II. Mechanism: Cellular Level

  1. Drugs act at receptors (Proteins or Glycoproteins) present on cell surfaces, organelles and in cytoplasm
    1. Drug response is related to a drug's affinity for receptor sites and the drugs efficacy
    2. Drugs must bind enough receptor sites to overcome a lower threshold to exert their effect
    3. Receptor sites are limited and there is a threshold at which no additional receptors are available for drug binding
      1. Drug response is proportional to number of receptors bound
      2. Not all receptors need to be bound for maximal effect
    4. Endogenous Ligands
      1. Endogenous chemicals that exert their physiologic cellular effects by binding receptor sites
  2. Drugs trigger various actions on binding to receptor sites
    1. Ion channel state change (open or closed)
    2. Second messenger activation (e.g. cAMP, Calcium, Inositol), triggering a cascade of further reactions
    3. Cell function is promoted or inhibited (e.g. specific Protein synthesis inhibition, increased specific DNA Transcription)
  3. Drug Affinity
    1. Affinity is the drug's binding strength to their receptor sites
    2. Drugs reach an equilibrium of receptor bound and unbound drug
      1. Higher affinity drugs have a higher ratio of receptor bound drug (more receptor bound drug than unbound drug)
      2. Lower affinity drugs have a lower ratio of receptor bound drug
    3. Dissociation Constant (Kd)
      1. Drug concentration (in moles) to reach 50% of receptor sites bound
      2. Kd reflects Drug Affinity, in that high affinity drugs will require lower drug concentrations (lower Kd)
  4. Agonists
    1. Agonist drugs bind cell receptors, triggering an effect on a cellular function
    2. Strong Agonists have maximal effects even at low concentration
    3. Weak Agonists require higher concentrations, and partial Agonists do not reach maximal activity even at 100% receptor binding
  5. Antagonists
    1. Antagonists block Agonist activity
    2. Competitive Antagonists
      1. Reversibly bind Agonist receptor sites, preventing Agonist binding
      2. Agonists, at higher concentration (higher Kd), may displace the Antagonists and reach target activity
      3. Examples: Naloxone at Opioid receptors, Flumazenil at Benzodiazepine receptors
    3. Noncompetitive Antagonists
      1. Bind other, non-Agonist receptor sites, modifying the Agonist receptor site so that it no longer recognizes the Agonist
      2. Agonists, reagardless of dose, can not overcome Noncompetitive Antagonist inhibition
      3. Example: Ketamine at NMDA-Glutamate receptor
    4. Irreversible Antagonists
      1. Permanently bind Agonist receptor sites, preventing future Agonist binding
      2. Agonists, reagardless of dose, can not overcome irreversible Antagonist inhibition (as with Noncompetitive Antagonists)
    5. Physiologic Antagonists
      1. Two different Agonists have opposing activity, each countering the other's function
    6. Neutralization
      1. Drugs that bind each other, inactivated both drugs

III. Mechanism: Individual and Population Effects

  1. Efficacy
    1. Maximal effect a drug is able to achieve
    2. Used to compare effect across Drug Classes (e.g. Analgesic effect of Ibuprofen or Acetaminophen versus Opioids)
    3. Drug effects may be plotted against dose (graded dose response curve) to identify an optimal drug dose
  2. Potency
    1. Drug dose required to achieve 50% of maximal effect
    2. Used to compare agents within a Drug Class (e.g. Morphine Equivalent)
  3. Toxicity and Safety
    1. Effective Concentration 50% (EC50)
      1. Drug concentration needed to reach target effect in 50% of a population reaching that drug level
    2. Lethal Dose 50% (LD50)
      1. Drug concentration high enough to kill 50% of a population reaching that drug level
    3. Therapeutic Index (LD50/ED50)
      1. Reflects drug safety in a ratio of lethal dose to therapeutic dose
    4. Margin of Safety
      1. Margin of safety reflects the margin between therapeutic doses and lethal doses

IV. Resources

V. References

  1. Olson (2020) Pharmacology, Medmaster, Miami, p. 1-12

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