Lecture 16 + 17 - Pharmacodynamics 1 + 2 Flashcards
what is pahrmacodynamics ?
What the drug does to a body
GPCR’s are good Drug targets
what is a ligand ?
something that binds to a receptor to activate a repsonse
the conc of drug/ligand around receptor is important in determining drug action
what is molarity ?
go over notes
it is the number of moles of solute (drug) per liter
(g/l)/Mwt
g/mwt = moles
molarity is often in the micro to nano range
we consider drug concentrations in molarity
what possible ways can drugs bind to receptors
most drugs bind reversibly to receptors - so consider asssociation and dissociation
what does affinity mean ?
to cause an action a drug must bind to a recptor and either block an agonist or activate a recptor
to be able to bind to a receptor a drug must have an affinity for that receptor
if a drug has a higher affinity it will bind stronger (more tightly)
high affinity allows a drug to bind at low concentrations
what is intrinsic efficacy
an agonsit drug binding is governed by affinity
the receptor activation level is governed by intrinsic efficacy
the ability of a drug to activate a receptor after binding to produce a response
what is efficacy
efficacy is the ability of a ligand to cause a response
it is governed by intrinsic efficacy AND other factors that may be cell/tissue dependent
what efficacy do agonisits and antagonists have respectively
agonists - have affinity as they bind - have intrinsic efficacy to activate a response
- have efficacy - cause a measurable resposne
antagonists - have affinity for the ligand - as they bind but do not cause a response so they have NO intrinsic efficacy - they block a response
how is clinical efficacy different ?
it is a measure of how well a treatment achieves its aim
it may cause a measurable response - efficacy - but if that response does not solve the issue, then it does not have clinical efficacy
How do we measure binding?
draw plots
we use radioactive labeling of ligands to measure the binding response
we can plot the No of receptors bound vs lingand conc
B max is the max binding capacity
Kd is the dissociation constant - the conc of drug where 50% of receptors are bound
what does Kd represent ?
Kd is the dissociation constant - the conc of drug to occupy 50% of available receptors
A lower Kd value means a higher affinity drug - as less conc is needed to bind 50% of receptors
explain the concepts of a concentration response curve
Drug concentration (x) vs Level of response (Y)
Emax is the maximal effect
can be logarithmic for drug conc or not - if in log form remember to convert out of it
what is EC50 ?
What is EC%) a measure of ?
the Effective Concentration to give 50% of Maximal Response (Emax)
Measures agonist potency
what does potency mean ?
potency is a measure of both affinity and intrinsic efficacy - so its ability to bind and then cause a level of response
and also cell/tissue specific factors (overall efficacy) - such as THE NUMBER OF RECEPTORS THAT CELL HAS
for a ligand receptor combo - affinity and efficacy are fixed values - but potency is not a fixed value as a drugs response to a tissue may change over time due to number of receptors changing on the cell over time for example
what is the difference between concentration and dose ?
we know the conc of a drug at site of action
in a DOSE the concentration of a drug at a site of action is unknown - what we give clinically is a dose
use the lungs as an example to explain functional antagonsim
an asthmatic suffers from bronchoconstriction of the aveoli ect
we treat the b2 adrenoceptors with a drug (eg sabutamol or salmetrol-longer acting) that causes relaxation of these constricted airways - since the drug opposes the response we call it functional antagonsim
bonus
how we find selectivty and specificty of a drug
Salbutamol - poor selectivity for b2 over b1 but it only has efficacy for b1 so will bind to both but only cause a response in b2
salmetrol - no efficacy selctivity will cause a response in both b1 and b2, however poor affinty for b1 means it does not readily bind to b1
1 heart 2 lungs
what are some cell or tissue dependent factors that influence potency
a muscle can only contract so much
a gland can only secrete so much
so there is a limit on level of response even is binding could be higher
60% of receptors bound could cause the maximum response
the reaming receptors are called spare receptors and have no immediate effect
what is the reason we have space recptors
spare receptors can increase sensitivity to a response
if we have a lot of receptors then a lower concentration of ligand can trigger a response - which can then undergo a amplification cascade in the cell
this influences potency and means we may need less drug to trigger the desired response - a change in receptor number will change the potency of an agonsit
it will also effct maximal response
the cell may simply not have enough receptors to trigger maximal response - so maximal binding is not effective
receptor numbers can be up-regulated or down regulated
if we have low activity then receptor level will increase
high activity and receptor level will decrease
for drugs this is the concept of tolerance - can go up and withdrawal symptoms - taper off
explain partial agonsits and full agnosists
Full agonist - does not need full binding to cause a maxiaml response - there may be spare receptors
partial agonsit - even when fully bound - no spare receptors - we do not cause a maximal response as the drug has insufficient intrinsic efficacy to cause a maximal response
what is intrinsic activity
the ability to cause a maxiamal response
so partial agonists have a lower intrinsic activity than full agonists
highest intrinsic activity is at the top of the graph
what is the relevance of partial agonsists as drugs ?
allow a controlled response
will work without a full agonsit - or they can act as an antagonsit for a full ligand - if full agonist conc is high
can have a higher affinity (bind better) but lower efficacy (cause a lesser response) - so give to reduce the effects of the full agonist with high efficacy
we can use buprenophine to out compete and inhibit with heroin to stop heroin full response - overdose/taper off
man takes heroin normally
take buprenorphine (high affinity partial agoninst)
gets very ill, why?
withdrawal symptoms - continued drug use gives higher tolerance - less receptors/signalling
body cant produce desired response when drug is removed
Partial agonsit - binds to reduce full effects
what are the three types of antagonist drugs ?
Reversible competitive antagonism - most important for drugs
irreversible competitive antagonism
Non competitive antagonism
what is an antagonist ?
block the effects of an agonsit - prevent receptor activation and response
what is Reversible competitive antagonism
what is IC50
agonsit and antagonsit compete for the receptor in a dynamic equilibrium - both form reversible binding with receptors
if we increase conc of antagonist in the system with antagonist it will out compete to reduce agonist response
similary if we increase agonist concentration we can overcome the inhibition
we need greater conc of agonist to cause a full response
the IC50 is the concentration of antagonist that gives 50% inhibition - it is an index of antagonist potency
we also use Kd to describe antagonist affinity
what is irreversible competitive antagonism
antagonist and agonist compete for the receptor but when antagonist bind its binds irreversibly/very slowly released
effectively blocking the receptor permanently
increase antagonist conc / just time and more receptors are blocked - this cannot be overcome
like Comp Rev Antagonists they will shift agonist response curve to the right - they will also at high concs suppress the maximal response - lower the line on graph
what is non competitive antagonism
antagonist will bind to an allosteric site - can enhance or reduce the effects of a drug or ligand - can reduce ligand affinity/efficacy
effects are similar to irreversible comp antagonism
