Lecture 16 + 17 - Pharmacodynamics 1 + 2

Question 1

what is pahrmacodynamics ?

Answer 1

What the drug does to a body

Question 2

GPCR’s are good Drug targets

what is a ligand ?

Answer 2

something that binds to a receptor to activate a repsonse

the conc of drug/ligand around receptor is important in determining drug action

Question 3

what is molarity ?

go over notes

Answer 3

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

Question 4

what possible ways can drugs bind to receptors

Answer 4

most drugs bind reversibly to receptors - so consider asssociation and dissociation

Question 5

what does affinity mean ?

Answer 5

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

Question 6

what is intrinsic efficacy

Answer 6

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

Question 7

what is efficacy

Answer 7

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

Question 8

what efficacy do agonisits and antagonists have respectively

Answer 8

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

Question 9

how is clinical efficacy different ?

Answer 9

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

Question 10

How do we measure binding?

draw plots

Answer 10

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

Question 11

what does Kd represent ?

Answer 11

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

Question 12

explain the concepts of a concentration response curve

Answer 12

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

Question 13

what is EC50 ?

What is EC%) a measure of ?

Answer 13

the Effective Concentration to give 50% of Maximal Response (Emax)

Measures agonist potency

Question 14

what does potency mean ?

Answer 14

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

Question 15

what is the difference between concentration and dose ?

Answer 15

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

Question 16

use the lungs as an example to explain functional antagonsim

Answer 16

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

Question 17

what are some cell or tissue dependent factors that influence potency

Answer 17

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

Question 18

what is the reason we have space recptors

Answer 18

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

Question 19

explain partial agonsits and full agnosists

Answer 19

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

Question 20

what is intrinsic activity

Answer 20

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

Question 21

what is the relevance of partial agonsists as drugs ?

Answer 21

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

Question 22

man takes heroin normally
take buprenorphine (high affinity partial agoninst)
gets very ill, why?

Answer 22

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

Question 23

what are the three types of antagonist drugs ?

Answer 23

Reversible competitive antagonism - most important for drugs
irreversible competitive antagonism
Non competitive antagonism

Question 24

what is an antagonist ?

Answer 24

block the effects of an agonsit - prevent receptor activation and response

Question 25

what is Reversible competitive antagonism

what is IC50

Answer 25

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

Question 26

what is irreversible competitive antagonism

Answer 26

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

Question 27

what is non competitive antagonism

Answer 27

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