Information about Proton Pump Inhibitor
Proton pump inhibitors (or "PPI"s) are a group of drugs whose main action is pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar effects, but different mode-of-action, called H2-receptor antagonists. These drugs are among the most widely-selling drugs in the world as a result of their outstanding efficacy and safety. Structurally, the vast majority of these drugs are benzimidazole derivatives; however, promising new research indicates that imidazopyridine derivatives may be a more effective means of treatment.
Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%.
The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. However, lack of stomach acid may also contribute to hypochlorhydria, a lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for absorption of nutrients, particularly calcium.
The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.
The elimination half-life of proton pump inhibitors ranges from 0.5–2 hours, however the effect of a single dose on acid secretion usually persists up to 2–3 days. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition.
Clinically used proton pump inhibitors:
Common adverse effects include: headache, nausea, diarrhea, abdominal pain, fatigue, dizziness.[4]
Infrequent adverse effects include: rash, itch, flatulence, constipation. Decreased cyanocobalamin (vitamin B12) absorption may occur with long-term use.[4] Rarely PPI cause ‘idiosyncratic’ reactions such as erythema multiforme, pancreatitis, Stevens Johnson syndrome and acute interstitial nephritis. [6]
It has been observed that gastric acid suppression, using H2-receptor antagonists and proton pump inhibitors, is associated with an increased risk of community-acquired pneumonia. It is suspected that acid suppression results in insufficient elimination of pathogenic organisms. It has therefore been suggested that patients at higher risk of pneumonia should only be prescribed proton pump inhibitors at lower doses and only when necessary. [7]
PPIs have also been shown to raise risk of C. dif infection.[8]
Long-term use of proton pump inhibitors has been less studied. But in a study of 135,000 people 50 or older, those taking high doses of PPIs for longer than one year have been found to be 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 years were 1.2 to 1.6 times more likely to break a hip. The risk of a fracture increased with the length of time taking PPIs.[9] Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts.[10]
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Clinical use
These drugs are utilized in the treatment of many conditions such as:- dyspepsia
- peptic ulcer disease (PUD)
- Zollinger-Ellison syndrome
- gastroesophageal reflux disease (GORD/GERD)
- Barrett's esophagus
- prevention of stress gastritis
- gastrinomas and other conditions that cause hypersecretion of acid
- Laryngopharyngeal Reflux Disease
Mechanism of action
Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly just gastric proton pump) of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%.
The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. However, lack of stomach acid may also contribute to hypochlorhydria, a lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for absorption of nutrients, particularly calcium.
The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.
Pharmacokinetics
Generally, the absorption of proton pump inhibitors is unaffected by co-administration with food. The rate of omeprazole absorption, however, is decreased by concomitant food intake. Additionally, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. These pharmacokinetic effects, however, reportedly have no significant impact on efficacy.[2][3]The elimination half-life of proton pump inhibitors ranges from 0.5–2 hours, however the effect of a single dose on acid secretion usually persists up to 2–3 days. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition.
Examples of proton pump inhibitors
)
The proton pump inhibitor Omeprazole.
- Omeprazole (brand names: Losec®, Prilosec®, Zegerid®)
- Lansoprazole (brand names: Prevacid®, Zoton®, Inhibitol®)
- Esomeprazole (brand names: Nexium®)
- Pantoprazole (brand names: Protonix®, Somac®, Pantoloc®, Pantozol®, Zurcal®)
- Rabeprazole (brand names: Rabecid, Aciphex®, Pariet®)
Adverse effects
Proton pump inhibitors are generally well tolerated, and the incidence of short-term adverse effects is relatively uncommon. The range and occurrence of adverse effects are similar for all of the proton pump inhibitors, though they have been reported more frequently with omeprazole. This may be due to its longer availability and hence clinical experience.Common adverse effects include: headache, nausea, diarrhea, abdominal pain, fatigue, dizziness.[4]
Infrequent adverse effects include: rash, itch, flatulence, constipation. Decreased cyanocobalamin (vitamin B12) absorption may occur with long-term use.[4] Rarely PPI cause ‘idiosyncratic’ reactions such as erythema multiforme, pancreatitis, Stevens Johnson syndrome and acute interstitial nephritis. [6]
It has been observed that gastric acid suppression, using H2-receptor antagonists and proton pump inhibitors, is associated with an increased risk of community-acquired pneumonia. It is suspected that acid suppression results in insufficient elimination of pathogenic organisms. It has therefore been suggested that patients at higher risk of pneumonia should only be prescribed proton pump inhibitors at lower doses and only when necessary. [7]
PPIs have also been shown to raise risk of C. dif infection.[8]
Long-term use of proton pump inhibitors has been less studied. But in a study of 135,000 people 50 or older, those taking high doses of PPIs for longer than one year have been found to be 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 years were 1.2 to 1.6 times more likely to break a hip. The risk of a fracture increased with the length of time taking PPIs.[9] Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts.[10]
References
1. ^ Cooper BT, Chapman W, Neumann CS, Gearty JC (2006). "Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence". Aliment. Pharmacol. Ther. 23 (6): 727-33. DOI:10.1111/j.1365-2036.2006.02825.x. PMID 16556174. Retrieved on 2007-08-16.
2. ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
3. ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.
4. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
5. ^
6. ^ Simpson IJ et all. NEPHROLOGY 2006;11, 381–385)
7. ^ Laheij RJF, Sturkenboom MCJM, Hassing R-J, Dieleman J, Stricker BHC, Jansen JBMJ. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292(16): 1955-60. PMID 15507580
8. ^ Branswell, Helen (September 25 2006). McGill researchers say re-analysis confirms antacids raise risk of C. difficile. CBC News. Retrieved on January 15, 2007.
9. ^ Yang, YX; Lewis JD, Epstein S, Metz DC (Dec 27 2006). "Long-term proton pump inhibitor therapy and risk of hip fracture". Journal of the American Medical Association 296 (24): 2947-53. PMID 17190895. Retrieved on 2007-01-15.
10. ^ Seppa, Nathan (January 7 2007). "Bad to the Bone: Acid stoppers appear to have a downside". Science News 171 (1): 3. Retrieved on 2007-01-15.
2. ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
3. ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.
4. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
5. ^
6. ^ Simpson IJ et all. NEPHROLOGY 2006;11, 381–385)
7. ^ Laheij RJF, Sturkenboom MCJM, Hassing R-J, Dieleman J, Stricker BHC, Jansen JBMJ. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292(16): 1955-60. PMID 15507580
8. ^ Branswell, Helen (September 25 2006). McGill researchers say re-analysis confirms antacids raise risk of C. difficile. CBC News. Retrieved on January 15, 2007.
9. ^ Yang, YX; Lewis JD, Epstein S, Metz DC (Dec 27 2006). "Long-term proton pump inhibitor therapy and risk of hip fracture". Journal of the American Medical Association 296 (24): 2947-53. PMID 17190895. Retrieved on 2007-01-15.
10. ^ Seppa, Nathan (January 7 2007). "Bad to the Bone: Acid stoppers appear to have a downside". Science News 171 (1): 3. Retrieved on 2007-01-15.
Drugs for acid related disorders: Drugs for peptic ulcer and GERD/GORD (A02B) | |
|---|---|
| H₂-receptor antagonists | Cimetidine, Famotidine, Nizatidine, Ranitidine, Roxatidine |
| Prostaglandins/analogues | Misoprostol, Enprostil |
| Proton pump inhibitors | Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Tenatoprazole |
| Other | Carbenoxolone, Sucralfate, Pirenzepine |
A medication, medicine or drug is any substance or combination of substances administered to human beings or animals to treat or prevent disease; alternatively to assist in medical diagnosis.
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Gastric acid is one of the main secretions of the stomach, together with several enzymes and intrinsic factor. Chemically it is an acid solution consisting mainly of hydrochloric acid (HCl), and small quantities of potassium chloride (KCl) and sodium chloride (NaCl).
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Pharmacology is the study of how drugs interact with living organisms to produce a change in function.[1] If substances have medicinal properties, they are considered pharmaceuticals.
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MeSH C23.888.821.236 Dyspepsia (from the Greek "δυς-" (Dys-), meaning hard or difficult, and "πέψη" (Pepse), meaning digestion) is chronic or recurrent pain or discomfort centered in the upper abdomen [1]
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MeSH D010437
A peptic ulcer, also known as PUD or peptic ulcer disease[1] is an ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful.
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A peptic ulcer, also known as PUD or peptic ulcer disease[1] is an ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful.
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MeSH D015043 Zollinger-Ellison syndrome is a disorder where increased levels of the hormone gastrin are produced, causing the stomach to produce excess hydrochloric acid. Often, the cause is a tumor (gastrinoma) of the duodenum or pancreas producing the hormone gastrin.
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MeSH D005764 Gastroesophageal Reflux Disease (GERD; or GORD when spelling œsophageal, the BrE form) is defined as chronic symptoms or mucosal damage produced by the abnormal reflux in the esophagus[1].
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Barrett's esophagus
Classification & external resources
Endoscopic image of Barrett's esophagus, which is the area of red mucosa projecting like a tongue. Biopsies showed intestinal metaplasia.
ICD-10 K 22.7
ICD-9 530.
