M&R session 8: drugs and receptors Flashcards
What is the relationship between concentration and molarity?
Drugs at equal molar concentrations have the same concentration of drug molecules, but drugs at equivalent concentration by weight may not.
molarity (M)= concentration (g/L)/molecular weight
Drugs usually in concentrations of uM or nM units:
uM=10^-6 M
nm=10^-9 M
What is the difference between antagonists and agonists?
ANTAGONISTS: block the binding of an endogenous agonist. They only possess affinity: unable to convert receptor into an active conformation
AGONISTS: activate a receptor, governed by intrinsic efficacy, then things must happen to generate response. They have affinity, intrinsic efficacy (can activate receptor) and efficacy (can generate a measurable response)
What is intrinsic efficacy?
How good an agonist is at generating the active state of the enzyme
What is efficacy and what does it determine?
The ability of a ligand to cause a response. Governed by the intrinsic efficacy plus other things that influence the response
How might affinity (binding) be measured?
- Binding a radioligand to cells or membranes (to find KD)
2. Pharmacologically to find KA (KD equivalent)
What is Bmax and KD?
Bmax: the maximum binding capacity, so gives information about receptor number. Highest point reached on graph as proportion of bound receptors
KD: the dissociation constant. The concentration of ligand at 50% binding of the available receptors. Measure of affinity: lower KD=higher affinity. Read off graph for [drug] where there is 50% of receptors bound
What does a high KD value indicate?
Low affinity
What is a logarithm?
An exponent by which a fixed base value has to be raised to give a particular number
What is IC50?
The inhibiting concentration giving 50% of the maximum inhibition. Used in inhibitory drugs
What could a response of a drug be?
- Change in a signalling pathway
2. Change in a cell or tissue behaviour
What do the values of Emax and EC50 refer to, and where are they found on a concentration-response curve?
Emax: maximum effect (highest point on curve)
EC50: effective concentration giving 50% of the maximal response. Describes the POTENCY of the agonist (depends on both affinity and intrinsic efficacy, in addition to the cell/tissue-specific components). Find the drug concentration at 50% of maximum response
What is required for a ligand to have potency (generate a measurable response)?
- Affinity (ligand binding to effector)
- Intrinsic efficacy (receptor activation)
- “Things” to generate a measurable response, e.g. no. receptors
2+3 constitute efficacy
The same potency could occur with different combinations of affinity and efficacy
E.g. drugs with identical affinites (same binding occupancy curve) could have different efficacies (one having a faster response than the other)
What is the difference between concentration and dose>
Terms often used interchangeably, but:
- CONCENTRATION: known concentration of drug at site of action e.g. in cells and tissues
- DOSE: concentration at a site of action that is unknown, e.g. the dose given to a patient in mg/kg
What factors are considered in the study of a drug?
Potency: affinity (does it bind?) and efficacy (does it do what its supposed to? zero/low=antagonist or antagonist; high=agonist)
Selectivity: are there off-target effects?
Pharmokinetics: how does the body metabolise it?
Physiochemical properties: solubility, pH, stability, crystallinity
Describe the therapeutic products used to treat asthma
SALBUTAMOL: agonist to relieve symptoms quickly when needed by reversing bronchoconstriction. 20-fold B2 selective (over B1; as B2 has lower Kd) which is poor selectivity but the affinity is increased by B2-selective efficacy and the route of administration (inhaled)
SALMETEROL: long acting agonist to relieve symptoms. 3455-fold B2 selective (good), but no selective efficacy (so selectivity is based on the affinity)
Problems with asthma drugs?
Salmeterol is insoluble
Salbutamol is also a beta 1 adrenoceptor agonist so speeds up heart rate
Need for drugs with enhanced selectivity: affinity and/or efficacy
Explain the concept of spare receptors
Can have
What is the effect of changing receptor number?
Changes agonist potency and can affect the maximal response
Receptor numbers are not fixed: how do they change?
Increase with low activity (up regulation)-can lead to hypersensitivity reactions
Decrease with high activity (down regulation)-can lead to tolerance/tachyphylaxis
Both of these changes in receptor number can be due to physiological, pathological or drug-induced changes
Describe the differences between full and partial agonists
Full agonists: EC50
Why might a partial agonist have a high potency despite having a low maximal effect?
Potency of partial agonist is the concentration to produce half of IT’S maximum effect (usually sub-maximal for the tissue), so even though maximal effect is low, potency could still be high if the drug binds with high affinity
How could a partial agonist have a better clinical effect than a full agonist?
