Principles Of Drug Action (2) : Drug Action At Receptors

Front 1

Receptors are protein macromolecules usually inserted across the lipid bilayer of the cell. What are their 2 main functions?

Back 1

Recognition/detection

Transduction

Front 2

How are receptors classed?

Back 2

With respect to the drugs they bind

e.g nicotinic acetylcholine receptors

Front 3

Pharmacologists utilise the specificity of interaction between drug and receptor by design drugs that bind to only certain subtypes of receptor. What does this lead to?

Back 3

Drugs with fewer side effects

Front 4

Binding is reversible in most cases. What does this show about the interaction between a drug and its receptor?

Back 4

Drugs continually go on and off receptor

Front 5

What does a plot of the proportion of receptors occupied (p) vs drug concentration [D] look like?

Back 5

A rectangular hyperbola

[D]

Front 6

What does a plot of the proportion of receptors occupied vs log [D] look like?

Back 6

A symmetrical sigmoid

Front 7

How is the affinity of a drug for its receptor quantified?

Back 7

The MOLAR concentration of a drug required to occupy 50 % of the receptors at equilibrium

This concentration is given the symbol K D

Front 8

Drugs with a high affinity have a high or low KD?

Back 8

Low

Front 9

K D is the equilibrium dissociation constant.

How is KD calculated?

Back 9

Front 10

What does k-1 determine?

For a drug to bind, do you need k-1 to be high or low?

Back 10

k-1 determines the affinity of receptor

You need a low k-1 for a drug to bind

Front 11

The KD is a measure of chemical attraction. Receptors are being continually bombarded by lots of "chemicals". Only the with affinity will "stick" or bind. Do drugs with a high affinity stay bound for a relatively long or short time?

Back 11

Relatively long ( fractions of a second) i.e they have a slow dissociation rate as k-1 is very small

Front 12

Many drugs bind to the receptor ( i.e have affinity) and do little else. How do agonists go a step further?

Back 12

Agonists bind and then activate the receptor

i.e the agonist have efficacy

After binding, agonists produce a conformational change , in the receptors that will ultimately lead to a response in a cell or tissue

Front 13

What does efficacy describe?

Back 13

The ability of a drug to activate the receptor

AR<---> AR*

Front 14

What is a full agonist?

Back 14

Has high efficacy

Very effective at producing a biological response

Front 15

What is a partial agonist?

Back 15

Has low efficacy

Less effective at activating receptors

Front 16

What does the response-number of receptors occupied curve look like for a full agonist?

Describe it

Back 16

The maximal response is produced whilst only a fraction of the available receptors are activated i.e there are lots of spare receptors

Front 17

What does the response-number of receptors occupied curve look like for a partial agonist?

Describe it

Back 17

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

Front 18

Does 50% of receptors being occupied lead to a 50% response?

Back 18

NO!!!!!

Front 19

What do the log [concentration] vs response curves look like for partial vs full agonists?

Back 19

Sigmoidal curve

Front 20

Why is it not possible to reach meaningful conclusions on agonist affinity from the curves:

log [agonist] vs response

log [agonist] vs receptor occupancy

N.B these curves are both sigmoidal

Back 20

The agonist response depends on efficacy AND affinity

There are often many steps between drug binding and the response

Front 21

Many clinically useful drugs are antagonists. What do they try and do?

Back 21

Inhibit the effects of a neurotransmitter, hormone or in some cases, a drug.

Front 22

Wha are the forms of antagonism?

Back 22

Chemical

Pharmacokinetic

Physiological

Front 23

What is meant by chemical antagonism?

Back 23

Two drugs interacting-one drug is used to chemically inactivate another

Nothing to do with receptors

Front 24

What is meant by pharmacokinetic antagonism?

Back 24

One drug alters the way the body deals with another-indirectly prevents a drug from working

e.g phenytoin needs an acidic environment to be absorbed. Antacids prevent absorption by raising the pH.

Nothing to do with receptors

Front 25

What is meant by physiological antagonism?

Back 25

Two drugs act to produce opposing effects so cancelling each other out.

e.g. noradrenalineincreases heart rate whilst acetylcholine decreasesit. Note that in this case both drugs are agonists butact on completely different receptors

Front 26

What do competitive antagonists do?

Back 26

Compete with the agonist for the same site on the receptor molecules, but don't activate it.

i.e have affinity but zero efficacy

Can be reversible or irreversible

Front 27

What do non-competitive antagonists do?

Back 27

Act at a different site on the receptor or another molecule closely associated with it

Can be reversible or irreversible

Front 28

What are some examples of reversible competitive antagonists?

Back 28

Pancuronium, terfenadine, propanolol

Front 29

Reversible competitive antagonists are used to inhibit the effects of a neurotransmitter or hormone. How can their effects be overcome?

Back 29

Increasing the concentration of agonist

Front 30

How do reversible- competitve antagonists affect the log [agonist] vs response curve?

Back 30

Produce a parallel shift to the right of the agonist i.e you need more of the agonist to get the same response

Front 31

How do irreversible- competitve antagonists affect the log [agonist] vs response curve?

Back 31

These drugs also produce a shift in the agonist log concentration-response curve, but the shift is not parallel. i.e the block is NOT surmountable .

You lose the ability of the agonist to produce a response.