Pharmacodynamics- Receptor Theory

Question 1

What governs the agonists ability to activate a receptor?

Answer 1

Intrinsic efficacy

Question 2

Which receptor types can the term affinity be used to describe?

Answer 2

Agonists and antagonists, both need to bind with the receptor and affinity describes how easily they do this.

Question 3

Compare agonists and antagonists

Answer 3

Agonists and antagonists have affinity
Agonists have efficacy as they activate the receptor.
Antagonists lack intrinsic efficacy, they do not activate the receptor- they tend to block endogenous binding.

Question 4

What measurement is most useful for drug concentration?

Answer 4

Molarity!!!

Grams/L doesn’t explain the number of molecules so is useless.

Question 5

What is Kd?

Answer 5

Dissociation constant which is a measure of affinity.
low value means high affinity (Km for a drug), note Kd is the reciprocal of affinity.
50% of available receptor sites bound at drug conc Kd

Question 6

Does it matter how many receptors you have on a cell when determining Kd?

Answer 6

No, because of the law of mass action.

That concentration will occupy 50% of the receptor sites irrespective of the number of sites.

Question 7

Do we want medication with high or low affinity?

Answer 7

High- means smaller tablets.

Question 8

Do drug pharmacist represent drug kinetics graphically in the same way as enzyme kinetics are?

Answer 8

No they tend to use logarithm is drug concentration to give a sigmoidal hyperbol from a rectangular hyperbole.

Question 9

If the number for the loagrithmic drug concentration is negative at 50% binding, what size do you expect Kd to be?

Answer 9

Less than 1.

Question 10

What is a concentration response curve useful for?

Answer 10

Useful for agonists to look at efficacy and calculate the maximum effect
The concentration of drug that gives half the maximum effect (EC50) or potency

Question 11

What is the difference between concentration and dose?

Answer 11

If you talk about concentration the assumption is you know the concentration of the site of action ( at the target cells and tissues.) More experimental.
Dose is what you give to someone and the concentration at the target site is unknown.

Question 12

What factors contribute to the potency of an agonist?

Answer 12

Affinity and efficacy and some cell-tissue specific factors

Potency is the EC50 which is the effective concentration giving 50% of max response.

Question 13

Describe the pharmacological management of asthma?

Answer 13

Physiology would use adrenaline to relax the muscle contraction by binding B2 receptor (GPCR) in the lungs, in asthma we need to use drugs instead.
Functional antagonism- a drug that antagonises the response with out interacting with the causal pathway.

Question 14

Which receptor is found in the heart and the lungs?

Answer 14

B1 in the heart- force and rate of heart increases with adrenaline and nor adrenaline binding.
B2 in the lungs- muscle relaxation with adrenaline and nor adrenaline binding

Question 15

Describe the pharmacodynamic properties of salbutamol.

Answer 15

Affinity 20 times better for Beta 2 found in the lungs (not a big factor difference)
Route of administration and Beta 2 selective efficacy helps utility in asthma treatment.

Question 16

Salmeterol if a long acting asthma inhaler, describe how it differs from salbutamol?

Answer 16

No selective efficacy in salmeterol with selective affinity( 3455 times). Salbutamol is the opposite

Question 17

Name a contraindication for salbutamol ( this is the only asthma treatment we have learnt about that you can infuse. Acutely unwell patients who cannot be nebuliser cannot have salmeterol).

Answer 17

Poor selectivity (equal affinity for B1 and B2 receptor) so effects heart- angina patient is a contraindication.

Question 18

Is salmeterol soluble?

Answer 18

No so it cannot be infused.

Question 19

Is response proportional to number of receptors?

Answer 19

Often not- there is a maximum response so some receptors aren’t actually contributing if it all the receptors were bound.

Question 20

Binding curve is to the right of the response curve- why is this important in pharmacodynamics?

Answer 20

Not all receptors must be bound to get maximum response.

Question 21

Why do spare receptors exist?

Answer 21

Signal amplification and limited post receptor event. A muscle can only contract so much for example. Spare receptors increases sensitivity- low conc of ligand still gets a response.