If only a small proportion of receptors need to be activated to produce a clinical effect , then a partial agonist with a higher potency could produce a larger response at a given low concentration of drug than a full agonist at a lower potency
Describe why buprenorphine can be advantageous over morphine in certain clinical settings
Buprenorphine has a higher affinity than morphine (lower Kd), but a lower efficacy (inability to produce a full response). This can be advantageous for pain control, as morphine acts more strongly at u-opioid GPCRs, causing respiratory depression so buprenorphine has less effect
Why does injecting buprenorphine instead of heroin (diamorphine) produce undesirable effects?
Heroin is a full agonist at the u-opioid receptor; if inject buprenorphine becomes very ill due to the withwarawl effects and partial agonism. The bunprenorphine is usually a partial agonist but in absence of heroin acts as an antagonist so occupies receptors, limiting response
How can opioid addiction be treated?
Buprenorphine can enable gradual withdrawal and produce the use of other illicit opioids
Why are partial agonists not always partial agonists?
It is compound and system-dependent. Increasing receptor number can change a partial agonist into a full agonist. The partial agonist still has low intrinsic efficacy at each receptor, but sufficient receptors to generate a full response. Although they have lower efficacy than full agonists, it is possible for FA with identical intrinsic activities to have different efficacies
Difference between clinical and pharmacological meaning of efficacy?
In clinical terms it is often used to describe how good a drug is at producing a response
Describe reversible competitive antagonism
- needs dynamic equilibrium between L and R
- greater [antagonist]=greater inhibition
- IC50: index of antagonist potency, determined by strength of stimulus ([agonist])
- Kd: to describe antagonist affinity
- KB: when derived pharmacologically
- compete with agonists for binding: inhibition is SURMOUNTABLE (can be overcome with increased agonist)
- cause a parallel shift to the right of the agonist concentration-response curve
Action of naloxone
A reversible competitive antagonist which has high affinity at u-opioid receptors. Can be used to reverse opioid-mediated respiratory depression as its high affinity means it will compete effectively with other opioids e.g. heroin for receptors
Describe irreversible competitive antagonism
- antagonist dissociates slowly/not at all
- more [antagonist] or more time: more receptors are blocked. Therefore is NON-SURMOUNTABLE
- cause parallel shift to the right of the agonist C-R curve
- at higher concentrations suppress the maximal response, as spare receptors are filled by antagonist so there are insufficient receptors for a full response
Action of phenoxybenzamine
Non-selective irreversible alpha 1 adrenoceptor antagonist used for hypertension episodes in pheochromocytoma. Prevents the action of adrenaline which would cause excess vasoconstriction
Describe non-competitive antagonism
- Endogenous ligand binds to the orthosteric site, antagonist binds elsewhere (ALLOSTERIC sites)
- provide binding for agonists and non-competitive antagonists
- effects similar to irreversible competitive antagonism, need additional experiments to distinguish
Describe allosteric regulation of GPCRs
Higher receptor subtype selectivity, non-competitive, often require orthosteric ligand. E.g. cinacalet: positive allosteric modulator of the calcium signalling receptor; stimulates calcitonin release from C cells of thyroid so used in hyperparathyroidism
What is tachyphylaxis?
Aka desensitisation
Increased exposure to an agonist causes receptor downregulation
What is supersensitivity?
Over-expression of a receptor to counter the chronic administration of antagonist. If the antagonist treatment is then removed, there are now more unoccupied receptors available to the endogenous agonist and supersensitivity results.
What mechanisms may be responsible for receptor desensitisation?
- Change in receptor properties: change to desensitised conformation due to prolonged agonist binding, receptor phosphorylation or binding of inhibitor protein
- Loss of receptors: reversible internalisation of receptors by RME (can be recycled), irreversible loss by endocytosis to lysosomes
What do homologous and heterologous receptor desensitisation mean?
Homologous desensitisation: the process by which only the signal from the stimulated receptor is reduced, signalling through other receptors is not affected
Heterologous desensitisation: the process where receptors for other agonists become less effective, even though only one has been continuously stimulated. Likely to involve negative feedback on a signalling pathway common to both the stimulated receptor and others. Receptor phosphorylation is commonly associated §
What might be the effect of increased breakdown of the agonist on the response of a drug?
Tissue desensitisation
What is the effect of receptor recycling in receptor REsensitisation?
Restores the levels of receptor in the plasma membrane
Why can receptor supersensitivity to beta blockers cause problems if a patient suddenly stops taking it?
May suddenly increase heart rate and contraction, increasing O2 consumption and potentially causing MI
