BS2013 Physiology and Pharmacology: Antagonists I Study Notes

BS2013: Physiology and Pharmacology: Topic 1

Lecture 1.4: Antagonists I

The Diversity of Antagonist Mechanisms

  • Date: 17 April 2020

  • Related topic: Decoy protein injection could potentially halt COVID-19.

  • Reference to medication: Warfarin 3 mg tablets, packaging contains 28 tablets by TARO.

Antagonists

  • Definition:

    • A drug that prevents the response of an agonist.

  • Importance:

    • The majority of clinically useful drugs are antagonists.

  • Classification of Antagonism:

    1. Chemical antagonism

    2. Pharmacokinetic antagonism

    3. Physiological (functional) antagonism

    4. Direct antagonism of signaling events

    5. Antagonism by receptor block

Chemical Antagonism

  • Description:

    • An antagonist combines with or chemically modifies an active drug, leading to a loss of the active drug's effects.

  • Examples:

    • Inactivation of toxic heavy metals through a chelating agent, such as dimercaprol, which is used to treat exposure to lead and mercury.

    • Formula:
      extheavymetal+extchelator→inactivated speciesext{heavy metal} + ext{chelator} \rightarrow \text{inactivated species}

    • Cytokines that cause inflammation or pain can be neutralized by injecting neutralizing antibodies.

    • Example: Infliximab targets TNF-α and is used in the treatment of Crohn’s disease.

Pharmacokinetic Antagonism

  • Description:

    • Involves a decrease in the effective concentration of a drug within the body.

  • Mechanisms of pharmacokinetic antagonism:

    1. Reduction in the amount of drug absorbed (such as decreased absorption from the gastrointestinal tract).

    2. Changes in the rate of renal excretion of a drug.

    3. Alterations in drug metabolism.

  • Clinical Example:

    • Care must be taken when treating patients on warfarin, which is an anticoagulant that inhibits vitamin K-dependent clotting factors.

    • Antibiotics may stimulate the metabolism of warfarin, leading to reduced effective concentration in the bloodstream.

Physiological (Functional) Antagonism

  • Description:

    • Refers to the interaction of two drugs that provoke opposing cellular or organ responses within the body.

  • Example:

    • Histamine causes contraction of smooth muscle in airways (H1 receptors), leading to bronchoconstriction.

    • Conversely, adrenaline causes relaxation of smooth muscles via β2 receptors, leading to bronchodilation.

  • Implications:

    • This concept describes opposing actions of two drugs acting through different transduction/receptor systems in the same cell or different cell types in one organ.

Antagonism of Signaling Events Downstream of Receptor

  • Description:

    • This type of antagonism blocks a specific step in the signaling pathway that occurs after the receptor is activated, without competing for the receptor site itself.

    • Term: Sometimes referred to as receptor:response linkage block.

  • Example:

    • Muscarinic contractions of the ileum can be inhibited by drugs that interfere with the muscle's ability to contract, such as metabolic inhibitors.

Antagonism by Receptor Block

  • Description:

    • This mechanism of action occurs at the receptor level, often involving competition with the agonist for receptor occupancy.

  • Properties of Competitive Receptor Antagonists:

    • A competitive receptor antagonist binds to the receptor, has no agonist activities (i.e., produces no response, defined as efficacy of 0), but reduces agonist receptor occupancy, inhibiting agonist-receptor responses.

Types of Competitive Receptor Antagonists

  1. Reversible Competitive (Surmountable) Antagonism:

    • The effects of the antagonist can be reversed or washed off.

  2. Irreversible Competitive (Insurmountable) Antagonism:

    • The antagonist dissociates from the receptor slowly or not at all.

    • In some cases, the antagonist may chemically bind to the receptor.

Graphical Representation of Antagonism

  • Reversible Competitive Antagonism:

    • As the concentration of the antagonist increases, a parallel rightward shift in the concentration-response curve is observed, with no change in maximum response.

    • Example: Effects of atropine on the response to acetylcholine for the guinea-pig ileum.

  • Irreversible Competitive Antagonism:

    • Characterized by a time-dependent effect that cannot be reversed by washing the tissue.

    • Example: The effects of the alkylating drug dibenamine (1 nM) on histamine responses in the guinea-pig ileum.

    • Graphical data representation includes:

    • Initial parallel shift indicating some degree of receptor reserve.

    • Measurement time points range from 5 to 20 minutes with various concentrations of histamine measured.

    • Response data shows varying maximum response percentages across different histamine concentrations (in molar units).

    ext0ext−20extminuteresponses:ext{0 ext{-}20 ext{ minute responses:}}

    • 5 mins

    • 10 mins

    • 15 mins

    • 20 mins

    extMeasurementscale:ext{Measurement scale:}

    • 0 ext{ to } 100 ext{ % max response; concentration range from } 10^{-9} ext{ to } 10^{-3} ext{ M}.

Conclusion

  • Understanding the various mechanisms of antagonists helps illustrate how drugs exert their effects and interact within the body, providing essential insights for clinical applications and therapeutic strategies.

  • Notable references:

    • Prof. Brindle's research regarding COVID-19 and decoy protein injections.