantly degrade by the action of CYP2C19. 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.
Pharmacokinetics properties
Proton pump inhibitors (PPIs) are typically administered as enteric-coated delayed-release prodrugs, facilitating extensive absorption in the small intestine. While oral formulations undergo first-pass metabolism, they maintain high bioavailability. Intravenous administration of pantoprazole circumvents hepatic first-pass metabolism. Omeprazole and esomeprazole exhibit increased bioavailability during the initial days of therapy, attributed to reduced first-pass extraction, possibly due to rising gastric pH and self-metabolism inhibition. Despite their short elimination half-lives, PPIs' pharmacodynamic properties are primarily influenced by covalent binding to the H+,K+-ATPase enzyme, ensuring prolonged antisecretory action.
Proton pump inhibitors (PPIs) are typically administered as enteric-coated delayed-release prodrugs, facilitating extensive absorption in the small intestine. While oral formulations undergo first-pass metabolism, they maintain high bioavailability. Intravenous administration of pantoprazole circumvents hepatic first-pass metabolism. Omeprazole and esomeprazole exhibit increased bioavailability during the initial days of therapy, attributed to reduced first-pass extraction, possibly due to rising gastric pH and self-metabolism inhibition. Despite their short elimination half-lives, PPIs' pharmacodynamic properties are primarily influenced by covalent binding to the H+,K+-ATPase enzyme, ensuring prolonged antisecretory action.
Regarding metabolism, all PPIs undergo extensive hepatic metabolism, primarily mediated by cytochrome P450 (CYP) enzymes, notably CYP2C19 and CYP3A. Omeprazole is mainly metabolized by CYP2C19, while pantoprazole undergoes metabolism by both CYP2C19 and CYP3A, alongside sulfotransferase activity. Rabeprazole undergoes enzymatic metabolism by CYP2C19 and CYP3A, as well as nonenzymatic reduction to a thioether metabolite. Genetic polymorphisms in CYP2C19, prevalent in Asian populations, affect metabolizer status, with slow metabolizers exhibiting higher plasma concentrations and prolonged elimination half-lives. This variation influences therapeutic response, with poor CYP2C19 metabolizers often experiencing enhanced efficacy due to increased exposure of parietal cells to the drug.
Regarding metabolism, all PPIs undergo extensive hepatic metabolism, primarily mediated by cytochrome P450 (CYP) enzymes, notably CYP2C19 and CYP3A. Omeprazole is mainly metabolized by CYP2C19, while pantoprazole undergoes metabolism by both CYP2C19 and CYP3A, alongside sulfotransferase activity. Rabeprazole undergoes enzymatic metabolism by CYP2C19 and CYP3A, as well as nonenzymatic reduction to a thioether metabolite. Genetic polymorphisms in CYP2C19, prevalent in Asian populations, affect metabolizer status, with slow metabolizers exhibiting higher plasma concentrations and prolonged elimination half-lives. This variation influences therapeutic response, with poor CYP2C19 metabolizers often experiencing enhanced efficacy due to increased exposure of parietal cells to the drug.
Furthermore, PPIs undergo stereoselective metabolism, exemplified by differences in clearance between the R- and S-enantiomers of omeprazole and esomeprazole. Extensive metabolizers show a significantly higher area under the curve (AUC) for esomeprazole compared to omeprazole, while poor CYP2C19 metabolizers exhibit lower plasma concentrations of esomeprazole compared to omeprazole, resulting in less variability in plasma concentrations between extensive and poor metabolizers for esomeprazole compared to omeprazole.
Furthermore, PPIs undergo stereoselective metabolism, exemplified by differences in clearance between the R- and S-enantiomers of omeprazole and esomeprazole. Extensive metabolizers show a significantly higher area under the curve (AUC) for esomeprazole compared to omeprazole, while poor CYP2C19 metabolizers exhibit lower plasma concentrations of esomeprazole compared to omeprazole, resulting in less variability in plasma concentrations between extensive and poor metabolizers for esomeprazole compared to omeprazole.
