Drug receptor theory Flashcards
(128 cards)
1
Q
what are the two types of drugs?
A
Small molecules and biologicals
2
Q
what are receptors?
A
proteins who’s function it is to recognise and respond to endogenous chemical signals
3
Q
what are drug targets? give two examples
A
macromolecules with which drugs interact with to produce their effects
- dna
- antibiotics react with macromolecules on bacterial coating
4
Q
what are receptors identified and classified by?
A
structure, pharmacology and signalling
5
Q
are drugs completely specific?
A
no, there are also off target effects.
6
Q
what does malfunction or loss of receptors lead to?
A
disease
7
Q
what are the 4 receptor families?
A
ligand gated ion channels
GPCR
kinase linked
nuclear receptors
8
Q
what are two examples of an endogenous ligand?
A
neurotransmitters and hormones
9
Q
are ionotropic or metatropic pathways faster?
A
ionotropic
10
Q
does a ligand only activate one class of receptor?
A
no it can activate more than one class
11
Q
what’s a kinase?
A
a phosphorylative enzyme
12
Q
give two examples of kinase receptors?
A
growth factor receptors and insulin receptors
13
Q
where are nuclear receptors usually found?
A
in the cytosol.
14
Q
what makes nuclear receptors different to the others receptor families
A
no TMD
15
Q
what is the proportion of receptors occupied by the drug dependant on?
A
the affinity of the drug for the receptor
16
Q
what is the affinity?
A
the balance between forward and backward reactions
17
Q
when measuring affinity can you tell wether a drug is an agonist or antagonist?
A
no
18
Q
what does efficacy govern?
A
how well a drug can stabalise a receptor in it’s active conformation
19
Q
what happens to receptors when agonists bind?
A
their structure is stabalised
20
Q
what characteristics are wanted from a drug? what if this drug is an agonist?
A
want high specificity with a high affinity.
if it’s an agonist efficacy also needs to be very high.
21
Q
what is occupacy? what does this allow us to calculate? how does this vary.
A
the proportion of receptors occupied will vary with drug conc.
allows us to calculate affinity.
varies between 0 where no drugs are present and 1 where all receptors are occupied.
22
Q
if measuring occupancy can we just measure response?
A
no because response depends on efficacy too so a response independant of efficacy is needed
23
Q
what technique is used to measure occupancy?
A
radioligand binding assays
24
Q
what are the five steps when doing a radioligand binding assays
A
- prepare cells and tissue, all receptors have to be isolated. break up plasma with detergent and centrifuge.
- place on a filter
3.add the drug (radioligand) at lots of different cons and allow to find equilibrium. - remove all unbound ligand.
count radioactivity of all the bound ligands
25
what are the 4 problesm with using radioligand assays?
there's non specific binding so isn't possible to remove all unbound ligands
the radioligand might not be stable and might interfere with receptor structure
the tissue might not have been treated properly.
might be issues with how bound and unbound ligands are seperated
26
why must a ligand be biologocially active?
because it's binding to recognition site is supposed to correlate with a pharmacological action
27
what must the purity of a ligand be like?
must be extremely pure chemically
28
how can the problem of degredation of the ligand be solved?
1. free radical scavanger e.g ethanol can be add to the drug solution
2. store at a low but not freezing temperature.
3. avoid light by storing in dark bottles.
4. incorportion of antioxidant such as ascorbic acid.
29
what must be done to label the ligand?
labelling the drug with radioacrivity must achieve very high specific activity to allow very low ("tracer") concentrations.
30
what are the advantages of 3H?
the labelled product is indistinguishable from native compound.
high specificity activates can be obtained (>80Ci/mmol)
has a long half life of around 12.5 years.
31
what are the disadvantages of 3H?
specialised labs are required
| labelling is expensive and difficult
32
what are the advantages of 125I?
if compund has aromatic hydroxy group e.g tyrosine residues in peptides can be incorporated at very specific activities (>2000 Ci/mmol)
- iodination easy in most labs and cheap
33
what are the disadvantages of 125I?
it's more readily degraded
the biological activity of the ligand can be reduced
it has a short half life of 67 days.
34
how is the tissue selected for use with radioligands?
| what can the tissue be?
selected to contain the receptors of interest.
isolated membranes, slices, synaptosomes, cultured cells or solubilized/purified receptors from the total brain or specific region.
35
what has to be preserved during the inclubation?
both the ligand and the binding site
36
what protein concentration is needed for the incubation?
need in range of 0.1 - 1mg membrane protein/ml with assay volumes 0.25-1 ml
37
why are additives used in incubation?
used to protect the tissue/ligand
38
what is the temperature like in incubation?
usually low room temperature to 0 degrees celcius.
