Pharmacodynamics

Question 1

What is the law of mass action?

Answer 1

L+RRL

Binding of ligand to receptor is an equilibrium so more ligands present shifts equilibrium to right.

Question 2

What is an antagonist?

Answer 2

A molecule which blocks the binding of an endogenous agonist.

Question 3

What is an agonist?

Answer 3

A molecule which activates a receptor

Question 4

What is intrinsic efficacy?

Answer 4

The ability of the ligand to activate the receptor

Question 5

What is efficacy?

Answer 5

The ability of a ligand to cause a response

Question 6

How do we measure drug receptor interactions by binding?

Answer 6

Bind radioactively labelled ligand to cells or membrane prepared from cells

A graph can be drawn of proportion of receptors bound vs drug concentration

Question 7

What is Kd?

Answer 7

The concentration at which half of the receptors are occupied

It is therefore an index of affinity
Lower value=higher affinity

Question 8

Why is a low Kd important for drugs?

Answer 8

Allows binding at low concentrations so we dont have to give huge amounts of drugs to patients

Question 9

What is EC50?

Answer 9

The effective concentration giving 50% of the maximal response?

Question 10

What is the difference between ‘concentration’ and ‘dose’?

Answer 10

Concentration =known concentration of drug at site of action

Dose=concentration at site of action unknown eg, amount given to patient

Question 11

What is EC50 a measure of?

Answer 11

POTENCY- depends on both affinity and intrinsic efficacy, plus cell specific components that allow something to happen eg. Number of receptors

Question 12

How does adrenaline act as a functional antagonist

Answer 12

It activates B2 adrenoceptors which counteract the contraction of the bronchioles (counteract function so functional antagonist)

Question 13

Why might there be a problem in treating athsma via B2 adrenoceptors? Why is this sometimes ok?

Answer 13

There are B1 adrenoceptors in the heart which increases force and rate which could cause a heart attack to someone with angina, so we need specific activation of B2 adrenoceptors.

Question 14

How is salbutamol selective to B2 receptors and how good is this selectivity?

Answer 14

B2 selective efficacy and route of administration- in other words, it has a slightly 20 fold higher affinity for B2, and is more effective at creating response.
Selectivity is poor as only slightly higher affinity
Route of administration (i.e via lungs)

Question 15

Why is salmeterol selective to B2 adrenoceptors?

Answer 15

Much higher affinity, no selective efficacy

Question 16

Why do spare receptors exist and why are they useful?

Answer 16

Exist because of:
-amplification in signal transduction pathway
Response limited by a post receptor event.

Why- increases sensitivity, makes it easier for Kd to be reached because receptor ligand binding depends on mass action law

Question 17

What does changing receptor number do?

Answer 17

Changes agonist potency and affects maximal response

Question 18

How is receptor number altered?

Answer 18

Up regulation with low activity
Down regulation with high activity
For drugs this can contribute to tolerance /tachyphylaxis

Question 19

What is a partial agonist?

Answer 19

One with a lower intrinsic efficacy so more receptors must be occupied by agonist to produce maximal response

Question 20

How can partial agonists act as antagonists and what is an example of this?

Answer 20

Sits in sites but produces a lower response , buprenorphine produces less of a high than morphine but blocks morphine having an affect so less harmful- used to wean patients off drug

If an addict accidentally injects this then will experience withdrawal symptoms

Question 21

How can a partial agonist stimulate a full response?

Answer 21

If it binds to enough receptors it can stimulate 100% response even though it has lower efficacy

Question 22

What is IC50?

Answer 22

The concentration of antagonist giving 50% inhibition

Question 23

What does surmountable inhibition?

Answer 23

The inhibitor can be out competed by adding more agonist

Question 24

Which way to reversible competitive antagonists move the concentration response curve?

Answer 24

Adding antagonists move the curve to the right

Question 25

How can competitive inhibition be used clinically in treatment of opioid mediated respiratory depression?

Answer 25

Haloxone is a high affinity competitive agonist at mu opioid receptors to competes with other opioids for receptors and stops them binding.

Question 26

What effect do irreversible competitive antagonists have on the shape or position of the agonist response curve?

Answer 26

Move it to the right then suppress maximal response as spare receptors run out.

Question 27

How can irreversible competitive antagonists be used clinically?

Answer 27

Used in treatment of pheochromocytoma- tumour in kidney produces too much insulin which causes constriction of blood vessels and therefore hypertension

Phenoxybenzamine is used to irreversibly inhibit binding sites of alpha 1 adrenoceptors so adrenaline cannot bind and cause blood vessel contraction.

Question 28

What is the site called at which endogenous ligands bind to GPCRs?

Answer 28

The Orthosteric site

Question 29

What is the effect of non competitive antagonism?

What is an example of a drug which uses this?

Answer 29

No competition for binding site so reduce orthosteric ligand affinity and or efficacy - similar pharmacological effects to irreversible competitive antagonism

Maraviroc- negative allosteric modulator of chemokine receptor 5 which is used by HIV to enter cells so is used in AIDS treatment.