Agonists and dose response curves L2 Flashcards
what is the sequence of events that agonists cause and give example
- bind to receptor forming agonist-receptor complex
- salbutamol binds to B2 adrenoceptor - causes an action
- increases cAMP levels - causes an effect
- bronchodilation
what are dose-response curves used for
to determine correct dose
describe dose-response curves
Y: biological response
X: log of agonist concentration
-semi log as only one factor is in log
describe the two dose-response relationships
- graded
- response of a particular (individual) system
- measured against agonist concentration - quantal
- drug dose required to produce specific response determined in each member of population
- tend to look like bell curve
what does a dose-response curve tell us
- estimation of Emax
- estimation of concentration or dose required to produce 50% of maximal response (EC50 or ED50)
- Allow efficacy to be determined
- potency to be determined
what is Emax
maximum effect of agonist
what is EC/ED50
estimation of concentration or dose required to produce 50% of maximal response
what is efficacy
the size of the effect
- uses Emax to be determined
if there is a high Emax, what is efficacy like
high efficacy
what is potency
The drug which can produce an effect at lower drug concentrations is “more potent”
use EC50 to work out
if an agonist has lower EC50, what kind of potency does it have
high potency
what is affinity
the strength with which an agonist/drug binds to a receptor
in the formation of agonist receptor complex, what does K1 and K-1 represent
K1: association constant
K-1: dissociation constant
one agonist receptor complex is formed, it either dissociates or produced biological response
how is receptor saturation easily measured
Bmax
maximum number of binding sites
what is difficult to get a measure of in terms of receptor saturation
how avidly the drug binds – affinity (KD)
how can affinity be determined
K1/K-1
- rate of association/ rate of dissociation
what does a large value of K1 and a small value of K-1 mean
high affinity and low dissociation rate
what is Kd
equilibrium dissociation constant
what does equilibrium dissociation (Kd) show
The KD is a physiochemical constant like Avogadros number and is the same for a given receptor and drug combination in any tissue, in any species (as long as the receptor is the same).
can be used to determine
1. unknown receptor
2. quantitatively compare the affinity of different drugs on the same receptor.
Kd is EC50
Kd and affinity are inversely proportional
what does a low Kd suggest
high affinity
on a binding-dose curve there are two curves
- one to the right and one to the left
which curve has the highest affinity
the one to the left as it has lower Kd so less agonist needed to get EC50 as it dissociates less readily
which will have the higher potency
the one to the left
what are potent drugs
Potent drugs are those which elicit a response by binding to a critical number of receptors at low concentration (high affinity) compared with other drugs acting on the same system with lower affinity
high affinity at low concentrations
what 4 factors is potency dependant on
1.affinity of drug
2. efficacy of drug
3. receptor density
4. Efficiency of stimulus-response mechanisms used
how does EC50 relate to potency
lower EC50, higher potency
- lower concentration needed to achieve half of the maximum biological response
agonists which are potent tend to have high affinity
why may only a fraction of total receptors may be needed to be stimulated to get maximum response
Many receptors can amplify signal duration and intensity
Systems that exhibit this behaviour are said to have spare receptors
what is efficacy
ability of agonist to activate receptor and evoke an action
determined by the nature of the receptor-effector system
refers to the maximum effect an agonist can produce regardless of dose
what are the two types of agonists and what is their efficacy
- full agonist: high efficacy
- the maximum response produced corresponds to the maximum response that the tissue can give. - partial agonist: low efficacy
- maximal response which falls short of the maximal response that the system is capable of producing
what is the relationship between type of agonist, efficacy and forming active agonist-receptor complex
full agonist mean active complx is likely
- produce a maximum response while occupying only a small % of receptors available
parital agonist means active complex is less likely
- unable to produce a maximum response even when occupying all the available receptors
give 3 examples of partial agonists
- Varenicline
-Nicotine receptor partial agonist for smoking cessation. - Tamoxifen
- Estrogen receptor partial agonists for use in estrogen dependent breast cancer. - Aripiprazole
- Antipsychotic – partial agonists at selected dopamine receptors.
describe inverse agonists
Have higher affinity for the AR (inactive) state than for AR* (active) state of the agonist receptor complex
Many ‘classical’ competitive antagonists display inverse agonist activity
give an example of inverse agonists
β-carbolines on GABAA receptors – anxiogenic rather than anxiolytic
what effect does the allosteric modulator Benzodiazepines have on GABA receptors
Increases KA for GABA
Increase efficacy of GABA
what are the two types of allosteric modulators and give examples
- Positive (PAM)
Not active alone but increase affinity and/or efficacy of endogenous agonist
Examples: Diazepam, Propofol, Isoflurane - Negative (NAM)
Not active alone but decrease affinity and/or efficacy of endogenous agonists
mGluR5 dipraglurant
describe desensitization of receptors
Effect of the drug reduces with continual/repeated administration.
what term is given to desenitization of receptors
tachyphylaxis
how does desentisation of receptors happen
Conformational changes in receptor
Internalisation of receptors
Depletion of mediators
Altered drug metabolism
Other physiological responses (homeostatic).
