Medicinal Chemistry of GI Drugs - Patient Care 4
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Questions and Answers

What is the primary structure that mimics histamine in H2 antagonists?

  • Imidazole ring (correct)
  • Pyridine ring
  • Thiazole ring
  • Benzene ring

    • At physiologic pH, what percentage of histamine exists as the monocation?

  • > 85%
  • > 75%
  • > 50%
  • > 96% (correct)

    • What happens to the proportion of dication at lower pH levels?

  • It becomes the predominant species.
  • It increases significantly. (correct)
  • It remains constant.
  • It decreases significantly.

    • Which modification increases the potency of H2 antagonists?

    <p>Extending the linker</p> Signup and view all the answers

    What potential issue arises from Cimetidine's mechanism of action?

    <p>Increased risk of drug-drug interactions</p> Signup and view all the answers

    What element included in the four-atom side chain of H2 antagonists increases potency?

    <p>Sulfur</p> Signup and view all the answers

    Which of the following is a characteristic of competitive antagonists?

    <p>They structurally mimic the target ligand.</p> Signup and view all the answers

    What is the principal biological form of histamine considered to be active?

    <p>Monocation</p> Signup and view all the answers

    What is the main physiological function mediated by H2 receptors?

    <p>Secretion of gastric acid</p> Signup and view all the answers

    Which of the following substitutions is critical for the antagonistic efficacy of H2 antagonists?

    <p>Alkyl substitutions at the nitrogen</p> Signup and view all the answers

    What was a significant development in the 1970s related to H2 receptors?

    <p>Discovery of H2 receptors for the treatment of stomach ulcers</p> Signup and view all the answers

    Which mechanism does H3 receptor engage in related to histamine?

    <p>Provides negative feedback on histamine release</p> Signup and view all the answers

    Which feature is important for the mechanism of action of proton pump inhibitors?

    <p>Specific substitutions at the benzimidazole ring</p> Signup and view all the answers

    What does the concept of racemic switch in medicinal chemistry refer to?

    <p>Developing enantiomeric forms of drugs for enhanced efficacy</p> Signup and view all the answers

    What structural feature is shared among all histamine receptors?

    <p>Four 7-transmembrane domains</p> Signup and view all the answers

    Which of the following is an example of a drug not classified under the proton pump inhibitors?

    <p>Misoprostol</p> Signup and view all the answers

    What is one major difference between famotidine and cimetidine in terms of drug interaction?

    <p>Famotidine has minimal effect on cytochrome P450 systems.</p> Signup and view all the answers

    Which of the following is true about ranitidine compared to cimetidine?

    <p>Ranitidine has a higher potency than cimetidine.</p> Signup and view all the answers

    What is a primary reason for the poor bioavailability of famotidine?

    <p>It is poorly soluble in the low pH of the stomach.</p> Signup and view all the answers

    Why was ranitidine removed from the market in 2021?

    <p>It was linked to potential carcinogen contamination.</p> Signup and view all the answers

    What type of substitution does nizatidine have compared to ranitidine?

    <p>A thiazole ring.</p> Signup and view all the answers

    How much more potent is famotidine compared to cimetidine?

    <p>It is approximately 30 times more potent.</p> Signup and view all the answers

    What characteristic contributes to nizatidine's minimal risk of drug-drug interactions?

    <p>It has minimal CYP inhibition.</p> Signup and view all the answers

    What is the main functional group that differs between cimetidine and ranitidine?

    <p>Imidazole ring.</p> Signup and view all the answers

    Study Notes

    Medicinal Chemistry of Gastrointestinal (GI) Drugs

    • Topic: Medicinal Chemistry of Gastrointestinal (GI) Drugs
    • Speaker: Chengguo Xing, Ph.D.
    • Course: Patient Care 4

    Learning Objectives

    • Recognize the general structures of H2 antagonists (H2 blockers) and proton pump inhibitors (PPI)
    • Understand how substitutions affect the antagonistic (inhibitory) efficacy, potency, and selectivity of H2 antagonists
    • Know how substitutions affect the mechanism of action of proton pump inhibitors
    • Recognize how substitutions contribute to drug-drug interactions and methods to reduce this risk through medicinal chemistry modifications
    • Understand the principle behind the development of enantiomeric proton pump inhibitors (racemic switch)

