Pharmacology of Histamine H2 Antagonists

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Questions and Answers

Which of the following best describes the primary mechanism of action of histamine H2 receptor antagonists?

Enhancing the effect of gastrin and acetylcholine on HCl secretion.

Reversible competitive antagonists of H1 receptors.

Irreversible competitive agonists of H2 receptors.

Reversible competitive antagonists of histamine H2 receptors. (correct)

What is the effect of histamine H2 receptor antagonists on gastric acid secretion?

Cause a dose-dependent decrease in gastric acid secretion. (correct)

Decrease gastric acid secretion in a non-dose dependent manner.

Has a greater effect on food- or pentagastrin-evoked acid release than basal secretion.

Increase gastric acid secretion.

Which characteristic is a known limitation of histamine H2 receptor antagonists when compared to other acid-reducing medications?

They do not have any first-pass effect.

They undergo very significant first pass metabolism.

They are more effective than proton pump inhibitors.

They are not as effective as proton pump inhibitors. (correct)

What is a typical bioavailability range for cimetidine when administered orally?

60-70% (D) Signup and view all the answers

Which of the following best describes the elimination of histamine H2 receptor antagonist drugs and their metabolites?

Excreted primarily via urine. (C) Signup and view all the answers

How does renal failure typically affect the half-life of histamine H2 receptor antagonist drugs?

It prolongs the half-life. (C) Signup and view all the answers

Which of the following is true regarding cimetidine's effects on drug metabolism?

It is metabolized through CYP1A2, CYP2C9, CYP2D6 with a significant first pass effect. (C) Signup and view all the answers

What is the primary mechanism of action for sucralfate?

All of the above (D) Signup and view all the answers

Which of the following histamine H2 antagonists has the least likely to inhibit the metabolism of other concurrently administered drugs?

Famotidine. (C) Signup and view all the answers

Which of the following is NOT a potential side effect of sucralfate?

Increased gastric acid production (B) Signup and view all the answers

Under what condition should sucralfate be avoided?

Renal failure (A) Signup and view all the answers

Which of these H2 antagonists has a high bioavailability and the least first pass effect?

Nizatidine. (B) Signup and view all the answers

If a patient is taking warfarin and needs an H2 receptor antagonist, which one should be avoided?

Cimetidine (D) Signup and view all the answers

What is a significant drawback of quadruple therapy for Helicobacter pylori infection?

High risk of developing drug resistance (C) Signup and view all the answers

What drug class can interfere with the activity of sucralfate?

Antacids (A) Signup and view all the answers

Why is sucralfate rarely used for the treatment of peptic ulcer disease (PUD)?

Proton pump inhibitors (PPIs) are more effective (A) Signup and view all the answers

What is the primary mechanism of action of colloidal bismuth subcitrate?

Coating the gastric lining and providing a barrier against acid (C) Signup and view all the answers

What is a key similarity between sucralfate and colloidal bismuth subcitrate?

Both act as coating agents to protect the gastric lining (A) Signup and view all the answers

Which signaling molecule directly stimulates parietal cells to release gastric acid?

Acetylcholine (B) Signup and view all the answers

Which brain structure is NOT directly involved in the neural regulation of gastric acid secretion?

Cerebellum (A) Signup and view all the answers

What is the primary function of antacids related to gastric acid?

Directly neutralize gastric acid (C) Signup and view all the answers

Which neurotransmitter primarily modulates the enteric nervous system's activity in gastric acid regulation?

Acetylcholine (C) Signup and view all the answers

How does the anticipation of food affect gastric acid secretion?

It stimulates the release of acetylcholine, thereby increasing HCl release. (A) Signup and view all the answers

What is the role of PLC in the signaling cascade of gastric acid production?

Its role is to convert IP2 to IP3. (D) Signup and view all the answers

Which of the following signaling molecules inhibits gastric acid production?

Somatostatin (B) Signup and view all the answers

Which of the following is NOT a direct effect of acetylcholine in the release of HCl from parietal cells?

Directly stimulating the production of potassium competitive acid blockers (A) Signup and view all the answers

Which of the following brain areas is part of the brainstem and involved in the neural regulation of gastric acid release?