Clinical uses
Proton pump inhibitors (PPIs) are widely used in clinical practice for various gastrointestinal conditions:
Proton pump inhibitors (PPIs) are widely used in clinical practice for various gastrointestinal conditions:
1. GERD: PPIs alleviate symptoms of gastroesophageal reflux disease (GERD) by reducing stomach acid production.
1. GERD: PPIs alleviate symptoms of gastroesophageal reflux disease (GERD) by reducing stomach acid production.
2. Peptic Ulcer Disease: PPIs heal and prevent recurrence of peptic ulcers by suppressing acid secretion and promoting ulcer healing.
2. Peptic Ulcer Disease: PPIs heal and prevent recurrence of peptic ulcers by suppressing acid secretion and promoting ulcer healing.
3. H. pylori Infection: PPIs are part of combination therapy to eradicate H. pylori bacteria, which cause peptic ulcers and gastritis.
3. H. pylori Infection: PPIs are part of combination therapy to eradicate H. pylori bacteria, which cause peptic ulcers and gastritis.
4. Zollinger-Ellison Syndrome: PPIs manage excessive gastric acid secretion caused by gastrin-secreting tumors.
4. Zollinger-Ellison Syndrome: PPIs manage excessive gastric acid secretion caused by gastrin-secreting tumors.
5. Stress Ulcer Prophylaxis: PPIs prevent stress-related mucosal damage and ulcers in critically ill patients.
5. Stress Ulcer Prophylaxis: PPIs prevent stress-related mucosal damage and ulcers in critically ill patients.
6. NSAID-Induced Ulcers: PPIs prevent ulcers and gastrointestinal bleeding associated with NSAID use.
6. NSAID-Induced Ulcers: PPIs prevent ulcers and gastrointestinal bleeding associated with NSAID use.
7. Barrett's Esophagus: PPIs reduce the risk of esophageal adenocarcinoma in patients with Barrett's esophagus
7. Barrett's Esophagus: PPIs reduce the risk of esophageal adenocarcinoma in patients with Barrett's esophagus
Dose
Route of administration
The formulations of PPIs are often specifically designed to prevent premature activation by gastric acid. The delivery methods include:
1- Enteric-coated tablets
2-Gelatin capsules
3-Coated granules as a suspension
4-In combination with bicarbonate to temporarily neutralize luminal gastric acid
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
DDI
What medications do PPIs interact with?
What medications do PPIs interact with?
PPIs are comparatively safe drugs with few drug interactions, but as PPIs are often used long-term and are the most commonly prescribed class of drug worldwide, these interactions need to be taken into account. Talk to your doctor before taking any other medicines or herbal remedies so they can determine whether the actions of these concomitant medications will affect the mechanism of the PPI or vice versa.
PPIs are comparatively safe drugs with few drug interactions, but as PPIs are often used long-term and are the most commonly prescribed class of drug worldwide, these interactions need to be taken into account. Talk to your doctor before taking any other medicines or herbal remedies so they can determine whether the actions of these concomitant medications will affect the mechanism of the PPI or vice versa.
Drug interactions with PPIs most commonly occur as a consequence of their effect on liver enzymes whereby they affect the metabolism and excretion of other medications. Drugs for which PPIs affect metabolism include:
Drug interactions with PPIs most commonly occur as a consequence of their effect on liver enzymes whereby they affect the metabolism and excretion of other medications. Drugs for which PPIs affect metabolism include:
Antiepileptics: Phenytoin;
Antiepileptics: Phenytoin;
Anticoagulants: Warfarin (e.g. Coumadin), clopidogrel (e.g. Plavix);
Anticoagulants: Warfarin (e.g. Coumadin), clopidogrel (e.g. Plavix);
Sedatives: Diazepam (e.g. Valium);
Sedatives: Diazepam (e.g. Valium);
Antibiotics: Clarithromycin, erythromycin;
Antibiotics: Clarithromycin, erythromycin;
Antidepressants: Clomipramine, imipramine (e.g. Tofranil).
Antidepressants: Clomipramine, imipramine (e.g. Tofranil).
