Theories of Drug Action at Receptors Flashcards
Explain action of receptors
1) Selective binding site on receptor to endogenous hormone/ transmitter (one that originates from within an org e.g. acetylcholine)
2) Changes receptor from inactive to active state
3) Activates a secondary messenger system- in which we have amplification of signal
4) Intracellular response brought about through activation of protein kinases
Explain different types of endogenous messengers
- small metal ions (often have fast response
- Gases
- Amino acids
- Biogenic amines e.g. acetylcholine, adrenaline
- Lipids e.g. oestrogen/ prostaglandins
- Peptides- insulin, substance P
- Protein hormones e.g. growth hormones
Explain 4 main super families of receptor
- Ligand gated ion channels e.f. acetylcholine reacting with nicotinic receptor
- G protein coupled receptors- involved in secondary messenger response
- Catalytic receptors- e.g. insulin activates tyrosine kinase receptor, causes phosphorylation of tyrosine residues on receptor and triggering intracellular events that lead to glucose uptake
- Nuclear receptors- steroid hormones go into cell, bind to nuclear receptors affecting transcription and causing longer term affects
Explain some common drug targets- giving examples
- Enzyme: aspirin is an inhibitor of cyclooxygenase involved in formation of prostaglandins
Transporters: Proton pump inhibitors in stomach to manage dyspepsia
Ion channels: voltage gated channels in anaesthesia can be prevented from opening
Receptors: Interact with agonists (activate receptor) or antagonists (block receptor)
Explain drug receptor interaction
Drug + receptor unbound–> DR inactive–> DR active–> response
Known as the law of mass action: as the agonist binds to the receptor this causes a conformational change activating the receptor
As the receptor has a molecular switch
It will then bind to a G couples protein receptor causing cascade
What is the affinity
- Affinity- ability of the agonist to bind to receptor
- Want to have a high affinity so we only need a small concentration of drug to bring out effect
What is efficacy
Efficacy: Measure of the ability of the agonist/ drug to activate the receptor by a conformational change
- Idea of receptor having molecular switch to become activated
- measure of the size of a response
- Some drugs may have a full efficacy (able to produce full response), partial efficacy (partial agonists) or no efficacy (antagonist)- cannot activate receptor so no response
What does an agonist do? What can this result in?
This binds and activates the target- so has affinity and efficacy
This can result in unwanted side effects
What does an antagonist do?
- Binds and blocks the receptor from agonist
- Only has affinity
- If [agonist] is high enough effect of antagonist can be overcome
What is the law of mass action
Rates of binding are proportional to concentration
What is Kd and how is this derived
- measure of binding affinity
- concentration of drug needed to occupy 50% of receptors
- If low= higher binding affinity
- measured using the receptor occupancy and radioactive markers
- Equilibrium dissociation constant
D + R DR
-at dynamic equilibrium
Kon[D][R]= Koff[DR]
therefore Koff/Kon= [d][R]/[DR]
Or Kd= [D][R]/[DR]
What is the receptor occupancy?
Proportion of receptors occupied by the agonist
Why is Kd useful?
- This is useful in determining a affinity for certain receptors
- Most drugs are selective meaning they have a high affinity for 1 target at a particular concentration
- Not specific (only bind to to 1 receptor at all concentrations)
- Affinity needs to be determined at different concentrations to limit side effects of drugs
Compare the binding affinity and specificity of formoterol and salbutamol for airway adrenoceptors in asthma
- Formoterol is more selective than salbutamol for B1/B2 adrenoceptors
- B2 adrenoceptors found in airways
- b1 adrenoceptors found in heart
(REM 1 heart, 2 lungs)
Therefore formoterol less likely to increase heart rate at therapeutic concentrations - Also has a higher affinity for airway adrenoceptors than salbutamol
Explain concentration response curve when adrenaline is released showing log conc of adrenaline ([agonist]) on X axis and airway smooth muscle relaxation on y (functional response)
See sigmoidal shaped curve
- As concentration increases airways relax more
- either side of concentration there is a 100 fold difference due to logarithmic relationship
What is the Rmax and what does this value mean in terms of efficacy?
- Maximum response induced by agonist
- Indication of the efficacy of the drug
- Decides whether full agonist (100% efficacy)
- Partial agonist (<100% efficacy)
- Antagonist (no efficacy)
What is the EC 50 value
Concentration that gives you 50% of the pharmacological response
Determines potency
Difference between Kd and EC50
Kd= measure of the drug receptor interaction
(measure of affinity)
Concentration of drug needed to occupy 50% receptors
EC50- Concentration that gives you 50% of the pharmacological response
- MANY steps between drug- receptor binding and pharmacological response
- Therefore dissociation constant not same as EC50 value
And when we see concentration response curves not direct measure of drug- receptor interaction
Explain differences in RC50 and R max values of adrenaline and salbutamol
Adrenaline- natural neurotransmitter
- Full agonist- Rmax value of 100%
- Efficacy of 1 so able to deliver max response
- Therefore has receptor reserve
- EC50 value higher: less potent drug higher concentration needed to reach 50% of physiological response
Salmeterol- therapeutic B2 agonist
- Rmax value 50 %
- Deliver 50% of maximum adrenaline response
- Therefore it has a lower efficacy than adrenaline (doesn’t cause 100% relaxation at any concentration)
- EC50 value lower: Salmeterol is a more potent drug as less needed to reach 50% of physiological response
What is receptor reserve
- Seen in full agonsist
- Not all of the drug needs to be bound to the receptor to have maximum response
What does CRCs depend on?
1) drug- receptor interaction: agonist affinity and efficacy
2) Properties of functional response e.g. amplification
Explain properties of the most common type of antagonist. Is it surmountable? Give e.g.
- Competitive and reversible
- Surmountable by increasing agonist concentration
- Formoterol VS
propranolol B2 adrenoceptor competitive antagonist
Effect of competitive antagonist on concentration response curve
- agonist potency (EC50) reduced
- not its maximum response (Rmax)
- Hence we see rightward shift in concentration curve
What about non-competitive antagonism- what happens? Give e.g. Any structural similarities to agonist?
- Antagonist binds at a different (allosteric site)
- Pore receptors for ligand gated ion channels e.g. glutamate ionotropic NMDA receptor
- Antagonist memantine blocks ion channel preventing Na+ and Ca2+ passing through
- Hence causing the blocking of the ion channel and not the receptor
- No structural similarities to agonist
- Effects on responses are non- surmountable
Effect of non-competitive antagonist on concentration response curve
- agonist potency (EC50) not reduced still able to bind to receptors and induce half response
- not its maximum response (Rmax)
- Hence we see rightward shift in concentration curve
