Pharmacodynamics

Question 1

Receptors are present in …. and show ….

Answer 1

Low concentrations

Saturable binding

Question 2

Density of receptors?

Answer 2

Pico (-12) to nano (-9)

Question 3

Affinity of receptors?

Answer 3

Many drugs have high affinities for their receptors so will bind at low concentrations

Question 4

KD?

Answer 4

Equilibrium dissociation constant. M.
High affinity = low KD (e.g. 1nM)
Low affinity = high KD (e.g. 1mM)

KD = k-1/k1
k1[D][R} = k-1 [DR]
KD = [D][R}/[DR]

Question 5

Pharmacodynamics?

Answer 5

Study of how a drug affects an organism

Question 6

Pharmacokinetics?

Answer 6

Study of how an organism affects a drug

Question 7

B-adrenoreceptor agonist affinity?

Answer 7

Isoprenaline > adrenaline > noradrenaline

Question 8

A-adrenoreceptor agonist affinity?

Answer 8

Noradrenaline > adrenaline&raquo_space; isoprenaline

Question 9

Example of a non reversible drug receptor interaction? (rare)

Answer 9

Phenoxybenzamine binds and alkylates the a-adrenoreceptor. Permanently changes it.

Irreversible antagonist.

Question 10

Use of phenoxybenzamine

Answer 10

In pheochromocytoma - tumour of adrenal gland. Alpha blocker which relaxes and widens blood vessels until patient produces new receptors.

Question 11

Mw of drug?

Answer 11

~200

Question 12

Mw of receptor?

Answer 12

~250,000

Question 13

What forces exist between the receptor’s binding site and drug?

Answer 13

Hydrogen Bonds.
van der waals forces.
Ionic binding.

Question 14

Dopamine specificity example?

Answer 14

Dopamine receptor has 7 transmembrane region. Aspartate at region 3, important due to negative charge. Dopamine no longer binds when it is removed.

Question 15

Are receptors rigid?

Answer 15

No, agonists induce a conformational changes. Antagonists do not cause these, as they block the agonist and don’t bring about a conformational change.

Question 16

Law of mass action

Answer 16

rate of chemical reaction is proportional to concentrations of reacting substances

Question 17

Assumptions?

Answer 17

Only a negligible amount of the total drug is bound –> free drug = total drug

Reaction is at equilibrium

Question 18

Important kD formula?

Answer 18

= [D][R] / [DR]

Question 19

What can’t you measure easily?

Answer 19

Number of free receptors in the tissue.

free = total - bound receptors

Question 20

Number of free receptors equation? **

Answer 20

r = [D] / [D] + KD

fractional occupancy
valid for simple bimolecular interactions

Question 21

Plot of r against [D]

Answer 21

Rectangular hyperbola.
Max y = 1.

KD = y = 0.5

Plotting r against log[D} gives a sigmoidal curve. Linear between 20-80% fractional occupancy.

Question 22

How to estimate KD?

Answer 22

When r = 1/2:
KD = [D]
At half maximal occupancy, KD is equal to the drug concentration.

Question 23

Examples of positive cooperativity?

Answer 23

Nicotinic receptors can bind 2 acetylcholine molecules at once.

Oxygen and haemoglobin.

Convert between high and low affinity forms.

Question 24

Example of negative cooperativity?

Answer 24

GPCRs sit in the membrane, can combine with G protein. When an agonist binds, dissociates from the G protein (lower affinity), starting the signalling cascade.

Question 25

Hill Equation?

Answer 25

nD + R DnR

n>1 positive
n=1 simple interaction
n<1 negative

Plot log[r/(1-r)] against log[D] and slope = n

Question 26

Occupation theory?

Answer 26

Response [E] ~ number of receptors occupied

Question 27

Rate theory?

Answer 27

Response [E] ~ rate of receptor occupation

Question 28

Rewritten r equation for occupation theory?

Answer 28

r = [D] / [D] + KD

r = E / Emax

so graphs of response or occupancy against [D] should b the same shape.

Question 29

pD2?