    Overview of Lectures

    • H2 Receptor Antagonists:
      • Introduction of H1, H2, H3, and H4 receptors
      • Representative drugs for H2 receptors
      • Structural features and key pharmacophores
      • Side effects and drug interactions
      • Case studies
    • Proton Pump Inhibitors:
      • Introduction of proton pump
      • Representative drugs
      • Structure requirements and mechanism of action
      • Racemic switch and cases
      • Case studies
    • Other GI Drugs:
      • Misoprostol
      • Anti-acids

    H1, H2, H3, and H4 Receptors

    • Histamine receptors are highly conserved in vertebrates
    • Histamine is the endogenous ligand for these receptors
    • Histamine has structural similarity to histidine
    • Histamine receptors are 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R)
    • H1R antagonists are commonly used for allergy treatment and show sedative effects
    • H2R antagonists (e.g., cimetidine) are used for treating stomach ulcers
    • H3R negatively regulates histamine release, and H4R is involved in immune responses

    Histamine Chemistry

    • Histamine exists as tautomers (structural isomers that readily interconvert)
    • At physiological pH, histamine exists as a mixture of tautomeric cations, primarily monocation (>96%)
    • At lower pHs, a larger proportion of the dication exists
    • Protonated species are generally considered the biologically active form

    Structures of H1, H2, H3, and H4 Receptors

    • Diagrams of the receptor structures are presented

    Discovery of H2 Antagonists

    • H2 antagonists structurally mimic histamine (competitive antagonists)
    • Introduction of a methyl group at position 4 may result in a partial agonist
    • H2 antagonists display high selectivity for H2 receptors, suggesting that substituent modifications at position 4 might lead to highly selective H2 drug candidates

    Representative H2 Antagonists

    • Structural features:
      • Competitive antagonists
      • Modifications to the imidazole ring might lead to selectivity toward H2 receptors
      • Four-atom side chains (including sulfur) are associated with higher potency than those with carbon or oxygen atoms
      • Terminal polar non-basic unit (e.g., nitrogen-containing group) are associated with neutral (non-protonated) form at physiological pH Structural representations of histamine, cimetidine, ranitidine, famotidine, and nizatidine are displayed

    Cimetidine (Tagamet)

    • First H2 antagonist clinically used for GI issues
    • Retains the imidazole ring for histamine mimicry
    • Inhibits CYP450 metabolic processes, potentially causing drug interactions with other medications (e.g., phenytoin, benzodiazepines, quinidine)
    • Less commonly used currently due, potentially, to metabolic processes

    Famotidine (Pepcid)

    • Significantly more potent than cimetidine
    • Minimizes cytochrome P450 enzyme interactions
    • Reduced risk of drug-drug interactions compared to cimetidine
    • Lower bioavailability due to poor solubility in acidic stomach conditions

    Ranitidine

    • Replaces imidazole ring with a furan ring, improving tolerability
    • Ten times more potent than cimetidine
    • Some interaction with cytochrome P450, and it was removed from the market due to potential carcinogen contaminants.

    Nizatidine (Tazac or Axid)

    • Structurally similar to ranitidine but uses a thiazole ring instead of a furan ring
    • Minimal risk of CYP inhibition and drug-drug interactions

    Case Study Questions (Pages 17-22)

    • Case Study 1:
      • Identify part of famotidine molecule that makes it an H2 antagonist
      • Explain this from molecular structure
    • Case Study 2:
      • Identify in/on famotidine the part that increases its potency
    • Case Study 3:
      • Choose appropriate alternative for cimetidine (A or B) based on potential for drug interactions with diazepam, explaining the structural rationale for your choice.

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    Medicinal Chemistry of Gastrointestinal (GI) Drugs PDF

    Description

    Explore the medicinal chemistry behind gastrointestinal drugs, focusing on H2 antagonists and proton pump inhibitors. This quiz covers their structures, mechanisms of action, and impacts of substitutions on efficacy and interactions. Enhance your understanding essential for patient care.

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