39
how is the tissue and bound ligand from the free ligand in incubation media done?
usually done by filteration or centrifugation
40
what other techniques can be used for removing soluble binding ligands?
dialysis,column,chromatography,precipitation/adsorption
41
what's the major problem with seperating the bound ligand from the free ligand?
the speed of seperation must be compatible with affinity of ligand for receptor.
the lower affinity (high kD) requires faster/more efficient seperation
42
how is the specific binding calculated from a graph?
total bound- nonspecific binding
43
why is a radioligand's binding saturable?
because the total number of receptors in the tissue and the preparation is limited. so there will be a point where all sites will be labelled and the binding curve will plateau
44
what does the langmuir equation describe?
the langmuir equation describes the relationship between receptors occupancy, affinity and drug concentration
45
what does it mean when some drugs have sub type selectivity? what are occupancy data graphs like in this case?
that they can distinguish between different subtypes of receptor
there's no overlap on occupancy data graphs due to it being a selective ligand
46
what are occupancy graphs like for drugs that don't have sub type selectivity?
there's overlapping data because the drug can bind to the subtypes equally well
47
what is the efficacy for agonists like?
it will always be greater than 0 as all agonists can stabalise receptors to issue a response.
48
can partial agonists issue a full response? what's their efficacy like?
no they can never issue a full responce no matter now much is add. their efficacy is greater than 0 but is never 1
49
what is the efficacy of an antagonist?
no matter how much is add it has an efficacy of 0 and never produces a response.
50
what is the efficacy of an inverse agonist like?
| how do these agonists work?
could be said that it has a negative efficacy.
receptors have a low constituative activity, every now and then without an agonist it can illicit a response due to it being dynamic, inverse agonists bind, stabalise and prevent the receptor from doing this.
51
what is the EC50?
the effecting concentration giving 50% of the maximum response
52
on binding and response graphs of agonists:
what's the relationship between the binding curve and occupancy?
what's the relationship between the response curve and occupancy?
binding curve is proportional to occupancy
| the response curve is not proportional to occupancy.
53
with a full agonist when does the max response curve often occur?
at a concentration of agonist that is less than the concentration needed for 100% occupancy.
54
what is the receptor reserve?
| what does this allow?
not 100% of receptors are occupied to issue a max response.
this amplifies the signal. some tissues can get a max response with under 5% occupancy.
this allows us to lose some receptors, it also increases the sensitivity of the tissue to the agonist.
ultimately provides spare receptors.
55
what's the problem with measuring just response?
you can't tell much without measuring the activity of the drug and receptor.
56
if binding and response curves have a similar sigmoidal shape what does this say?
it says there's contraction dependence.
57
why can binding and response curves differ?
what does this mean for contraction after binding?
what else may influence the size of response?
because when the receptor is in it's active confirmation it can activate g-proteins, it doesn't just activate one g-protein, this leads to amplification.
it means that contraction is several steps downstream from binding.
the efficacy of an agonist may influence the size of response.
58
give the equation for response..
[max response X (conc of agonist)to the power of the slope factor]/ [(conc of agonist)to the power n] + ([EC50]to the power of n)
59
what can response vary depending on?
can vary depending on the number of ligand binding sites. for example nicotinic receptors have two sites.
60
what does the potency of an agonist depend on?
the affinity, efficacy and spare receptors.
61
what's the relationship between EC50 and potency?
the higher the EC50 the lower the potency.
62
what causes this relationship between EC50 and potency?
the high potency drug may have a high efficacy
the high potency drug may have a higher affinity
if the experiment is done in two different tissues there might be varying receptor reserves in the tissues.
63
does the EC50 shift for partial agonists?
it doesn't have to shift, some partial agonists are equipotent.
if they are more potent the EC50 shifts to the left
if they are less potent the EC50 shifts to the right.
64
do partial agonists ever get a full response?
they never get a full response.
65
what is the relationship between occupancy and response in a partial agonist?
how does this differ from a full agonist?
what does this mean for working out affinity?
occupancy is proportional to response.
EC50=Kd
in a full agonist the EC50 is much less than Kd
in a full agonist the EC50 is much lower than Kd.
A response curve can be used to work out affinity but this is only the case in partial agonists.
66
what is efficacy?
it's a measure of a single agonists-receptor complex's ability to generate a response.
67
what happens to the response when a full agonist is mixed with a partial agonist?
the response is lowered, the partial agonist has a lower efficy, this is antagonistic like towards the full agonist meaning this prevents the full agonist binding = a full response can't occur.
