1.3 Agonists and dose response curves Flashcards
To assist you in acquiring the knowledge & understanding to: Compare the potency and efficacy of drugs on the basis of their dose-response curves Determine whether an antagonist is competitive or non-competitive (irreversible) on the basis of its effect on the dose-response curve of the agonist Define graded and quantal dose-response curves Discuss affinity and receptor-binding curves Compare potency and efficacy from dose-response curves Explain the concept of full, partial and inverse agonist
What is an agonist?
a ligand (drug, hormone or neurotransmitter) that combines with receptors to elicit a cellular response
Give an example of an agonist:
salbutamol
How does salbutamol effect beta2-adrenorecptors?
binds to form salbutamol-beta2-adrenoceptor complex
2) increased cAMP
3) bronchodilation
Why are dose-response curves presented as a semi-logarithmic plot?
as concentration is a very big number so you can identify the concentration required to have an effect without negative side effects.
What is a graded dose-repsonse curve?
response of a particular system: isolated tissue, animal or patient. measure against agonist concentration.
What is a quantal dose response curve?
– Drug doses • (agonist or antagonist) – required to produce a specified response determined in each member of a population, using absolute measures so we quantify where the vast majority is effected, therefore if its per a number of people its quantal, usually a bell shaped curve
Dose response curve vs concentration-effect curve
Dose is the amount you take, concentration is the amount that actually enters the body.
Whats the easiest way to differ between graded and quantal response?
quantal response involves looking at response determined in each member of the population, usually bell shaped curve. There is a yes or no reponse. While in graded the response has different levels/grades, and doesn’t look at a population but how extreme that reponse is
what is the 2 state hypothesis of receptor drug interactions?
receptor has 2 states, active or rested.
When will more receptors be in rested state?
2) When will more receptors be in active state?
3) Why does this change occur?
1) when there is less drug agonist
2) when drug agonist is added
3) If we add a drug agonist it will shift the equilibrium to the right and more drug will bind to receptor dependent on affinity, then receptor will be activated.
1) What is another way of describing receptor saturation?
2) How do you find it??
1) Receptor saturation is easily measured i.e. maximum number of binding sites (Bmax)
2) do total drug bound-non specific= specific
non-specific is when a drug binds to another receptor you are no interested in
What is Bmax?
binding saturation
What 2 properties must a drug have to have a high affinity?
2) what constant can tell you this?
bind more relative to dissociate determined by
a) the number of bonds
b) the “level of fit” between ligand and receptor
2) Kd (equilibrium dissociation constant)
What does affinitiy desribe?
the strength at which a drug binds to receptor
1) what is Kd the inverse of??
2) What would a low Kd indicate?
3) the formula is k-1 over k1. what does
a) k1
b) k-1
mean?
1) affinity
2) a tighter ligand-receptor interaction (high affinity)
3) a) is the rate of association of the agonist with receptor
b) is the rate of AR complex dissociation
a) What is the 2 state hypothesise?
b) What properties determines if a drug causes a response in receptor?
a) 1. Drug occupies receptor
2. complx causes acitvation of receptor
3. response occurs
b) the affinity (1) and ht efficacy (2)
The KD is the same for a given receptor and drug combination in any tissue, in any species (as long as the receptor is the same), anywhere in the universe.
A) What can Kd be used for? (2)
A) 1) The KD can therefore be used to identify an unknown receptor.
2)The KD can be used to quantitatively compare the affinity of different drugs on the same receptor.
How do you compare affinities of 2 different drugs?
- read dose-dependent graph (y axis reads % receptors occupied, x axis reads drug concentration)
- find the value of Kd, by reading drug concentration at 50% occupancy
- The one with a lower Kd value has a greater affinity
How do you find
a) Emax
b) EC50
- read dose-response graph (y axis= percentage response, x axis is concentration )
a) read value of drug concentration at 100% response
b) read value of drug concentration at 50% response
What value do you use to find out
a) efficacy
b) potency
a) Emax
b) potency
What is potency dependent on? (4)
Affinity of drug
Efficacy of drug
Receptor density
Efficiency of stimulus-response mechanisms used
If there is a linear relationship between receptor occupation and biological effect then Kd and EC50 are equal
TRUE OR FALSE
TRUE
Why may Kd and EC50 not always be equal?
2) When are they equal?
1) Many receptors can amplify signal duration and intensity
Because of this amplification only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell
2) when there is a linear relationship between receptor occupancy and biological effect.
what behaviour doe spare receptor systems exhibit?
Many receptors can amplify signal duration and intensity
Because of this amplification only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell
describe efficacy
2) What determines efficacy?
the ability of an agonist to activate a receptor i.e. to evoke an ‘action’ at the cellular level
2) the nature of the receptor-effector system
the ability of an agonist to activate a receptor i.e. to evoke an ‘action’ at the cellular level
What word describes this?
2) What is it used in reference to?
efficacy
2) the maximum effect an agonist can produce regardless of dose
Describe the efficacy of full agonists?
2) what is the probability of a drug and receptor complex that causes a response?
1) high efficacy
2) very likely
Describe the efficacy of partial agonists?
2) what is the probability of a drug and receptor complex that causes a response?
3) is it able to produce a maxium response if all receptors are occupied?
1) low efficacy
2) less likely
3) no
With full agonists, the maximum response produced corresponds to ….
the maximum response that the tissue can give.
A partial agonist is a ligand that combines with receptors to elicit a maximal response which ….
falls short of the maximal response that the system is capable of producing
name:
Nicotine receptor partial agonist for smoking cessation.
varenicline
what is varenicline
Nicotine receptor partial agonist for smoking cessation.
what is tamoxifen?
Estrogen receptor partial agonists for use in estrogen dependent breast cancer.
Name:
Estrogen receptor partial agonists for use in estrogen dependent breast cancer.
tamoxifen
what is aripiprazole?
Antipsychotic – partial agonists at selected dopamine receptors.
Name:
Antipsychotic – partial agonists at selected dopamine receptors.
aripiprazole
What is the significance of spare receptors or receptors reserve systems in medicine?
you only need to bind to some of the receptors so maximum dose is not required to have max effect.
is there ever a situation where the response to a partial agonist and full agonist is the same
yes, growing body of data
e.g. some ion channels
what are inverse agonists?
some receptors are active without even been bound to. inverse agonists binds to a receptor and reduces activity,
what is a positive allosteric modulator?
Not active alone but increase affinity and/or efficacy of endogenous agonist
What is a negative allosteric modulator?
Not active alone but decrease affinity and/or efficacy of endogenous agonist
1) what is traphylaxis?
2) What a contributing factors? (5)
desensitisation to a drug from continous binding to receptors over a long period of time
2) Conformational changes in receptor
Internalisation of receptors
Depletion of mediators
Altered drug metabolism
Other physiological responses (homeostatic).