Nucleus tractus solitarius (NTS) (D) Signup and view all the answers

What is the clinical use of Potassium Competitive Acid Blockers?

Reduction of gastric acid production (A) Signup and view all the answers

Which of the following is NOT a common side effect associated with high doses of Cimetidine?

Increased sperm count (B) Signup and view all the answers

Which of the following histamine H2 receptor antagonists is LEAST likely to have antiandrogen effects?

Nizatidine (A), Ranitidine (B), Famotidine (D) Signup and view all the answers

Which of the following conditions is LEAST effectively treated with histamine H2 receptor antagonists?

Bleeding ulcers (B) Signup and view all the answers

Which of the following is the S-enantiomer form of omeprazole?

Esomeprazole (D) Signup and view all the answers

What is the primary mechanism by which proton pump inhibitors (PPIs) reduce gastric acid secretion?

Covalent binding to the H+-K+-ATPase (B) Signup and view all the answers

PPIs are considered prodrugs, which means that:

They require conversion into active metabolites by acid catalysis in the canaliculi (A) Signup and view all the answers

Why are PPIs considered to have a longer duration of action than their half-life would suggest?

Their covalent bond with the proton pump inactivates it until new pumps are synthesized (A) Signup and view all the answers

Where do proton pump inhibitors (PPIs) undergo the necessary conversion into active compounds?

In the canaliculi of parietal cells (B) Signup and view all the answers

What is the effect of fasting on the efficacy of PPIs?

Fasting increases the tissue levels of proton pumps (A) Signup and view all the answers

Compared to histamine H2 antagonists, how do Proton Pump Inhibitors differ in terms of onset of action and efficacy?

PPIs have a slower onset of action and greater efficacy. (A) Signup and view all the answers

What role does H.Pylori play in increasing HCl acid levels in the stomach?

It produces urease, which converts urea to ammonia and buffers HCl, leading to increased gastrin release. (C) Signup and view all the answers

What is the primary reason why monotherapy with antibiotics is often ineffective in treating H.Pylori?

Resistance to the antibiotic develops quickly. (A) Signup and view all the answers

Which of the following therapies is considered the most effective for eradicating H.Pylori?

Quadruple therapy including two antibiotics, a PPI, and Bismuth salts. (C) Signup and view all the answers

What is the effect of H.Pylori on somatostatin release from D cells?

H.Pylori inhibits somatostatin release, resulting in disinhibition of gastrin release. (B) Signup and view all the answers

Which of the following statements about H.Pylori infection is false?

Eradication is necessary if patients are taking NSAIDs. (C) Signup and view all the answers

What effect do Proton Pump Inhibitors (PPIs) have on the absorption of itraconazole?

They decrease absorption. (B) Signup and view all the answers

Which statement accurately describes the role of omeprazole in drug interactions?

Omeprazole inhibits CYP2C19. (C) Signup and view all the answers

What is one significant advantage of PPIs over histamine H2 blockers?

PPIs inhibit both nocturnal and meal-stimulated secretions more effectively. (D) Signup and view all the answers

Potassium-Competitive Acid Blockers (P-CABs) are characterized by which of the following?

They block the K+ exchange channel of the proton pump. (A) Signup and view all the answers

What is the initial action of P-CABs in relation to gastric acid secretion?

They immediately control acid secretion after the first dose. (B) Signup and view all the answers

Which condition is commonly associated with H.Pylori infection?

Inflammatory gastritis. (B) Signup and view all the answers

Which drug class provides better symptom relief in GERD compared to H2 blockers?

Proton Pump Inhibitors (PPIs). (C) Signup and view all the answers

What is the mechanism by which H.Pylori attaches to gastric epithelial cells?

By attaching to adhesion molecules on damaged cells. (B) Signup and view all the answers

Study Notes

Peptic Ulcer Therapy

Lecture Objectives:
- Understand the diverse signaling systems for gastric acid production.
- Explain the development of peptic ulcer disease (PUD).
- Detail the mechanism of action and pharmacological differences among antacids.
- Define histamine H2 blockers, their pharmacology, and use in PUD.
- Discuss proton pump inhibitors and potassium competitive acid blockers, and their use in PUD.
- Discuss H. pylori-evoked gastric acid production and its eradication for PUD prevention.
- Detail the pharmacology of cytoprotective agents related to gastric acid production in PUD.

