Pharmacodynamics Flashcards
Receptors are present in …. and show ….
Low concentrations
Saturable binding
Density of receptors?
Pico (-12) to nano (-9)
Affinity of receptors?
Many drugs have high affinities for their receptors so will bind at low concentrations
KD?
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]
Pharmacodynamics?
Study of how a drug affects an organism
Pharmacokinetics?
Study of how an organism affects a drug
B-adrenoreceptor agonist affinity?
Isoprenaline > adrenaline > noradrenaline
A-adrenoreceptor agonist affinity?
Noradrenaline > adrenaline»_space; isoprenaline
Example of a non reversible drug receptor interaction? (rare)
Phenoxybenzamine binds and alkylates the a-adrenoreceptor. Permanently changes it.
Irreversible antagonist.
Use of phenoxybenzamine
In pheochromocytoma - tumour of adrenal gland. Alpha blocker which relaxes and widens blood vessels until patient produces new receptors.
Mw of drug?
~200
Mw of receptor?
~250,000
What forces exist between the receptor’s binding site and drug?
Hydrogen Bonds.
van der waals forces.
Ionic binding.
Dopamine specificity example?
Dopamine receptor has 7 transmembrane region. Aspartate at region 3, important due to negative charge. Dopamine no longer binds when it is removed.
Are receptors rigid?
No, agonists induce a conformational changes. Antagonists do not cause these, as they block the agonist and don’t bring about a conformational change.
Law of mass action
rate of chemical reaction is proportional to concentrations of reacting substances
Assumptions?
Only a negligible amount of the total drug is bound –> free drug = total drug
Reaction is at equilibrium
Important kD formula?
= [D][R] / [DR]
What can’t you measure easily?
Number of free receptors in the tissue.
free = total - bound receptors
Number of free receptors equation? **
r = [D] / [D] + KD
fractional occupancy
valid for simple bimolecular interactions
Plot of r against [D]
Rectangular hyperbola.
Max y = 1.
KD = y = 0.5
Plotting r against log[D} gives a sigmoidal curve. Linear between 20-80% fractional occupancy.
How to estimate KD?
When r = 1/2:
KD = [D]
At half maximal occupancy, KD is equal to the drug concentration.
Examples of positive cooperativity?
Nicotinic receptors can bind 2 acetylcholine molecules at once.
Oxygen and haemoglobin.
Convert between high and low affinity forms.
Example of negative cooperativity?
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.
Hill Equation?
nD + R DnR
n>1 positive
n=1 simple interaction
n<1 negative
Plot log[r/(1-r)] against log[D] and slope = n
Occupation theory?
Response [E] ~ number of receptors occupied
Rate theory?
Response [E] ~ rate of receptor occupation
Rewritten r equation for occupation theory?
r = [D] / [D] + KD
r = E / Emax
so graphs of response or occupancy against [D] should b the same shape.
pD2?
quantifies the affinity of an agonist for its receptor
= -log (KD)
conc of agonist that gives half the maximal response
high pD2 means?
acts at low concentrations
pD2 isn’t an accurate estimate?
for many receptor systems, pD2 overestimates the KD, so the drug appears to bind more tightly than it does.
Competitive antagonism?
bind to same site as agonist
can be overcome by increasing agonist conc.
Non competitive antagonism?
binds to a different site or irreversibly
block cannot be overcome by increasing agonist conc
What happens to dose response curve with competitive antagonism?
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
What happens to dose response curve with non competitive antagonism?
dose response curves aren’t parallel
pD2 doesn’t change
Emax decreases
e.g. benzilycholine mustard against acetylcholine
KA?
KA = [A][R] / [AR]
Dose ratio?
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.
r accounting for antagonists?
r = KA[D] / KDKA + KD[A] + KA[D]
Gaddum Schild Equation?
[DA]/[D0] - 1 = [A] / KA
Assumptions for Gaddum Schild Equation
Simple competitive antagonism
Simple bimolecular interaction
Reaction is at equilibrium
Free drug = Total drug
Independent of agonist, just has to compete for same receptor.
pA2?
-log[A] which gives a dose ratio of 2 (have to double the agonist conc to give same response in antagonist presence)
Which values do not have units?
KA and KD - also always positive
Schild plot?
log (dose ratio -1 ) = log [A] + pA2
Y = mx + c
if m = 1 –> competitive
pAx?
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
Assumptions of occupation theory?
- 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
Partial agonists?
Act on receptors and only produce a weak response. Act as competitive antagonists of the full agonist. See an intermediate response.
Alpha?
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
Can a maximum response be obtained when not all receptors are occupied?
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
Modification of occupation theory to account for partial agonists?
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.
Inverse agonists?
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.
