Antagonists and dose-response curves Flashcards
What is an antagonist?
A drug that blocks the response to an agonist
Antagonist examples
Terfenadine at the H1 receptor.
What are pure antagonists?
Do not by themselves cause any action by binding to the receptor
General classes of antagonists
Chemical
Physiological
Pharmacological
Chemical antagonists
Binding of 2 agents to render active drug, inactive.
Commonly called chelating agents
Example of a chemical antagonist
Protamine binds (sequesters) heparin
Physiological antagonists
Two agents with opposite effects cancel each other out
Example of physiological antagonist
Glucocorticoids and insulin
Pharmacological antagonists
Binds to a receptor and blocks the normal action of the agonist on receptor responses.
Types of active binding site receptor antagonists
Reversible (Competitive antagonist)
Irreversible (Non-competitive active site antagonist)
Type of allosteric site receptor antagonists
Reversible and irreversible (Non-competitive antagonists)
Efficacy and antagonists
Pure antagonists do not by themselves cause any ‘action’ by binding to the receptor.
Antagonists (no efficacy) - AR* doesn’t exist.
Competitive pharmacological antagonism
Binds and prevents agonist action but can be overcome with increased agonist concentration
Causes parallel shift to the right of the agonist response curve.
The dose ratio
Agonist plus increasing concentrations of competitive antagonist
(Agonist + antagonist EC50 (x) / Agonist EC50 (y) )
Schild plot for competitive antagonists
r - 1 = [B] / Kb
r = Dose ratio
[B] = Antagonist concentration
Kb = Antagonism dissociation constant
What do pA2 values describe?
The activity of a receptor antagonist in simple numbers
pA2 =
- Log Kb
Irreversible (Non-competitive active site) pharmacological antagonism
Bind and forms irreversible covalent bonds with receptors.
Causes parallel shift to the right of the agonist-response curve and reduced maximal asymptote.
Partial agonist or irreversible antagonist?
An antagonism on its own will do nothing, has to have an agonist as well. Agonists will work on their own.
Non-competitive (allosteric site) pharmacological antagonism.
Signal transduction rather than receptor effects.
Downstream responses are blocked (EG Nifedipine blocks Ca2+ influx)
Reduces slope and maximum dose-response curve
Therapeutic window/index
Risk:benefit ratio
TD50 / ED50
or
LD50 / ED50