M&R S8 - Drugs and Receptors Flashcards
What is a drug target?
Something a drug binds to to exert its effect
Majority are proteins
Some bind to DNA (E.g. Anti-microbial and anti-tumour drugs)
Give the different types of drug targets and percentage of drugs that bind to that target type
Enzymes (47%) GPCRs (30%) Ion channels (7%) Transporters (4%) Nuclear hormone receptors (4%) Other receptors (4%) Integrins (1%) Miscellaneous (2%)
What is the function of agonist drugs?
What is the function of antagonist drugs?
To mimic endogenous ligands
To block endogenous ligands from binding to their target
What is the relevance of concentration of drug molecules around receptors?
Critical to determining drug action
What is the difference between two solutions of equivalent molar concentration and two solutions of equivalent concentration by weight?
Solutions of equivalent molar concentration have the same number of molecules
Solutions of equivalent concentration by weight may not
What is the definition of Affinity?
Likelihood of a ligand binding to its target
What is the definition of efficacy?
The likelihood a drug bound to its target activates the target
What is the difference between agonists and antagonists in terms of efficacy and affinity?
Agonists:
- Have both an affinity and efficacy
Antagonist:
- Have Affinity
- Not efficacy (as binding doesn’t result in activation)
What factors does the ability of an agonist to cause a response in a cell or tissue depend on?
What do these factors combined equate to?
Intrinsic Efficacy:
- The ability to produce an active form of the receptor
Other cell/tissue dependent factors
These factors combined reflect efficacy
Do most drugs bind reversibly or irreversibly to targets?
Reversibly
What governs the amount of drug bound to receptors at any given time?
Association and dissociation rates
Binding obeys the law of mass action:
- It is related to the concentrations of reactants and products
Explain the term ‘KD’
On what type of graph might it be seen?
KD is the dissociation constant
It is used as a measure of drug affinity
It gives the [drug] required to reach 50% receptor occupancy
Lower KD = Higher affinity
Seen in graphs plotting [drug] against receptor occupancy
How is information about drug binding obtained?
Using radioactive versions of the drug in question
‘Radioligands’
In graphs that plot [drug] against other factors, how is [drug] commonly expressed?
Logarithmically
What is meant by the term Bmax?
On what type of graph would it be found?
Bmax is the maximum binding capacity
This gives information about the number of receptors available for binding to ligands
Found on graphs plotting [drug] against receptor occupancy
What is the difference between a concentration response curve and a dose response curve?
What do the axis show in each graph?
Concentration response curves used in measuring the response in tissues/cells
Dose response curve used in measuring the response of the whole animal
X axis = [drug]
Y axis = Response (%)
What is the Emax?
In what graphs does an Emax appear?
Emax is the maximum response of a cell/tissue/organism to a drug
Emax appears on concentration response curves and dose response curves
What is EC50?
The effective [drug] giving 50% of maximum response (Emax)
EC50 is also a measure of potency (a combination of both affinity and efficacy + number of receptors)
What is IC50?
The [antagonist] that give 50% of maximal inhibition
Will two agonists with identical Emax have identical efficacy?
Explain your answer
Not necessarily
Affinity may differ between the two agonists
This means the relationship between occupancy and response will be different
One may be more able to convert binding into function
Discuss how affinity and efficacy affect salbutamol
Salbutamol is a B2 adrenoagonist
Kd = 20uM for B1 Kd = 1uM for B2
Affinity is 20x higher for B2
Salbutamol also has has B2 selective-efficacy (efficacy is higher for B2 than B1)
Along with route of administration (oral spray), this helps prevent unwanted side effects through activation of B1 receptors
Compare Salmeterol to salbutamol
Salmeterol is a longer lasting B2 adrenoagonist as compared to salbutamol
Kd = 1900nM for B1 Kd = 0.55nM for B2
Therefore salmeterol affinity is 3,455x higher for B2
This is much better than the 20x higher affinity for B2 shown by salbutamol
Salmeterol shows no selective efficacy
Explain the issues surrounding the treatment of an acutely ill severely asthmatic patient with either salmeterol or salbutamol
Assume the patient is unable to use an inhaler
Describe an ideal drug in this situation
Salmeterol is preferable, as there is relatively lower B1 affinity, however it is insoluble, so cannot be given via IV
Salbutamol has relatively high B1 affinity as compared to B2 affinity leading to increased side effects such as increased heart rate
An ideal drug in this situation would have relatively little B1 activation (as in salmeterol) but would be soluble so as to be given by IV
Briefly explain the concept of spare receptors
Often the case that less than 100% occupancy will give 100% response
i.e. EC50 < Kd
Some tissues must therefore have more receptors than are required to produce maximum response, these are spare receptors (receptor reserve)
What influences the relationship between receptor occupancy and response?
The transduction system and amplification by secondary messengers
Properties of the tissue
What is the function of spare receptors?
Increase sensitivity of the tissue, allowing for responses at low concentrations of agonist
To put it another way, it is easier to obtain maximal response when not all receptors need to be filled (think about the shape of binding curves)
How might a cell react to having lower or higher than normal activity of a specific receptor type?
The number of receptors in a cell is not fixed
Number can increase (up-regulation) in response to low activity and increase sensitivity, raising activity
Number can decrease *down-regulation) in response to high activity and decreases sensitivity, lowering activity
In what 3 conditions is maximal response of a receptor not achieved?
The [drug] is too low to reach occupancy needed for Emax
There are not enough receptors available to reach Emax
The [drug] is only a partial agonist
What is a partial agonist?
Some drugs cannot reach Emax even with maximum receptor occupancy reached
This is a partial agonist
Describe the relationship between EC50 and Kd of a partial agonist
Explain your answer
EC50 = Kd
Half of maximal response (EC50) of a partial agonist is always obtained by 50% receptor occupancy (Kd) as there are no spare receptors when Emax/Bmax is reached
Are partial agonists less potent than full agonists?
