Drug Development: Ranitidine and H2 Antagonists
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Drug Development: Ranitidine and H2 Antagonists

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Questions and Answers

What was the main clinical issue that prompted the proposal of a new histamine receptor for drug development?

  • No antagonist for H3 receptors was available.
  • Existing H1 antagonists were ineffective against gastric acid secretion. (correct)
  • The H1 receptor was linked to increased blood pressure.
  • Peptic ulcers had multiple causative factors.

    • Which compound had the highest selectivity for H2 receptors based on the provided dissociation constants?

  • Histamine
  • Burimamide (correct)
  • Metiamide
  • None of the above

    • What was a significant issue with the compound Burimamide despite its selectivity?

  • It had a narrow therapeutic window.
  • It exhibited poor oral absorption. (correct)
  • It was too expensive to synthesize.
  • It caused severe allergic reactions.

    • What was the year when the program at SKF to develop antagonists of H2 receptors was established?

    <p>1964</p> Signup and view all the answers

    Which compound is associated with granulocytopenia according to the development information provided?

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

    What is the nature of specific binding in receptor-ligand interactions?

    <p>It is saturable and has an upper limit.</p> Signup and view all the answers

    Which statement correctly describes non-specific binding?

    <p>Non-specific binding always increases with higher ligand concentrations.</p> Signup and view all the answers

    What is the formula to estimate specific binding from total and non-specific binding?

    <p>Specific binding = total binding - non-specific binding.</p> Signup and view all the answers

    In competition binding analysis, which of the following factors is essential for determining affinity?

    <p>The relative affinities and concentration of both radioligand and unlabelled ligand.</p> Signup and view all the answers

    What characterizes the condition when receptors are referred to as ‘free’?

    <p>They are unbound and available for ligand interaction.</p> Signup and view all the answers

    What does KD represent in saturation binding analysis?

    <p>The concentration of radioligand required to achieve 50% specific binding.</p> Signup and view all the answers

    What is implied by the statement that all receptors are equally accessible to ligands?

    <p>There is no variation in receptor affinity across the population.</p> Signup and view all the answers

    What denotes the maximum specific binding condition in saturation analysis?

    <p>All receptors are occupied by ligands.</p> Signup and view all the answers

    What is bioavailability defined as?

    <p>The fraction of the administered dose that reaches systemic circulation as intact drug</p> Signup and view all the answers

    How is the percentage bioavailability calculated?

    <p>AUCoral / AUCIV x 100</p> Signup and view all the answers

    What percentage of bioavailability would be expected from an IV administration?

    <p>100%</p> Signup and view all the answers

    Which of the following statements about the extent of absorption is correct?

    <p>The extent of absorption affects the total therapeutic effect of a drug.</p> Signup and view all the answers

    Which method is used to determine the bioavailability of a drug?

    <p>Comparing plasma levels of a drug administered orally with levels after IV administration</p> Signup and view all the answers

    In respect to bioavailability, what does an F value of 25% signify?

    <p>Only 25% of the administered dose is available to exert effects.</p> Signup and view all the answers

    Why is understanding the concept of bioavailability important?

    <p>It influences the required dose based on the route of administration.</p> Signup and view all the answers

    Which type of drug administration has the highest bioavailability?

    <p>Intravenous administration</p> Signup and view all the answers

    What is the significance of the area under the curve (AUC) in pharmacokinetics?

    <p>It measures the total amount of drug that enters the body after administration.</p> Signup and view all the answers

    Which route of administration is noted for having the least reliability in absorption due to gastrointestinal factors?

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

    Which of the following routes of administration would most likely achieve rapid onset of action?

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

    For which route of administration would lipid solubility be a critical factor for effective absorption?

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

    How is the duration of action of a drug defined?

    <p>Length of time plasma levels remain at or above minimal effective concentration.</p> Signup and view all the answers

    Which route of administration offers a significant advantage of avoiding first pass metabolism?

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

    Which statement best describes the concept of maximum safe concentration (MSC)?

    <p>It is the highest concentration at which adverse reactions are minimized.</p> Signup and view all the answers

    Why might intramuscular injections be preferred for certain medications?

    <p>They allow for controlled release of medication.</p> Signup and view all the answers

    What primary consideration determines the route of administration for a drug?

    <p>The need for localized versus systemic effects.</p> Signup and view all the answers

    Which of the following is an example of a drug that can be administered via the inhalation route?

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

    What distinguishes a full agonist from a partial agonist at the receptor level?

    <p>Full agonists cause a complete biological response, whereas partial agonists induce a reduced signaling response.</p> Signup and view all the answers

    Which of the following statements best describes a partial agonist?

    <p>It causes a biological response but has an efficacy of less than 1.</p> Signup and view all the answers

    In what way do spare receptors influence the effect of a partial agonist?

    <p>They allow partial agonists to exert a maximal biological response despite not fully activating the receptor.</p> Signup and view all the answers

    Which of the following is NOT an example of a full agonist?

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

    What is the primary role of nicotinic partial agonists in nicotine replacement therapy?

    <p>They prompt greater receptor expression while inducing a mild signal.</p> Signup and view all the answers

    How is potency of a drug typically measured?

