Antagonists and dose-response curves L3

Question 1

What is an antagonist and give example

Answer 1

An antagonist is a drug which blocks the response to an agonist.
e.g. terfenadine at the H1 receptor
Pure antagonists do not by themselves cause any action by binding to the receptor.

Question 2

what are the stages of antagonist process and give an example

Answer 2

1. binds to receptor forming antagonist-receptor complex
   - propranolol binds to B adrenoceptors
2. effect
   - decrease in blood pressure
   - blocks the natural activity of the receptor when it is bound with ligand

Question 3

what are the 3 classes of antagonists

Answer 3

1. chemical
   - binding of chelating agents to inactivate drug
   -protamine binds (sequesters) heparin
2. physiological
   - two agents with opposite effects cancel each other out
   - glucocorticoids and insulin
   3.pharmalogical
   -Binds to receptor and blocks the normal action of an agonist on receptor responses

Question 4

what kind of antagonists are chemical and physiological

Answer 4

nonreceptor antagonists

Question 5

what kind of antagonists is Pharmacological

Answer 5

receptor antagonist

Question 6

what are the two types of binding that pharmacological antagonists can do

Answer 6

1. active site binding
2. allosteric binding

Question 7

describe the two types of active binding

Answer 7

1. reversable
   - competitive antagonist
   - binds to active site and is overcome by increasing substrate concentration
2. irreversible
   - non competitive antagonist
   - Binds and forms irreversible covalent bonds with receptor

Question 8

describe the two types of allosteric binding

Answer 8

1. reversible
2. irreversible
   both non-competitive antagonists
   bind away from active site

Question 9

what effect do antagonists have on efficacy

Answer 9

results in no efficacy between receptor and agonist
the active agonist-receptor complex does not exist
AGONIST (A) + RECEPTOR (R) = AR COMPLEX = ACTION
ANTAGONIST (D) + RECEPTOR (R) = DR COMPLEX = NO ACTION

Question 10

what effect does competitive antagonist have on agonist-response curve

Answer 10

Causes parallel shift to right of the agonist-response curve
- same Emax value reached
- EC50 increased as more agonist needed to reach Emax
- Agonist curves have the same form

Question 11

what is the dose ratio

Answer 11

indicates the fold increase of the agonist needed to achieve the same response at a given concentration of antagonist.

Question 12

how is dose ratio calculated

Answer 12

agonist + antagonist EC50/ agonist EC50

Question 13

what is the Schild Plot

Answer 13

allows to quantify the potency of a competitive antagonist and to test whether the blockade of response by a molecule is consistent with simple competitive antagonism.
should have a gradient of 1

Question 14

what is schild equation

Answer 14

r -1 = [B]/ Kb
r = dose ratio
B = antagonist conc
Kb = antagonist dissociation constant

Question 15

what does the X intercept show on schild’s plot

Answer 15

shows log of Kb so allows us to quantify dissociation constant of antagonist

Question 16

what are pA2 values

Answer 16

Describes the activity of a receptor antagonist in simple numbers.
the negative logarithm of the molar concentration of antagonist required to produce an agonist dose ratio equal to 2
How much antagonist do you need to add to achieve 2x the amount of agonist to overcome it

Question 17

what is the pA2 equations

Answer 17

pA2 = - log Kb
Only if relationship is linear and slope of Schild plot = 1
i.e. only if a competitive antagonist.

Question 18

what does the extent of antagonist inhibition depend on

Answer 18

concentration of the competing agonist and antagonist’s concentration

Question 19

what effect do irreversible antagonists have on agonist-response curve

Answer 19

lowers Emax
Agonist curves do not have the same form
antagonist binds irreversibly with the receptor
gives rise to antagonism which cannot be overcome by an increased concentration of agonist
increases EC50
Curve shifts to right

Question 20

competitive antagonists are much more common than irreversible
give examples of both

Answer 20

competitive
- cimetidine at the H2 receptor
- tamoxifen at the oestrogen receptor
irreversible
- phenoxybenzamine at the a1 adrenoceptor

Question 21

what are the effects of non-competitive antagonists

Answer 21

as they dont bind to active site, they block signal transduction events therefore reduces maximal effect and increases EC50

Question 22

what is the therapeutic window

Answer 22

risk to benefit ratio (TI)

Question 23

how is therapeutic window calculated

Answer 23

(TI) = TD50/ED50 or LD50/ED50
Concentration needed to get half the therapeutic response compared to half unwanted affects

Question 24

give example of large and small TI

Answer 24

large is better as bigger window of benefit before toix
- penicillin
small: Warfarin