No, partial agonists can be less or more potent than full agonists
What are opioids used for?
What is one major side effect?
How type of drugs are opioids?
Used for:
- Pain relief
- Recreationally
Side effect:
- Respiratory depression - can lead to death
Drug type:
- u-opioid receptor (GPCR) agonists
Compare morphine and buprenorphine
Why might buprenorphine be advantageous compared to morphine?
Morphine is a full agonist
Buprenorphine is a partial agonist
Morphine has a lower affinity but higher efficacy
Buprenorphine may be advantageous in some situations:
- If pain is not too great then it may provide adequate pain relief with less respiratory depression
Carl the heroin addict injects buprenorphine, why does he become ill?
Buprenorphine is not having the maximal response that his body is used to and would satisfy his cravings
He begins to withdraw, becoming ill
When might a partial agonist become a full agonist?
If more receptors are available then more of the partial agonist can bind and a signal for maximum response can be achieved and the partial agonist now acts like a full agonist
Note: you would still need a greater concentration of the partial agonist than a full agonist to achieve maximal response
What are the 3 types of antagonist?
Reversible competitive antagonism
Irreversible competitive antagonism
Non-competitive antagonism
Describe reversible competitive anatagonism
Most common form in therapeutics
Relies on a dynamic equilibrium between ligands and receptors
Introducing reversible antagonists shifts the [agonist]/response curve to the right
Doesn’t effect Emax
Antagonism can be overcome by increasing [agonist] (shifts the curve back to the left)
Describe irreversible competitive antagonism
Occurs when the antagonist dissociates slowly or not at all
Shifts the [agonist]/response curve to the right
No loss in Emax until all spare receptors are filled
Then Emax is lowered as available receptors for the agonist to bind is reduced below the level required for maximal response
The inhibition cannot be overcome by increasing [agonist]
Describe non-competitive antagonism
The allosteric binding of an antagonist to a receptor not at the ligand binding site
Give an example of a drug that is a reversible competitive antagonist
Include it’s use and explain why it is suitable
Naxolone
High affinity u-opioid antagonist
Used to reverse opioid induced respiratory depression
The high affinity means it competes effectively with other opioids for receptors
Give an example of a drug that is an irreversible competitive antagonist
Include its use
Phenoxybenzamine
Non-selective irreversible A1 adrenoceptor antagonist
Used in hypertension episodes in pheochromocytoma (which causes excessive noradrenaline/adrenaline release)
Give an example of a drug that is a competitive antagonist
Ketamine
NDMA receptor antagonist
NDMA-R is an ion channel, ketamine closes the ion channel causing analgesia (at low concentrations)
What is receptor desensitisation?
Receptor desensitisation is a reduction in tissue response to an agonist following exposure to that agonist
Many mechanisms might be responsible
Give some of the possible mechanisms of receptor desensitisation
Binding to an agonist/antagonist
Irreversible agonist binding
-ve feedback
Decrease in receptor numbers expressed due to repeated activation
What is homologous desensitisation?
The desensitisation of one type of receptor in response to prolonged exposure to high levels of agonist
What is heterologous desensitisation
The desensitisation of a broad category of receptors in response to prolonged activation of one type of receptor in that category
What other mechanisms may underlie a tissue becoming desensitised to a drug?
Pharmacokinetic tolerance
Drug is metabolised faster as expression of relevant enzymes is increased
An agonist is applied to a tissue, then applied again a few minutes later and a smaller tissue response is seen, this ‘tolerance’ only persists for a few minutes
Give a likely mechanism
Agonist binds covalently to the receptor
This prevents more agonist binding until the agonist dissociates
When second round of agonist is applied some of the original application won’t yet have dissociated and will limit tissue response
Agonist is applied to a tissue and then the tissue is washed, a second application of agonist is done immediately after washing
What difference will there be in tissue response?
Almost none
Short term desensitisation due to receptors being blocked by agonist still bound is negated by washing
By what 3 mechanisms can GPCRs become desensitised?
Give a short description of each
Modification of receptor by phosphorylation:
- Receptor is phosphorylated preventing the G proteins from binding
- Fast acting
Reversible receptor internalisation:
- Receptors on the membrane are taken into the cell and into endosomes before being recycled back to the membrane
Down-regulation:
- Expression of the gene(s) encoding for receptor is reduced so less receptor is available for agonists to bind to
Which mechanism of GPCR desensitisation is most commonly associated with heterologous desensitisation?
Phosphorylation modification of receptor
Enzymes which phosphorylate the receptor can be non specific and desensitise other GPCR types
Which mechanism of GPCR desensitisation is most likely to underlie drug tolerance?
Long term drug use will trigger down-regulation of the relevant receptors, which will cause the receptor desensitisation
What is receptor supersensitivity?
Suggest how B-adrenoceptor supersensitivity might be induced
The over-expression of receptors due to prolonged reduction in tissue response
Treatment with B-adrenoceptor antagonists will reduce tissue response to endogenous ligands and the receptor expression will be up-regulated
If treatment with antagonists is stopped there will be excess receptors and receptor supersensitivity can occur
How can termination of treatment with B-adrenoceptor antagonists cause a heart attack?
Receptor supersensitivity occurs due to treatment
Lack of antagonist causes adrenaline and noradrenaline to produce a greater tissue response
BP and HR rise, this can lead to ischaemia and subsequent myocardial infarction
How can receptor recycling resensitise a membrane?
Receptors that have been desensitised can be replaced from receptor reserves in the endosomes
Addition of receptors from the endosome to the cell membrane can therefore restore sensitivity and correct tissue response