Question 22

In lungs smooth muscle what percentage of the receptors binding gives the maximal contraction and why?

Answer 22

10% binding gives Emax.

This is important for ligand sensitivity, lots of receptors allows response at low agonist concentrations. If you bind Kd at any receptor number you need the same concentration but more receptors means 50% binding will bind more receptors which will in turn give a larger response at the same agonist concentration.

Question 23

Are receptor number fixed?

Answer 23

No they can up and down regulate.
If the cell feels it’s being over stimulated it will remove receptors. This is why chronic pain patients tend to need higher morphine doses after a period of time.
Conversely if cells are under stimulated more receptors will be presented to try and get an effect.
Cells respond to alter effectivity and sensitivity.

Question 24

List key features of partial agonists:

Answer 24

Lower intrinsic activity giving insufficient efficacy

Question 25

Endogenous Ligands tend to be full or partial agonists?

Answer 25

Full

Question 26

Name a side effect of morphine

Answer 26

Respiratory depression

Question 27

What is the clinical significance of bupremorphine having higher affinity but lower efficacy than morphine?

Answer 27

Bupremorphine has a lower Kd(Higher affinity) but a lower efficacy. Opioid users will get withdrawal on bupremorphine - good to give partial withdrawal and move people off heroin. The receptors are occupied but the effect is lower.
Bupremorphine is less likely to give respiratory depression. It can be used to antagonise heroin.

Question 28

What 2 factors is partial agonism dependent on?

Answer 28

The compound

The target system (lots of receptors can make it a fill agonist).

Question 29

Define efficacy clinically.

Answer 29

How good a drug is at producing a response

Question 30

Do antagonists turn things off?

Answer 30

No they prevent it being switched on.

Question 31

Name 3 types of antagonists

Answer 31

Reversible competitive antagonism

Irreversible competitive antagonism

Non-competitive antagonism (allosteric or post receptor.)

Question 32

What is the IC50?

Answer 32

Concentration of inhibitor (antagonist) that gives you 50% inhibition.

Question 33

What are Kd and KB (pharmacological term) can be used for ?

Answer 33

Measures of affinity for antagonists

Question 34

Which type of antagonist exhibit surmountable inhibition?

Answer 34

competitive antagonists

Question 35

Why is surmount ability clinically relevant??

Answer 35

In overdoses you need to compete with the drug and block it binding. Mew opiod receptor inhibited by Naxalone a competitive inhibitor in heroin overdose.

Question 36

Name an example of a irreversible competitive antagonism.

Answer 36

Pheochromocytoma- a tumour that results in hypertension.
The tumour makes adrenaline which affects the heart and vast smooth muscle.
Phenoxybenzamine which selectively irreversible inhibits the adrenaline at alpha 1 receptors to lower BP

Question 37

What’s a binding site of an endogenous ligand called?

Answer 37

Orthosteric binding site

Question 38

Give an example of a site non-competitive antagonists bind to?

Answer 38

Allosteric sites

Question 39

Allosteric binding sites can effect the receptor in several ways. What result does this have?

Answer 39

Can bind and reduce the affinity or increase the affinity.

Question 40

Name a HIV drug that acts on chemokine5 receptor 5 on leukocyte to stop HIV binding and internalises the virus.

Answer 40

Maravoric- allosteric modulator to stop viral entry to cells

Question 41

What is a ligand?

Answer 41

Molecule or ion that binds specifically to receptor

Question 42

What two actions can drugs have at receptors?

Answer 42

Block endogenous ligand binding - antagoniset

Activate receptor- agonist

Question 43

What is the efficacy of an agonist?

Answer 43

The ability of an agonist to give a measurable response

Question 44

What are the advantageous of partial agonist use?

Answer 44

Allow a more controlled response
Work in the absence of endogenous ligand
If lots of full agonist present can act as an antagonist (by blocking receptors but inducing a lower response)

Question 45

List uses of opiods

Answer 45

pain relief

recreational

Question 46

How does clopidogrol work?

Answer 46

Prodrug- converted by P450 to a metabolite that irreversibly binds platelet P2Y12- antagonist of thrombosis.