H2 Agonists and PPI's Flashcards
Causes of ulcers
Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs like aspirin, ibuprofen, and naproxen can irritate the lining of the stomach and small intestine, leading to ulcers.
Excessive alcohol consumption: Alcohol can irritate the lining of the stomach and increase the production of stomach acid, which can contribute to the development of ulcers.
Smoking: Smoking can increase the production of stomach acid and decrease the amount of protective mucus in the stomach, making it easier for ulcers to form.
Stress: While stress alone does not cause ulcers, it can worsen existing ulcers or delay the healing process.
Genetics: Some people may be more prone to developing ulcers due to genetic factors.
Other medical conditions: Certain medical conditions, such as Zollinger-Ellison syndrome or Crohn’s disease, can increase the risk of developing ulcers.
Parietal cells and sites of intervention
Parietal cells are specialized cells found in the lining of the stomach that produce hydrochloric acid (HCl) and intrinsic factor, which is important for the absorption of vitamin B12. The secretion of HCl by parietal cells plays a crucial role in the digestion of food and the destruction of potentially harmful microorganisms that may be ingested.
Proton pump inhibitors (PPIs): These drugs block the activity of the proton pump on the surface of the parietal cells, which is responsible for the final step in the production of stomach acid. By reducing the production of stomach acid, PPIs can help to treat conditions such as gastroesophageal reflux disease (GERD) and peptic ulcers.
H2 receptor blockers: These drugs block the activity of histamine receptors on the surface of the parietal cells, which reduces the amount of acid that is produced in the stomach. H2 receptor blockers are often used to treat conditions such as GERD and peptic ulcers.
Antacids: These are medications that neutralize the acid in the stomach, providing quick relief from symptoms such as heartburn. Antacids can be used in combination with PPIs or H2 receptor blockers for more effective treatment of GERD and other conditions.
Antibiotics: In cases where H. pylori infection is the cause of peptic ulcers, antibiotics may be used to eradicate the bacteria and promote healing of the ulcer.
explain the proton pump in hcl production
The proton pump, also known as H+/K+ ATPase, works by pumping positively charged hydrogen ions (protons) from inside the parietal cell into the stomach. At the same time, negatively charged chloride ions (Cl-) are transported from the blood into the parietal cell, where they combine with the protons to form HCl.
Antacids and their chemistry
They work by neutralizing the acid in the stomach, reducing the irritation and discomfort caused by excess stomach acid.
The active ingredients in antacids are typically bases, such as magnesium hydroxide, aluminum hydroxide, calcium carbonate, and sodium bicarbonate. These bases react with the hydrochloric acid in the stomach, forming a salt and water, which reduces the acidity of the stomach.
Histamines and their chemistry
Chemically, histamine is an amine, which means that it contains a nitrogen atom that is attached to two or three hydrogen atoms. The chemical formula for histamine is C5H9N3, and its systematic name is 2-(1H-imidazol-4-yl)ethylamine.
Histamine is synthesized from the amino acid histidine, which is converted into histamine by an enzyme called histidine decarboxylase. The reaction involves the removal of a carboxyl group (-COOH) from histidine, resulting in the formation of histamine.
The structure of histamine contains two nitrogen atoms: one in the imidazole ring and one in the amino group. The imidazole ring is responsible for the basicity of histamine, which allows it to act as a weak base and to form salts with acids.
Development of H2 agonists
The first H2 antagonist to be developed was cimetidine, which was introduced in 1976 by the pharmaceutical company GlaxoSmithKline. Cimetidine was followed by other H2 blockers, such as ranitidine, famotidine, and nizatidine, which were developed by other pharmaceutical companies.
The development of H2 antagonists was a significant breakthrough in the treatment of acid-related disorders. Before the introduction of these drugs, the main treatment options for these conditions were antacids and surgery. H2 antagonists provided a more effective and convenient treatment option that could be taken orally and had fewer side effects than surgery.
The development of H2 antagonists was based on a better understanding of the role of histamine in the regulation of gastric acid secretion. Histamine is released by certain cells in the stomach in response to various stimuli, such as food, and acts on parietal cells to stimulate the production of acid. H2 antagonists block the action of histamine on these cells, thus reducing acid production.
Development of PPI’s
The development of PPIs began in the 1970s when researchers discovered that proton pumps were responsible for acid production in the stomach. The first PPI, omeprazole, was developed by AstraZeneca and approved by the US Food and Drug Administration (FDA) in 1989.
Since then, several other PPIs have been developed and approved for clinical use, including lansoprazole, pantoprazole, rabeprazole, and esomeprazole. These drugs have similar mechanisms of action, but differ in their pharmacokinetic and pharmacodynamic properties.
The development of PPIs has significantly improved the treatment of acid-related disorders and has reduced the need for surgical interventions. However, long-term use of PPIs has been associated with several adverse effects, such as an increased risk of bone fractures, infections, and kidney disease. Therefore, it is important to use PPIs judiciously and under the guidance of a healthcare professional.
PPI mechanism of action
Proton pump inhibitors (PPIs) such as omeprazole work by irreversibly inhibiting the hydrogen/potassium ATPase pump in the parietal cells of the stomach. This pump is responsible for the final step in the production of gastric acid, which involves the transport of hydrogen ions (protons) from the cell into the stomach lumen in exchange for potassium ions. By inhibiting this pump, PPIs effectively reduce the amount of acid produced in the stomach.
The pKa of PPIs is important for their effective use in treatment because it determines the degree to which they can accumulate in the acidic environment of the parietal cells. PPIs are weak bases with a pKa of around 4, which means that they are predominantly ionized at physiological pH. However, in the highly acidic environment of the parietal cells (pH ~1-2), the PPIs become largely protonated and therefore more lipophilic. This allows them to diffuse across the cell membrane and accumulate in the acidic canaliculi where the proton pump is located, enabling them to effectively inhibit acid secretion.
