Theories of Drug Action at Receptors

Question 1

Explain action of receptors

Answer 1

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

Question 2

Explain different types of endogenous messengers

Answer 2

• 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

Question 3

Explain 4 main super families of receptor

Answer 3

• 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

Question 4

Explain some common drug targets- giving examples

Answer 4

• 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)

Question 5

Explain drug receptor interaction

Answer 5

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

Question 6

What is the affinity

Answer 6

• 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

Question 7

What is efficacy

Answer 7

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

Question 8

What does an agonist do? What can this result in?

Answer 8

This binds and activates the target- so has affinity and efficacy
This can result in unwanted side effects

Question 9

What does an antagonist do?

Answer 9

• Binds and blocks the receptor from agonist
• Only has affinity
• If [agonist] is high enough effect of antagonist can be overcome

Question 10

What is the law of mass action

Answer 10

Rates of binding are proportional to concentration

Question 11

What is Kd and how is this derived

Answer 11

• 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]

Question 12

What is the receptor occupancy?

Answer 12

Proportion of receptors occupied by the agonist

Question 13

Why is Kd useful?

Answer 13

• 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

Question 14

Compare the binding affinity and specificity of formoterol and salbutamol for airway adrenoceptors in asthma

Answer 14

• 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

Question 15

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)

Answer 15

See sigmoidal shaped curve

• As concentration increases airways relax more
• either side of concentration there is a 100 fold difference due to logarithmic relationship

Question 16

What is the Rmax and what does this value mean in terms of efficacy?

Answer 16

• 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)

Question 17

What is the EC 50 value

Answer 17

Concentration that gives you 50% of the pharmacological response
Determines potency

Question 18

Difference between Kd and EC50

Answer 18

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

Question 19

Explain differences in RC50 and R max values of adrenaline and salbutamol

Answer 19

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

Question 20

What is receptor reserve

Answer 20

• Seen in full agonsist

- Not all of the drug needs to be bound to the receptor to have maximum response

Question 21

What does CRCs depend on?

Answer 21

1) drug- receptor interaction: agonist affinity and efficacy
2) Properties of functional response e.g. amplification

Question 22

Explain properties of the most common type of antagonist. Is it surmountable? Give e.g.

Answer 22

• Competitive and reversible
• Surmountable by increasing agonist concentration
• Formoterol VS
  propranolol B2 adrenoceptor competitive antagonist

Question 23

Effect of competitive antagonist on concentration response curve

Answer 23

• agonist potency (EC50) reduced
• not its maximum response (Rmax)
• Hence we see rightward shift in concentration curve

Question 24

What about non-competitive antagonism- what happens? Give e.g. Any structural similarities to agonist?

Answer 24

• 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

Question 25

Effect of non-competitive antagonist on concentration response curve

Answer 25

• 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