Answer 29

quantifies the affinity of an agonist for its receptor

= -log (KD)

conc of agonist that gives half the maximal response

Question 30

high pD2 means?

Answer 30

acts at low concentrations

Question 31

pD2 isn’t an accurate estimate?

Answer 31

for many receptor systems, pD2 overestimates the KD, so the drug appears to bind more tightly than it does.

Question 32

Competitive antagonism?

Answer 32

bind to same site as agonist

can be overcome by increasing agonist conc.

Question 33

Non competitive antagonism?

Answer 33

binds to a different site or irreversibly

block cannot be overcome by increasing agonist conc

Question 34

What happens to dose response curve with competitive antagonism?

Answer 34

curves shift to the right (parallel)
apparent pD2 decreases in the presence of the antagonist
no change in Emax

e.g. atropine against acetylcholine in guinea pig ileum

Question 35

What happens to dose response curve with non competitive antagonism?

Answer 35

dose response curves aren’t parallel
pD2 doesn’t change
Emax decreases

e.g. benzilycholine mustard against acetylcholine

Question 36

KA?

Answer 36

KA = [A][R] / [AR]

Question 37

Dose ratio?

Answer 37

Ratio of the agonist concentrations that elicit the same response in the absence [D0] or presence [DA] of the antagonist.

= DA / D0

Choose any response, then work out the dose ratios for this response.

Question 38

r accounting for antagonists?

Answer 38

r = KA[D] / KDKA + KD[A] + KA[D]

Question 39

Gaddum Schild Equation?

Answer 39

[DA]/[D0] - 1 = [A] / KA

Question 40

Assumptions for Gaddum Schild Equation

Answer 40

Simple competitive antagonism
Simple bimolecular interaction
Reaction is at equilibrium
Free drug = Total drug

Independent of agonist, just has to compete for same receptor.

Question 41

pA2?

Answer 41

-log[A] which gives a dose ratio of 2 (have to double the agonist conc to give same response in antagonist presence)

Question 42

Which values do not have units?

Answer 42

KA and KD - also always positive

Question 43

Schild plot?

Answer 43

log (dose ratio -1 ) = log [A] + pA2
Y = mx + c
if m = 1 –> competitive

Question 44

pAx?

Answer 44

negative log of the conc of antagonist that gives a dose ratio of x

log(x-1) = pA2 - pAx 
log(9) = pA2 - pA10 = 0.95

if there is a substantial deviation from expected value, then the interaction isn’t competitive

Question 45

Assumptions of occupation theory?

Answer 45

• specific receptors for specific agonists
• all agonists for a given receptor produce the same maximal response
• drug receptor interaction is rapidly reversible
• all receptors are equally accessible to the drug
• receptors don’t interact with each other
• max response occurs when all receptors are occupied

Question 46

Partial agonists?

Answer 46

Act on receptors and only produce a weak response. Act as competitive antagonists of the full agonist. See an intermediate response.

Question 47

Alpha?

Answer 47

Ability to produce an effect (intrinsic activity) from DR –> DR*

r = aD / D + KD

a = 1 ; full agonist
a < 1 ; partial agonist
a = 0 ; antagonist

Question 48

Can a maximum response be obtained when not all receptors are occupied?

Answer 48

Yes. Shown in histamine receptor. When an irreversible antagonist (BH - B halolakylamine) irreversibly alkylates the receptor. When you add this, would expect to see a reduction in the max response, but can still elicit this up to a certain conc of BH.

Low conc - appears competitive
High conc - appears non-competitive

An agonist with high efficacy may only need to bind to a small no of receptors for maximal response

Question 49

Modification of occupation theory to account for partial agonists?

Answer 49

Effect depends on affinity of drug for receptor.
Effect depends on ability of the drug to induce a conformational change.

An agonist with high efficacy will preferentially bind to 2 and stabilise the active conformation.
An agonist with low efficacy may bind to either.
An antagonist will only bind to 1.

Question 50

Inverse agonists?

Answer 50

Some receptors have constitutive activity. This is reversed by inverse agonists, which decrease the basal activity.
Widespread phenomenon which also applies to G-protein coupled receptors.