L3- Antagonists and dose-response curves

define a drug antagonist

a drug which blocks the response to an agonist

give an example of an antagonist

• terfenadine at the H1 receptor

• many clinical useful drugs

what do pure antagonists not do

by themselves cause any action by binding to a receptor

what are the functions of an antagonist

• antagonist

• receptor

• antagonist-receptor complex

• effect

what are the functions of propranolol as an antagonist

• propranolol

• beta-adrenoceptor

• propranolol-beta-adrenoceptor complex

• decreased blood pressure

what is the function of chemical antagonists

• binding of 2 agents to render active drug, inactive

• commonly called chelating agents

what is an example of chemical antagonists

• protamine binds (sequesters) heparin

what is the function of physiological antagonists

2 agents with opposite effects cancel each other out

what is an example of physiological antagonists

glucocorticoids and insulin

what is the function of pharmacological antagonists

binds to receptor and blocks the normal action of an agonist on receptor responses

what antagonist is a receptor which binds at an active site reversibly

competitive antagonist

what antagonist is a receptor which binds at an active site irreversibly

non-competitive active site antagonist

what antagonist is a receptor which binds at an allosteric site reversibly/irreversibly

non-competitive antagonist

what is an antagonist effect on AR*

antagonist (no efficacy) - AR* doesn’t exist

what are the functions of 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

what are the functions of irreversible (non-competitive active site) pharmacological antagonism

• binds and forms irreversible covalent bonds with receptor

• causes parallel shift to the right of the agonist-response curve and reduced maximal asymptote

what are the functions of non-competitive (allosteric site) pharmacological antagonism

• signal transduction rather than receptor effects

• downstream responses are blocked (e.g. Ca2+ influx)

• reduces slope and maximum of dose response curve

how do competitive antagonists influence the dose-response curve

• agonist curves have the same form

• agonist curves are displaced to the right

• agonist curves have the same maximal response

• the linear portion of the curves are parallel

how do you find the dose ratio

agonist + antagonist EC50 (x)/ agonist EC50 (y)

what is the Schild equation

r-1 = [B]/Kb

• r = dose ratio

• B = antagonist conc

• Kb = antagonist dissociation constant

what are pA2 values

the activity of a receptor antagonist in simple number

what is an equation to show the relationship between the pA2 values and log

pA2 = -log Kb

when does Schild plot equal 1

only if the relationship is linear (e.g. competitive antagonist)

what are the implications for the clinician -competitive antagonist

• the extent of antagonist inhibition depends upon the conc of the competing agonist and the antagonists conc

how do irreversible antagonists influence the dose-response curve

• agonist curves do not have the same form

• agonist curves have a reduced maximal response

how do irreversible antagonists influence EC50

• increase EC50

• duration of effect is related to receptor turnover

• receptor reserves allow parallel shift to the right

give examples of competitive antagonists

common type of antagonism

• cimetidine at the H2 receptor

• tamoxifen at the oestrogen receptor

give examples of irreversible antagonists

much less common type of antagonism

• phenoxybenzamine at the alpha 1 adrenoceptor

how does the non-competitive antagonist effect dose-response curves

• blocks signal transduction events

• reduces slope and maximal effect

give an example of non-competitive antagonism

nifedipine blocks Ca2+ influx

what is the therapeutic window/index (TI)

risk: benefit ratio (TI) = TD50/ED50 or LD50/ED50

give an example of a small TI

Warforin

give an example of a large TI

Penicillin