    <p>By the amount required to produce a specific response intensity.</p> Signup and view all the answers

    What can be inferred about a drug with an efficacy value of α=0?

    <p>It functions as an antagonist.</p> Signup and view all the answers

    Which factor primarily determines the signaling efficacy of an agonist?

    <p>The intrinsic activity associated with the agonist.</p> Signup and view all the answers

    What characterizes opioids in terms of receptor interaction?

    <p>Opioids can either be full agonists or partial agonists depending on their chemical structure.</p> Signup and view all the answers

    Study Notes

    Drug Development

    • Ranitidine, a drug used for treating peptic ulcers, is an example of successful chemistry-based drug development
    • The idea for this drug was proposed in 1948 as an antagonist for a newly recognized histamine receptor (H2).
    • This was important because existing histamine antagonists were only selective for the H1 receptor and did not effectively treat gastric acid secretion.

    Compound Development

    • In 1964, a research program was established to develop H2 receptor antagonists.
    • Scientists synthesized histamine analogues, testing for H2 selectivity.
    • Burimamide, a histamine analogue, showed high H2 selectivity but had poor oral absorption.
    • Metiamide, another histamine analogue, showed improved oral absorption but caused granulocytopenia (low white blood cell count).

    Routes of Administration

    • The route of administration of a drug is determined by various factors including the drug's physical characteristics, the speed of absorption and/or release, and the need to bypass hepatic metabolism.
    • Oral administration is convenient, but doesn't have a rapid onset of action or a localized effect; intravenous administration is a common approach when a rapid onset of action is required.
    • For localized effects, inhalation and transdermal routes are effective. Per rectal administration is used to bypass intestinal enzymes and low pH and is useful for individuals who are vomiting.

    Drug Plasma Concentration

    • The plasma concentration of a drug over time is important for understanding the kinetics of drug absorption, distribution, metabolism, and elimination.
    • After intravenous administration, the maximum plasma concentration (Cmax) is reached immediately after dosing.
    • With oral administration, Cmax is reached at a later time (tmax) and usually lower compared to IV administration.
    • The minimum effective concentration (MEC) refers to the minimum plasma level for a drug to exert its desired effect.
    • The maximum safe concentration (MSC) is the upper limit of the therapeutic window, where the concentration exceeds the risk of adverse effects.
    • The duration of action is the time period during which the plasma level is at or above the MEC.

    Area Under the Curve (AUC)

    • The area under the curve (AUC) provides a measure of the total amount of drug that enters the body after administration.
    • AUC is calculated from a plasma concentration–time curve with units of concentration × time (e.g., mg.hr L−1).
    • The AUC is typically higher following IV administration compared to oral administration of the same dose.

    Bioavailability

    • Bioavailability (F) is the fraction of the administered dose that reaches the systemic circulation as intact drug.
    • It determines the required dose for different routes of administration.
    • F is calculated as (AUCoral/AUCIV) x 100 and is expressed as a percentage.
    • F for IV administration is 100% and ranges from 0 to 100% for non-IV routes.

    Receptor-ligand Interactions

    • Receptor-ligand interactions are analogous to enzyme-substrate interactions, where drugs only act when bound to a specific target.
    • Many drugs bind to receptors.
    • Receptors are specific protein molecules on the surface of cells that bind to signaling molecules (ligands) to trigger cellular responses.

    Receptor Properties

    • Receptors are assumed to be saturable and reversible, meaning there is a limit to the number of ligands that can bind and they can detach from the receptor.
    • Receptors are either free or bound to a drug.
    • The binding of a ligand to a receptor is specific and can be measured using techniques like saturation binding analysis.
    • Saturation binding analysis can be used to determine the dissociation constant (Kd) and the maximum number of binding sites (Bmax).

    Competition Binding

    • Competition binding analysis is used to determine the relative affinity of different ligands for a receptor.
    • In this approach, a fixed concentration of labeled ligand is added to a receptor preparation, and the binding of the labeled ligand is then measured in the presence of varying concentrations of unlabeled ligand.
    • The concentration of unlabeled ligand required to reduce the binding of the labeled ligand by 50% is called the IC50.

    Drug Potency and Efficacy

    • Potency refers to the amount of drug required to produce a specific effect.
    • Efficacy refers to the maximal effect a drug can produce.
    • A partial agonist binds to a receptor and induces a reduced biological response compared to a full agonist, which induces a full biological response.

    Spare Receptors

    • Spare receptors refer to the presence of more receptors than needed to produce a maximum effect.
    • This means that even when some receptors are blocked, a full effect can still be achieved.

    Nicotine Replacement Therapy (NRT)

    • NRT involves using nicotine-based medications to reduce withdrawal symptoms and cravings associated with smoking cessation.
    • Partial nicotinic agonists, such as varenicline, are used in NRT.
    • Varenicline has a higher affinity for nicotinic receptors than nicotine, reducing the effects of nicotine from cigarette smoke.

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    Description

    Explore the journey of drug development with a focus on ranitidine, an effective H2 receptor antagonist. This quiz covers key milestones in the synthesis of H2 receptor antagonists and the importance of various routes of administration. Test your knowledge on the chemistry, efficacy, and safety of these pivotal drugs.

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