Receptors & Signals for Gastric Acid Production

The presentation outlines the receptors and signaling pathways involved in gastric acid production.
Key players include G cells, ECL cells, parietal cells, and vagus nerve.
Various signaling pathways, like muscarinic, histamine, and gastrin, regulate gastric acid secretion.
Drugs targeting these pathways, like antacids or H2 blockers, are described.

Role of CNS in Gastric Acid Release

The Dorsal motor nucleus of the vagus (DMNV) in the brainstem is critical.
Vagal efferent nerves releases acetylcholine affecting parietal cells to enhance HCl release.
Sight, smell, taste, anticipate food trigger vagal nerve activity.

Antacids I

Antacids are weak bases, neutralizing gastric acid.
They are salts of Mg2+, Al3+, Ca2+, or bismuth.
Sodium bicarbonate (NaHCO3) is very water-soluble and rapidly absorbed but its action is short-lived.
Carbonates can lead to various side effects like belching, nausea, and diarrhoea.
Calcium carbonate (CaCO3) is less soluble and can rapidly neutralize gastric HCI.
It can cause hypercalcemia, milk-alkali syndrome, and acid rebound.

Antacids II

Aluminum hydroxide (Amphojel) is insoluble, with a slow onset of action.
Binds drugs like tetracyclines and phosphates, preventing their absorption.
It can cause constipation due to relaxation of gastric smooth muscle.
Magnesium hydroxide (Gelusil) is rapidly acting, but less absorbed than Sodium bicarbonate.
This compound increases GIT motility and catharsis—resulting in a laxative effect.
Al and Mg hydroxides (example: Maalox, Mylanta) can offset side effects like constipation/diarrhea.
Alginates are polysaccharides to increase mucus viscosity.
Simeticone relieves bloating and flatulence.

Antacids III

Antacids neutralize gastric HCI and bind bile salts.
They do not reduce HCl release, but can affect prostaglandin, mucus production, epithelial growth, lower esophageal sphincter pressure, and pepsin activity.
Their main use is for indigestion, reflux esophagitis, and gastric/duodenal ulcers.
Better drugs for PUD treatment are now available.

Antacids IV

Frequent dosing, bad taste, and poor compliance are disadvantages.
Al3+ and Ca2+ salts cause constipation, while Mg2+ salts cause diarrhoea.
Milk-alkali syndrome is a severe condition from excess intake of NaHCO3 or CaCO3 with milk, causing metabolic alkalosis and potentially life-threatening hypercalcaemia.
Acid rebound is a side eﬀect of some antacids.

Antacids V

Phosphate depletion and osteomalacia can result from aluminum salts.
Al compounds precipitate phosphates, potentially useful for renal failure but not for chronic use.
Hypernatremia and Mg toxicity are possible adverse effects, also with water retention, muscle weakness.
Drug interactions like the change in pH altering bioavailability.

Histamine H₂ Receptor Antagonists I

Cimetidine, famotidine, nizatidine, and ranitidine are competitive reversible antagonists of histamine H₂ receptors.
They aim to reduce gastric acid secretion.
They are frequently used in the treatment of PUD.

Histamine H₂ Receptor Antagonists II

The mechanism of action of histamine H₂ receptor antagonists involves competitively inhibiting histamine H₂ receptors.
This leads to decreased gastric acid secretion.
They are generally less effective than proton pump inhibitors.

Histamine H₂ Receptor Antagonists III

Effective absorption after oral intake, varying bioavailability among drugs.
Short half-lives (1-3.5 hours) and durations of action (5-12 hours).
Many H₂ blockers should be taken at night to minimize night-time acid rebound.
Limited metabolism with some drugs showing significant first-pass hepatic effects.

Histamine H₂ Receptor Antagonists IV

These drugs and their metabolites are excreted through the urine.
Half-lives may increase in some patients with renal impairment
This class of drugs can change acid production and pH to alter bioavailability of other drugs (e.g., aspirin, diazepam, warfarin, phenytoin).