68
what do antagonists do?
decrease the activity of the receptor
69
why can the effect of a drug decline when it's given continuously or repetedly?
receptors may be lost from it's surface (intenalisation by endocytosis followed by recycling or degredation)
the receptor may change itself 9 through phosphorylation, resulting in decreased coupling of receptors to effectors)
exhausion of mediators
increased metabolic degradation or extrusion of drug
physiological adaptation.
70
what are the 5 classes of antagonists?
```
chemical antagonism
pharmocokinetic
physiolological antagonism
non competitive antagonists
competitive antagonists
```
71
what happens during chemical antagonism?
drug binds to another drug in solution decreasing it's concentration and preventing activity.
72
what happens with pharmacokinetic antagonists?
drug interferes to effect factors such as absorption, metabolism and excretion of the agonist
73
how does physiological antagonism work?
two drugs have opposing effects, this occurs at the level of the tissue
74
what is non-competitive antagonism?
the drug doesn't interfere directly in the ligand binding site, it acts some where else on the receptor or the effector.
75
what is competitive antagonism?
the antagonist binds directly to the receptor, preventing the agonist from binding.
76
when antagonists are add what happens to the agonist response curve?
there is a parallel shift in conc, slope hasn't changed and the same max response is reached, however more agonist is needed when more antagonist is add.
77
what can agonist max response curves with the addition of antagonists be used to determine?
the affinity of the antagonist
78
what is the dose ratio?
how many more times the agonist is needed in the presence of an antagonist
79
how is the dose ratio calculated?
use an agonist response curve with added antagonist.
use EC50 (or 20, 80) as long as on parallel part of slope.
(conc of agonist in presence of antagonist)/ (conc of agonist in absence of antagonist)
80
what's the schild analysis used for?
to measure antagonist affinity
81
what is the schild analysis equation
DR= [Xb]/Kd +1
Xb= conc of antagonist
Kd =antagonist afficity constant
82
what is PA2 equal to
-logKd
83
what do lower KDs mean for affinity?
the lower the Kd the higher the affinity
84
what's the relationship between PA2 and affinity
the higher the affinity the higher the antagonists affinity for it's receptor.
85
what is irreversible antagonism dependant on?
it's time- dependant
86
what happens to the response curve if the conc of irreversible agonist is increased?
why is this?
at first there's a parallel shift with increasing conc, then there's a decrease in max response.
because reaction irreversible as more antagonist is add = receptor reserve being depleted.
leading to a decrease in max response.
87
what happens if overdose on irreversible antagonists?
nothing can be done, have to wait for tissue to re-synthesize receptors.
88
what do drugs effects depend on?
```
the mechanisms of action and effects on cellular proteins(receptors, ion channels, enzymes, transporters)
physiochemical properties (affinity, efficacy, potency)
pharmokinetics (absorption, distribution, metabolism, excretion)
```
89
how are drugs distributed through the body?
- bulk flow transfer through bloodstream (CVS)
- Diffusion (Conc gradient, would have to be lipid soluble)
- Carriers (transporters, pumps etc)
- Ion channels/pores
90
what does the system a drug uses for distribution depend on?
the drugs properties
91
to diffuse through lipids what physiochemical properties are needed?
lipid solubility - partition coefficient
| diffusivity - diffusion coefficient
92
how is the diffusion of non-polar molecules?
they dissolve freely in lipids and penetrate cell membranes freely
93
what characteristics do lipid soluble drugs have?
they lead to an increased rate of absorption from gut
increased penetration into brain and other tissues
increased renal elimination
94
what are factors effecting drug absorption in the body?
- route of administration
-molecular weight og drug (diffusion)
lipid solubility
pH and ionisation
95
what are the pros of intravenous injection?
the cons?
when is this used?
the fastest route into the plasma, rapid transportation to tissues and also avoids drug being metabolised, bound by other things and biodegredation.
requires specialists
used in bioptics and emergency situations.
96
what are the problems with intramuscular injection?
| what is rate dependant on?
drug has to pass through muscle layers
| rate dependant on site of injection and blood flow to this site.
97
what's intrathecal administration?
pros?
cons?
inject drug into CSF
this is used mainly for anesthetic so you can choose which place is under the anesthetic?
need a specialist to do it
98
what are some of the problems with oral administration?
drugs enters gut before plasma,
some proportion of drug might go to liver and be metabolised.
some might be excreted by kidney
there may be interactions with gut contents
99
when is rectal administration usually used?
for young children or if some one is vommitting.
