Lecture 3. Pharmacodynamics

Question 1

What are receptors?

Answer 1

Proteins inserted into the membrane which bind neurotransmitters, hormones etc and produce a cellular response

Question 2

What are four different types of receptors?

Answer 2

1. Ligand gated ion channels (ionotropic)
2. G-protein coupled receptors (metabotropic)
3. Kinase-linked receptors
4. Receptors linked to gene transcription (nuclear receptors)

Question 3

What responses caused by agonists can be measured experimentally?

Answer 3

Muscle contraction
Electrical current/change in membrane potential (electrophys)
Production of a second messenger (cAMP, IP3 etc) Inhibition of transmitter release change in heart rate, blood pressure etc

Question 4

What do agonists do?

Answer 4

Agonists bind to receptors, creating an AR complex which then causes a response

Question 5

What is the standard way of measuring agonists?

Answer 5

Using a log concentration graph

Question 6

What does EC₅₀ mean?

Answer 6

The concentration of agonist that causes 50% of the maximum response

Question 7

Why is there a maximum response?

Answer 7

1. Finite number of receptors: all occupied (response = α[AR])
2. Property of tissue/cell (for example maximum muscle contraction)

Question 8

What is affinity?

Answer 8

How well a drug binds to the receptor

Question 9

What is efficacy?

Answer 9

The measure of the response once a drug is bound to the receptor

Question 10

What is potency?

Answer 10

The combination of both affinity and efficacy

Question 11

What does Kd tell us?

Answer 11

The concentration of drug required to occupy 50% of the receptors

Question 12

What does a lower Kd result in?

Answer 12

Higher affinity

Question 13

How do you calculate the proportion (P) of receptors occupied?

Answer 13

P = [Drug]/(Kd+[D])

Question 14

Why can’t ligand affinity be measured?

Answer 14

It involves a combination of affinity and efficacy

Question 15

What occurs in a ligand bidning assay?

Answer 15

Displacement of radio-labelled ligand (³H, ¹⁴C or ¹²⁵I) by cold ligand

Question 16

How can the concentration of bound ligand be calculated?

Answer 16

[bound] = Bmax Xa / (Xa + Kd)
Xa = concentration of ligand
Bmax = total number of binding sites in prep (pmol/mg protein)

Question 17

What occurs in desensitisation/tachyphylaxis?

Answer 17

Loss of receptors (internalisation)
Exhaustion of mediators
Physiological adaptation (homeostatic response)

Question 18

What is the difference between receptor desensitisation and tachyphylaxis?

Answer 18

Tachyphylaxis when response in muscles get smaller

Question 19

What are clinical uses for agonists?

Answer 19

Adrenaline (heart: increase rate and force of contraction) also anaphylactic shock
Salbutamol (asthma)
Oxymetazoline (nasal congestion)
Dopamine (heart, increase rate and force of contraction)
Morphine (analgesic for severe pain) (opiate receptor agonist)

Question 20

Do partial agonists have lower affinity than full agonists?

Answer 20

Partial agonists can have a higher affinity than full agonists, they’ll just have a much lower efficacy

Question 21

In theory, what are the clinical uses of partial agonists?

Answer 21

Reduce over-activity but not block basal activity

Question 22

What do inverse agonists reduce?

Answer 22

A receptor’s constitutive activity (activity that goes on without any agonist)

Question 23

What are many antagonists?

Answer 23

Inverse agonists

Question 24

What increases the opening of the GABA-A receptor?

Answer 24

Benzodiazepines (BZ)

Question 25

What decreases the opening of the GABA-A receptor?

Answer 25

Inverse agonists

Question 26

What is an antagonist’s potency?

Answer 26

pA₂
Negative log of the molar concentration of antagonist that reduces the effect of a known concentration of agonist to that of half the concentration

Question 27

What does a bigger pA₂ mean?

Answer 27

The bigger the pA₂ value the better the antagonist

Question 28

How can the spare receptor reserve be measured?

Answer 28

With an irreversible antagonist

Question 29

What does the existence of spare receptors show?

Answer 29

Do not need to occupy all receptors for full response Thus Kd does not always equal EC₅₀

Question 30

What are the two theories to why spare receptors exist?

Answer 30

1. Allows maximum response without occupying all receptors: increases system sensitivity (as need less ligand)
2. In theory: the additional receptors can mop up excess agonist preventing an exaggerated response

Question 31

What are examples of clinically used non-competitive antagonists?

Answer 31

Ketamine is a non-competitive NMDA receptor antagonist
Perampanel is a non-competitive AMPA receptor antagonist

Question 32

What is an example of a toxin that is an irreversible anatgonist?

Answer 32

α-bungarotoxin (nicotinic receptors)

Question 33

The greater a receptor/ion channel is activated, the greater the what?

Answer 33

Block