Histamine H₂ Receptor Antagonists V

Overall, histamine H₂ receptor antagonists are well tolerated.
Potential CNS effects, endocrine effects (e.g., impotence, gynecomastia), gastrointestinal issues (e.g., diarrhea).
Some blood disorders including thrombocytopenia and vitamin B12 deficiency can occur in some instances

Proton Pump Inhibitors I

Omeprazole is the prototype, a racemic mixture of R- and S-isomers.
Esomeprazole is the S-isomer.
Lansoprazole is a racemic R and S mixture, has an R-enantiomer.
Pantoprazole, and Rabeprazole are also available.
Second-generation PPI include Rabeprazole, and Esomeprazole.

Proton Pump Inhibitors II

PPI are prodrugs that are activated into active metabolites.
Active metabolites bind to H+-K+ ATPase, which is the final step in HCl production.
This effectively inhibits acid secretion.

Proton Pump Inhibitors III

Rapid absorption, but variable depending on patient factors (e.g., fasting or presence of food).
Bioavailability varies based on formulation.
Dosage form and formulation are crucial as some need to be given before meals to prevent acid degradation.
Extensive metabolism by the liver and often rapid hepatic first-pass metabolism is common.

Proton Pump Inhibitors IV

Extensive metabolism in the liver, primarily by CYP2C19.
Important consideration: patients with genetic polymorphism of CYP2C19 may have decreased enzyme activity leading to differences in efficacy and toxicity.
Excretion mainly depends on hepatic metabolism followed by renal clearance. Renal failure patients may require lower levels of PPI.

Proton Pump Inhibitors V

Adverse effects are mostly gastrointestinal, possibly including nausea, diarrhea, and constipation.
Other potential effects include CNS issues, skin rash, liver enzyme impacts, and increased risk of interstitial nephritis.
Decreased vitamin B12 absorption is also mentioned as a chronic therapy concern.
Drug interactions are possible due to changes in gut pH.

Helicobacter Pylori Eradication I

H. Pylori is a gram-negative rod.
It lives in the acidic environment of the gastric lumen.
It often infects individuals with or without symptoms.
Eradication is necessary for some high-risk patients.

Helicobacter Pylori Eradication II

Monotherapy with antibiotics is usually ineffective and can create resistance quickly.
Combination therapy (at least two antibiotics) and acid suppression therapy is more effective.
Triple therapy (PPI+amoxicillin+clarithromycin) or quadruple therapy are common approaches.

Cytoprotective Agents I

Sucralfate is a coating agent that forms a viscous gel in the presence of acid, protecting the gastric mucosa.
It is activated by acidic environments.
It is used to treat PUD, with limited bioavailability.
Not often used, replaced by more effective options like PPIs.

Cytoprotective Agents II

Colloidal bismuth subcitrate (CBS) is a coating agent that protects the gastric mucosa through complex interaction with citric acid and bismuth.
It does not exhibit substantial antacid properties.
It is used to eradicate H. pylori.
Side effects include black stools, darkening tongue, nausea, and diarrhoea, potentially resulting in bismuth poisoning with prolonged use.

Cytoprotective Agents III

Misoprostol is a synthetic analog of PGE1 (prostaglandin).
It can inhibit gastric acid secretion by impacting adenylate cyclase processes and stimulating different receptor types (e.g. EP3), especially in parietal cells.
It is used to treat PUD and in situations of NSAID-induced ulcers and with pregnancy-associated issues
Side effects can include abdominal cramps, diarrhea, uterine contractions (pregnancy contraindication) and inflammatory bowel disease exacerbation. Misoprostol is often less preferable and has been mostly replaced by alternative treatments.

Practice Questions

Question 1: Pantoprazole is a proton pump inhibitor used in PUD treatment.
Question 2: Calcium carbonate is likely to cause acid rebound.

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Description

This quiz covers essential aspects of histamine H2 receptor antagonists, including their mechanism of action, effects on gastric acid secretion, and limitations compared to other acid-reducing medications. Additionally, it explores the pharmacokinetics of drugs like cimetidine and sucralfate. Test your knowledge on these crucial pharmaceutical topics!