PPIs interact with membrane transporter systems, which can affect the systemic distribution of other medications.
PPIs interact with membrane transporter systems, which can affect the systemic distribution of other medications.
Additionally, PPIs alter the acidity of gastric acids. Some medications require a specific acidity level (pH level) to be soluble, so a gastric pH which is too high or too low can affect how the drug is absorbed into the systemic circulation. PPIs may affect the solubility and absorption of:
Additionally, PPIs alter the acidity of gastric acids. Some medications require a specific acidity level (pH level) to be soluble, so a gastric pH which is too high or too low can affect how the drug is absorbed into the systemic circulation. PPIs may affect the solubility and absorption of:
Cyclosporin;
Cyclosporin;
Midazolam;Nifedipine;
Midazolam;Nifedipine;
Antifungals: Ketoconazole (e.g. Nizoral), itraconazole;
Antifungals: Ketoconazole (e.g. Nizoral), itraconazole;
Antiretrovirals: Indinavir.
Antiretrovirals: Indinavir.
The different PPIs have slightly different mechanisms of actions and therefore will interact differently with different drugs. Your doctor will review your medication needs and choose the PPI which has the less potential to interfere with your individual treatment regime. If there is no way to avoid cocommitant use with PPIs, then it is important to have regular reviews of your treatment regime to avoid any side effects that may occur.
The different PPIs have slightly different mechanisms of actions and therefore will interact differently with different drugs. Your doctor will review your medication needs and choose the PPI which has the less potential to interfere with your individual treatment regime. If there is no way to avoid cocommitant use with PPIs, then it is important to have regular reviews of your treatment regime to avoid any side effects that may occur.
PPI Drug Interactions
PPI Drug Interactions
Proton pump inhibitor drug interactions can happen with medicines ranging from aspirin to cancer drugs. People should be aware of how proton pump inhibitors interact with other drugs they take.
Proton pump inhibitor drug interactions can happen with medicines ranging from aspirin to cancer drugs. People should be aware of how proton pump inhibitors interact with other drugs they take.
PPIs alter the pH of the stomach. The pH is a measure of stomach acidity. An altered pH can change the way certain drugs work within the body. It can affect the way the body absorbs or filters them. It can also change the way the body activates certain drugs.
PPIs alter the pH of the stomach. The pH is a measure of stomach acidity. An altered pH can change the way certain drugs work within the body. It can affect the way the body absorbs or filters them. It can also change the way the body activates certain drugs.
Not all PPIs have the same drug interactions. Doctors may recommend a different PPI if a patient is taking certain other medicines. Sometimes, they may recommend a medicine other than proton pump inhibitors.
Not all PPIs have the same drug interactions. Doctors may recommend a different PPI if a patient is taking certain other medicines. Sometimes, they may recommend a medicine other than proton pump inhibitors.
DFI
Food and Drink Interactions with PPIs
Food and Drink Interactions with PPIs
Proton pump inhibitors have no serious interactions with food and drinks. But a person’s diet can affect the underlying condition PPIs treat. This means PPIs may have a harder time providing relief.
Proton pump inhibitors have no serious interactions with food and drinks. But a person’s diet can affect the underlying condition PPIs treat. This means PPIs may have a harder time providing relief.
People should avoid foods that can trigger acid reflux. This helps them receive the full healing benefit of PPIs.
People should avoid foods that can trigger acid reflux. This helps them receive the full healing benefit of PPIs.
Drug Interaction
Proton pump inhibitor drug interactions can happen with medicines ranging from aspirin to cancer drugs. People should be aware of how proton pump inhibitors interact with other drugs they take.
PPIs alter the pH of the stomach. The pH is a measure of stomach acidity. An altered pH can change the way certain drugs work within the body. It can affect the way the body absorbs or filters them. It can also change the way the body activates certain drugs.
Not all PPIs have the same drug interactions. Doctors may recommend a different PPI if a patient is taking certain other medicines. Sometimes, they may recommend a medicine other than proton pump inhibitors.
Side effects:
Side effects:
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