II. Mechanism: Cellular Level
- Drugs act at receptors (Proteins or Glycoproteins) present on cell surfaces, organelles and in cytoplasm
- Drug response is related to a drug's affinity for receptor sites and the drugs efficacy
- Drugs must bind enough receptor sites to overcome a lower threshold to exert their effect
- Receptor sites are limited and there is a threshold at which no additional receptors are available for drug binding
- Drug response is proportional to number of receptors bound
- Not all receptors need to be bound for maximal effect
- Endogenous Ligands
- Endogenous chemicals that exert their physiologic cellular effects by binding receptor sites
- Drugs trigger various actions on binding to receptor sites
- Ion channel state change (open or closed)
- Second messenger activation (e.g. cAMP, Calcium, Inositol), triggering a cascade of further reactions
- Cell function is promoted or inhibited (e.g. specific Protein synthesis inhibition, increased specific DNA Transcription)
- Drug Affinity
- Affinity is the drug's binding strength to their receptor sites
- Drugs reach an equilibrium of receptor bound and unbound drug
- Higher affinity drugs have a higher ratio of receptor bound drug (more receptor bound drug than unbound drug)
- Lower affinity drugs have a lower ratio of receptor bound drug
- Dissociation Constant (Kd)
- Drug concentration (in moles) to reach 50% of receptor sites bound
- Kd reflects Drug Affinity, in that high affinity drugs will require lower drug concentrations (lower Kd)
- Agonists
- Agonist drugs bind cell receptors, triggering an effect on a cellular function
- Strong Agonists have maximal effects even at low concentration
- Weak Agonists require higher concentrations, and partial Agonists do not reach maximal activity even at 100% receptor binding
- Antagonists
- Antagonists block Agonist activity
- Competitive Antagonists
- Reversibly bind Agonist receptor sites, preventing Agonist binding
- Agonists, at higher concentration (higher Kd), may displace the Antagonists and reach target activity
- Examples: Naloxone at Opioid receptors, Flumazenil at Benzodiazepine receptors
- Noncompetitive Antagonists
- Irreversible Antagonists
- Permanently bind Agonist receptor sites, preventing future Agonist binding
- Agonists, reagardless of dose, can not overcome irreversible Antagonist inhibition (as with Noncompetitive Antagonists)
- Physiologic Antagonists
- Two different Agonists have opposing activity, each countering the other's function
- Neutralization
- Drugs that bind each other, inactivated both drugs
III. Mechanism: Individual and Population Effects
- Efficacy
- Maximal effect a drug is able to achieve
- Used to compare effect across Drug Classes (e.g. Analgesic effect of Ibuprofen or Acetaminophen versus Opioids)
- Drug effects may be plotted against dose (graded dose response curve) to identify an optimal drug dose
- Potency
- Drug dose required to achieve 50% of maximal effect
- Used to compare agents within a Drug Class (e.g. Morphine Equivalent)
- Toxicity and Safety
- Effective Concentration 50% (EC50)
- Drug concentration needed to reach target effect in 50% of a population reaching that drug level
- Lethal Dose 50% (LD50)
- Drug concentration high enough to kill 50% of a population reaching that drug level
- Therapeutic Index (LD50/ED50)
- Reflects drug safety in a ratio of lethal dose to therapeutic dose
- Margin of Safety
- Margin of safety reflects the margin between therapeutic doses and lethal doses
- Effective Concentration 50% (EC50)
IV. Resources
- Receptor Agonist (Wikipedia)
- Receptor Antagonist (Wikipedia)
V. References
- Olson (2020) Pharmacology, Medmaster, Miami, p. 1-12