Principles Of Drug Action At Receptors

Front 1

list some key features of receptors...

Back 1

Receptors are protein macromolecules usually inserted across the lipid bilayer of the cell.

They perform two main functions:

1) recognition/detection

2) transduction- when the NT or hormone binds to the receptor it crosses the cell membrane.

receptors are very specific, they are classified with respect to the drugs which they bind e.g nicotinic acetylcholine receptors.

Front 2

Binding of drug to receptors.

In most cases, binding is irreversible...

Back 2

D + R <==> DR

Front 3

define affinity

Back 3

Affinity is a measure of how strongly the drug binds to the receptor. Both agonists and antagonistshave affinity for their receptor. Quantified by the Kd value (drug concentration needed for 50%receptor occupancy; a lower Kd corresponds to a higher affinity).

(the affinity is determined by the backwards rate constant, Kd)

Front 4

define efficacy

Back 4

Efficacy is a measure of the ability of a drug, once bound to the receptor, to initiate a response(the response could be molecular, cellular, tissue, system or therapeutic, though definedhistorically at the tissue level). Full agonists have high efficacy, partial agonists have low efficacy,competitive antagonists have zero efficacy.

Front 5

50% of the receptors occupied leads to 50% response- true or false?

Back 5

false- not all bound receptors will lead to a response.

Front 6

Drugs with a high affinity will have a low or high Kd? (for example in the micro or nanomolar range)

Back 6

low Kd (meaning the molecules have a slow dissociation rate)

because it means that 50% of the receptors are occupied at lower drug concentrations.

Front 7

agonists bind to a receptor and then activate it meaning they have...

Back 7

both affinity and efficacy.

Naturally occurring neurotransmitters and hormones are agonists e.g adrenaline.

Front 8

There are 2 main types of agonist, partial and full agonists.

Describe partial agonists...

Back 8

low efficacy and are therefore less effective

partial agonists often fail to produce a full response despite occupying all the available receptors.

Front 9

describe full agonists...

Back 9

-high efficacy and as a result are very effective at producing a biological response

full agonists often produce maximal response whilst activating only a fraction of the available receptors i.e there are lots of spare receptors.

Front 10

differences between partial and full agonists can be seen in the concentration vs response curves...

Back 10

It is not possible to reach meaningful conclusions on agonist affinity from such curves since:

- the agonist response depends on efficacy and affinity

-there are often many steps between drug binding and the response

Front 11

define antagonist...

Back 11

molecules that act to inhibit the effects of a neurotransmitter, hormone or in some cases another drug.

Front 12

There are several forms of antagonism.

Forms of antagonism I...

Back 12

chemical- use of one drug to chemically inactivate another

pharmacokinetic- one drug alters the way the body deals with another e.g antacids prevent absorption of phenytoin from the gut.

physiological- two drugs act to produce opposing effects so cancelling eachother out e.g nonadrenaline increases heart rate and acetylcholine decreases it.

Front 13

forms of antagonism II (antagonistis that act at the receptor or close by)...

Back 13

- competitive antagonists compete with the agonist for the same site on the receptor molecule but don't activate it i.e have affinity but zero efficacy.

-non-competitive antagonists act at a different site on the receptor or another molecule closely associated with it.

Front 14

reversible competitive antagonists...

Back 14

-very important drugs e.g pancuronium

-used to inhibit the effects of a neurotransmitter or hormone

-their effects can be overcome by increasing the concentration of the agonist --> blockade is surmountable.

Front 15

reversible competitive antagonists produce a parallel shift to the right of the log concentration vs response curve...

Back 15

Front 16

for irreversible competitive antagonists, there is a shift to the right in the concentration vs response curve but the shift is not parallel...

Back 16

the blockade is not surmountable

Front 17

How, at the molecular level (i.e. in terms of drugs and receptors), does a reversible competitiveantagonist produce this change in the log concentration – response curve?

Back 17

The agonist and antagonist molecules are continually binding to the receptor and rapidly comingoff again. While an antagonist molecule is occupying the receptor binding site at any instant oftime, an agonist molecule cannot bind. The presence of the antagonist thus reduces the numberof agonist – receptor complexes (i.e. the form of the receptor that leads to a cellular response)present at any one instant of time, so the response at a given agonist concentration is reduced.The number of agonist – receptor complexes can be restored by increasing the agonistconcentration further, so the cellular response is restored but at a higher concentration of theagonist. This produces the rightward shift of the curve. At very high agonist concentrations the antagonist has little chance to bind to the receptor, so themaximum response can still be obtained in the presence of the antagonist.

Front 18

Noradrenaline increases the heart rate by activating “beta‐adrenergic” receptors in the heart.What type of drug might you administer to a patient who was suffering from an inappropriately‐high heart rate due to over‐activity of the sympathetic nervous system?

Back 18

A reversible competitive antagonist at beta‐adrenergic receptors. Such drugs are the “beta‐blockers”, examples of which are propranolol and metoprolol. The majority of clinically‐usefuldrugs are receptor antagonists or enzyme inhibitors, rather than agonists or activators.