4 - Essentials of Drug Action Part 1

• • focuses on the action and effects of drugs within the body
  • concerned with what and how the drug can produce an effect

  Pharmacodynamics
• Terminologies used to define the pharmacodynamic properties of a drug include:

  1. receptor; 2) ligand; 3) drug activity; 4) affinity; 5) efficacy / intrinsic activity; and 6) potency
• macromolecular component of body tissues with which a drug interacts to initiate its pharmacologic effects


  Receptors
• muscarinic receptors on cells of the heart, smooth muscle, or exocrine glands


  Proteins
• acetylcholinesterase (AChE)


  Enzymes
• nucleic acids, ion channels tubulin

  Other cellular constituents
• Properties of receptors

  • saturability
  • specificity
  • reversibility
• a finite number of receptors are

  present in a cell

  saturability
• the binding of the drug with receptors is made possible by their complementary structures similar to a lock and key


  specificity
• the drug that binds to a recpetor can dissociate in its non-metabolized form

  reversibility
• any drug or substance with

  specific affinity to a receptor

  Ligand
• also known as efficacy, it is the property of the drug that permits it to initiate post-receptor processes, which lead to a response

  Intrinsic activity
• the tendency of the drug to combine with a particular kind of receptor

  affinity
• ligands (drugs) with both affinity and intrinsic

  activity (e.g epinephrine, acetylcholine)

  Agonists
• Produces full cell/tissue response

  Full agonists
• Provokes a response, but the maximum response is less than the maximum response of a full agonist, due to a higher affinity for the receptor but a lesser activity than a full agonist

  Partial agonist
• Drugs that bind to the receptor, suppressing the signaling activity (e.g propanolol and antihistamines)

  Inverse agonist
• Have affinity for receptor site but with no intrinsic activity, and block or reduce the effects of agonists


  Antagonists
• Antagonist effect is seen as a DEFICIENCY of the normal physiological effects of the blocked hormone, transmitter or substrate
• Reversible on removal, where the degree of antagonism depends on the quantity of the antagonist relative to the quantity of the agonist

  Competitive antagonist
• Irreversible, removes the receptor or response potential from the system, where the agonist has no influence upon the degree of antagonism or reversibility

  Noncompetitive antagonist
• Occurs on the same receptor protein such that two drugs, an agonist and an antagonist, compete and bind to the same receptor protein

  Competitive Antagonism
• Occurs as the result of activating receptors with opposite physiological effects

  Physiologic Antagonism
• • occurs as the result of a drug combining with two or more molecules via the formation of chemical bonds
  • often does not require animal tissue to be demonstrated, commonly used to treat heavy metal intoxication
  • e.g dimercaprol chelates Hg and As, penicillamine chelates Cu, Pb, and Hg


  Chemical Antagonism
• Ligand-gated ion channels (Type 1)

  • regulates flow of ions through the cellular plasma

  membrane channels

  • rapid response
  • e.g Ach at nicotinic receptors
• GTP-binding proteins (Type 2)

  • couple the binding of the ligand on the cell surface receptor to intracellular second messengers
  • catecholamines cause displacement of GDP from G protein and its replacement by GTP
• Kinase-linked receptors (Type 3)

  • signal transduction occurs through activation of an enzyme associated with the intracellular domain of a receptor
  • e.g tyrosine kinase
• Intracellularreceptors (Type 4)

  • activated receptor proteins form dimer and move to the promoter region of the DNA, altering transcription processes
  • e.g steroid hormones and thyroid hormones
• • refers to the dose of a drug that must be administered to produce a particular effect of a given intensity
  • influenced by affinity and by pharmacokinetic processes
  • not necessarily correlated with efficacy or safety

  Potency
• The most potent drug in a series is not necessarily clinically superior