Ci: To define and explain dose-effect relationships of drugs, including dose-response curves

Graded Dose Response Curves

  • As drug [ ] ↑=  pharmacologic affect ↑
  • Response is continuous & gradual, as opposed to quantal, which is all-or-nothing
  • ED50 = median effective dose → the dose of a drug that induces specific response in 50% population taking it
  • EC50 = median effective concentration → the [ ] of a drug that produces a specific response half way b/w baseline (zero) & maximal (100%) response
  • Potency = measure of quantity of drug needed in order to produce maximal effect e. if you need a large dose for maximal effect, drug is not v. potent
    • To compare potency, compare ED50 or EC50
  • Efficacy (intrinsic activity) = the ability of the drug to illicit a physiological response when it interacts with receptor
    • Maximal response = EMAX
  • At zero, drug [ ] = no response (0% max effect)
  • By ↑drug dose, % max effect ↑
  • Until we reach maximal effect at which no extra ↑dose will have effect (100%)
  • We use log [dose]
  • Because spreads out the low dose of the curve, where the most important things are happening
  • ∴magnifies the little dose where you expect to see $$$
  • Scale is SIGMOID
  • Steep part = linear
  • ED50 is a linear part of curve → makes assessment of dose-responses easier to see
  • But makes it difficult at top to compare maximal response b/w agonists/antagonists

Agonist = drug which binds receptor with high affinity & full intrinsic activity

    • Intrinsic activity = 1
    • Mimics response of endogenous ligand
    • Both NA & Phenylephrine = full agonists
    • NA is more potent
    • ∴NA has to have EC50 with less dose
    • Both must go to full potency (IA = 1.0)

Partial Agonist= drug with high receptor affinity but an intrinsic activity <1.0

  • Intrinsic activity b/w 0 and 1
  • Even when all receptors occupied, it will never give a response as great as the Full Agonist
  • Neither can hit 1.0 because partial agonist
  • Clonidine EC50 less ∴more potent
  • Methoxamine has to go further along x axis to show more effect
  • Partial agonists can act as Antagonists
  • If you were giving maximal dose Methadone & added Buprenorphine, Buprenorphine would be occupying some receptors but not giving the full 1.0 response that Methadone would
  • So partial agonists always fail to produce maximal effect even at v. high doses

Inverse Agonist= drug with high receptor affinity and intrinsic activity, but exerts an opposite effect to the endogenous agonist

    • Has extrinsic activity from baseline to – 1.0
    • In reverse direction of agonist i.e. beta-blocker

Antagonist

  • ∴when binds receptor → no effect mediated
  • Intrinsic activity = 0
  • IRREVERSIBLE
    • Binds receptor irreversibly
    • Effects cannot be overcome by ↑[agonist]
    • e. ASPIRIN
  • COMPETITIVE ANTAGONIST
    • Binds reversibly
    • Can be overcome by ↑[Agonist]
    • Efficacy unchanged
    • ↓potency because you need to give ↑dose of agonist for same effect
  • NON-COMPETITIVE ANTAGONIST
    • Binds at another site to receptor & ∆conformational shape so that agonist cannot bind
    • Effectively ↓no receptors
    • You can’t overcome by ↑[agonist]
    • Depresses efficacy → because for more effect you need all receptors available

Additive & Synergistic

  • Additive 1 + 1 = 2 (PPF + opioids)
  • Synergistic 1 + 1 > 2 (volatiles)