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Classification & external resources
Endoscopic image of Barrett's esophagus, which is the area of red mucosa projecting like a tongue. Biopsies showed intestinal metaplasia.
ICD-10 K 22.7
ICD-9 530.
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Gastritis
Classification & external resources
ICD-10 K 29.0 -K29.7
ICD-9 535.0 -535.5
Gastritis is inflammation of the gastric mucosa. The word comes from the Greek gastro- meaning of the stomach and -itis meaning inflammation.
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Classification & external resources
ICD-10 K 29.0 -K29.7
ICD-9 535.0 -535.5
Gastritis is inflammation of the gastric mucosa. The word comes from the Greek gastro- meaning of the stomach and -itis meaning inflammation.
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Gastrinoma
Classification & external resources
ICD-O: 8153
DiseasesDB 14279
eMedicine med/2678
MeSH D015408 A gastrinoma is a tumor that secretes gastrin.
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Classification & external resources
ICD-O: 8153
DiseasesDB 14279
eMedicine med/2678
MeSH D015408 A gastrinoma is a tumor that secretes gastrin.
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Laryngopharyngeal Reflux Disease (LPRD) is a reflux disease similar to Gastroesophageal reflux disease (GERD) but with some differences. Heartburn is not very common in patients diagnosed with LPRD.
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proton pump is an integral membrane protein that is capable of moving protons across the membrane of a cell, mitochondrion, or other subcellular compartment.
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Function
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1, −1
(amphoteric oxide)
Electronegativity 2.20 (Pauling scale) More
Atomic radius 25 pm
Atomic radius (calc.) 53 pm
Covalent radius 37 pm
Van der Waals radius 120 pm
Miscellaneous
Thermal conductivity (300 K) 180.
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(amphoteric oxide)
Electronegativity 2.20 (Pauling scale) More
Atomic radius 25 pm
Atomic radius (calc.) 53 pm
Covalent radius 37 pm
Van der Waals radius 120 pm
Miscellaneous
Thermal conductivity (300 K) 180.
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Potassium (IPA: /pə(ʊ)ˈtasiəm/, /pə'tæsiəm/) is a chemical element. It has the symbol K (Arabic: al qalja
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ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions
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Enzymes are proteins that catalyze (i.e. accelerate) chemical reactions.[1] In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products.
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Identifiers
Symbol ATP4B
Entrez 496
HUGO 820
OMIM 137217
RefSeq NM_000705
UniProt P51164
Other data
EC number 3.6.3.10
Locus Chr. 13 q34 Gastric hydrogen potassium ATPase is also known as H+/K+
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Symbol ATP4B
Entrez 496
HUGO 820
OMIM 137217
RefSeq NM_000705
UniProt P51164
Other data
EC number 3.6.3.10
Locus Chr. 13 q34 Gastric hydrogen potassium ATPase is also known as H+/K+
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proton pump is an integral membrane protein that is capable of moving protons across the membrane of a cell, mitochondrion, or other subcellular compartment.
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Function
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Parietal cells (also called oxyntic cells) are the stomach epithelium cells which secrete gastric acid and intrinsic factor.
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Acid production
Parietal cells produce gastric acid (hydrochloric acid) in response to histamine (via H2..... Click the link for more information.
In anatomy of the digestive system, the duodenum is a hollow jointed tube about 25-30 cm long connecting the stomach to the jejunum. It is the first and shortest part of the small intestine and it is where most chemical digestion takes place.
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Heartburn
Classifications and external resources
ICD-10 R 12.
ICD-9 787.1
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Classifications and external resources
ICD-10 R 12.
ICD-9 787.1
- This article is about the medical condition. For the film see Heartburn (film).
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MeSH D000126 Achlorhydria and hypochlorhydria refer to states where gastric acid levels are either absent or low in the stomach.
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Causes
- Autoimmune disorders where there is antibody production against parietal cells which normally produce gastric acid.
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hydrochloric acid is the aqueous (water-based) solution of hydrogen chloride gas (HCl). It is a strong acid, the major component of gastric acid and of wide industrial use. Hydrochloric acid must be handled with appropriate safety precautions because it is a highly corrosive liquid.
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Lipophilicity, fat-liking, refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene.[1] These non-polar solvents are themselves lipophilic — the axiom that like dissolves like
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Covalent bonding is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms, or between atoms and other covalent bonds.
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Pharmacokinetics (in Greek: "pharmacon" meaning drug and "kinetikos" meaning putting in motion, the study of time dependency) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism.
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Parietal cells (also called oxyntic cells) are the stomach epithelium cells which secrete gastric acid and intrinsic factor.
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Acid production
Parietal cells produce gastric acid (hydrochloric acid) in response to histamine (via H2..... Click the link for more information.
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