100
what is percutaneous administration?
what type of administration is this?
what does it depend on?
administration through the skin
long and slow
depends on properties of drugs
101
how does inhalation administration work?
| when is this used?
drug into the lungs then into the plasma
used if want drug to act in lungs
used for general aneasthetics
102
why does pH and ionisation effect absorption?
many drugs are weak acids or bases.
at low pH weak acids will be unionised, only uncharged species can cross lipids.
have to measure the balance of charged and uncharged..
103
why do weak acids become trapped in basic compartments?
basic compartments favour dissociation of acids, causing them to form ions, can't diffuse.
104
why is carrier mediated transport used?
| what is it dependant on?
it's to transport polar molecules
| it's dependant on saturation and competitive inhibition by the natural substrate for that carrier
105
what's the distribution of drugs based on?
permeability and lipid solubility and also if the drug gets trapped in a body compartment due to binding.
106
how does the blood-brain barrier regulate drug access to the CNS?
the endothelial cells lining blood vessels of the CNA form tight junctions that are impermeable to water soluble molecules.
107
why can some meningitis be treated with IV penicillin?
because during inflammation tight junctions become leaky, because of this leakiness the penicillin can reach the brain.
108
what's bioavailability?
the fraction of injested drug that gains access to circulation
109
what is the chemoreceptor trigger zone?
how can this be inhibited?
why would it be inhibited?
it triggers a vomitting response. it has receptors for dopamine
inhibited by giving domperidone which is an antagonist for the receptors.
this can stop vommitting, useful if given a drug that induces vomitting.
110
why is drugs binding to plasma proteins an issue?
the drug is then unavailable, this meaning the bioavailability is reduced.
also there's a difference in equilibriums when adding a drug and it's binding to proteins than when all plasma protein is bound (free drug conc shoots up)
it can lead to unexpected drug interactions and toxicity.
111
why does Sulphomanide need a high dosage?
binds to albumin well (plasma protein) and has a low affinity for it's target.
112
what properties does a drug need to have to enter brain? what problem does this cause?
has to be lipophillic to cross plasma memba and BBB
| problem as it will also enter body fat.
113
why do drug dosages have to be increased for people with a larger % of body fat?
because less drug will reach the target as it will enter more body fat.
114
what's the main problem with drugs entering body fat?
it effects the duration of drug effects, drug is slowed down from entering back into circulation.
the drug isn't eliminated as fast
"drug hangover" as have to wait for drug to leave body fat.
115
what are the two biochemical reactions in drug metabolism?
phase 1 - catabolic reactions, can produce a more reactive compound
phase 2 - synthetic reactions, involves conjugation to produce inactive product.
116
how is the liver involved in metabolism of drugs?
| what properties must a drug have to be metabolised in the liver?
it has microsoma enzymes intracellularly such as cytochrome P450, alcohol dehydrogenase and MAO.
the drug must be able to cross the plasma membrane (lipid soluble or able to bind to specific transporter)
117
what's different about pro-drugs?
| when can these be beneficial?
pro-drugs only become active after metabolized, in their original state they are inactive.
when undergo the first phase of metabolism the free active drug is liberated.
can be beneficial when a constant low conc of drug is needed.
118
what happens during the elimination of asprin?
it undergoes phase one of metabolism and produces a derivative, this derivative is still active however it usually undergoes phase two rapidly.
after phase two a conjugate is formed, the diffusion is altered due to an increase in Mr.
119
why can paracetamol be toxic?
because the derivative from phase one is toxic to the liver, however if take the right amount then the intermediate is rapidly conjugated.
120
what happens if cytochrome p450 enzymes are upregulated/ downregulated.
the metabolism of other drugs are effected.
if upregulated then metabolism is increased meaning the effective conc of drug is higher than usual.
if downregulated then the effective concentration is lower than usual.
121
how do sprouts and grapfruit juice effect cytochrome p450?
sprouts - upregulate p450
| grapfruit juice - downregulate
122
what are the routes of drug elimination?
urine
faeces
milk and sweat
expired air
123
what happens to lipophillic drugs during elimination?
they aren't eliminated through the kidney well, they have to be conjugated.
124
what is the problem with elimination of polar drugs?
some go straight to the kidney without acting.
125
why can renal disease lead to toxicity?
because it can effect drug clearance
126
how can transporters effect the rate of excretion?
because the transporters may become saturated
127
how can excretion of acidic polar drugs be effected?
they can become dissociated at high pHs of urine, leading to them becoming trapped and easily excreted.
128
what is the drug half life?
when the drug is at half conc
