PHAR1: Introduction - pharmocodynamics

Question 1

What is pharmacodynamics?

Answer 1

what the drug does to the body

Question 2

What is pharmacokinetics?

Answer 2

what the body does to the drug

Question 3

What are the four types of drug targets?

Answer 3

• Receptors
• Enzymes
• Ion channels
• Carrier proteins

Question 4

Where do aspirin, anaesthetics, Prozac and nicotine have their effect?

Answer 4

aspirin -> binds to the enzyme cyclooxgygenase and blocks the production of prostaglandins
anaesthetics -> block sodium ‘ion channels’ and thus prevent nerve conduction
prozac -> blocks serotonin
nicotine -> binds to and activates the nicotinic acetylcholine

Question 5

What are the major structural differences between dopamine, noradrenaline and serotonin?

Answer 5

• Noradrenaline has a hydroxyl group extra than dopamine
• Serotonin is similar to dopamine but possesses an indole ring with one hydroxyl group instead of a benzene ring with hydroxyl groups. It does possess the same ethyl side chain with one amine group.

Question 6

Because dopamine, noradrenaline and serotonin all have a similar structure what does this mean?

Answer 6

They all have some degree of specificity for the other receptors

Question 7

What is the main problem when molecules have some affinity for other molecule’s receptors?

Answer 7

Side effects due to unspecific binding

Question 8

What is Pergolide?

Answer 8

A parkingson’s disease drug

Question 9

For Pergolide, what are the different effects induced at different concentrations?

Answer 9

0.4nM: therapeutic effect (D2 receptor target)
5nM Hallucinations (5HT2B Receptor - serotonin)
40nM: Hypotension (alpha1 receptor - Adrenergic)

Question 10

Why does the effect become less specific as the concentration of the drug increases?

Answer 10

Because Pergolide starts to interact with other drug targets producing other unwanted effects.

Question 11

What does therapeutic window mean?

What is it for?

Answer 11

A concept linked to drug target selectivity and dose This provides an indication of the safety of the drug.

Question 12

What quantifies the therapeutic window?

Answer 12

The therapeutic index

Question 13

What does the therapeutic index do?

Answer 13

Compares the dose of a drug that produces therapeutic effect with the dose of the drug that produces a toxic effect

Question 14

How do you measure the therapeutic effect?

Answer 14

ED50 – the effective dose to produce a specific therapeutic effect in 50% of the population.
Or 50% of maximal response

Question 15

How do you measure the toxic effect?

Answer 15

TD50 – the dose required to produce a specific toxic effect in 50% of the population

Question 16

How do you calculate therapeutic index?

Answer 16

Therapeutic index = TD50 / ED50

Question 17

The higher or lower the therapeutic index the better?

Answer 17

The higher = the safer the drug

Question 18

If you were to increase the concentration of the drug, what happens to the drug receptor complex equilibrium?

Answer 18

It is strongly shifted to the right - this is because there is more drug available to bind to free receptors.

Question 19

If you were to dramatically reduce the amount of drug available what happens to the shift in equilibrium?

Answer 19

Then more receptors would become available again due to the lower drug concentration. This shifts the equilibrium to the left.

Question 20

What does affinity mean?

Answer 20

Determines the strength of binding of the drug to the receptor

Question 21

Why is affinity is strongly linked to receptor occupancy?

Answer 21

The strength of each drug-receptor complex is determined by the affinity of the drug

Question 22

If two drugs are present in a tissue then why would a drug that has a higher affinity, at any given moment have more of its molecules bound to receptors?

Answer 22

It will form stronger drug receptor complexes and thus at any given moment, it is more likely that more of this drug will be bound to receptors.

Question 23

What does efficacy refer to?

Answer 23

The ability of an individual drug molecule to produce an effect once bound to a receptor

Question 24

How must an agonist act?

Answer 24

An agonist must possess affinity i.e. the ability to bind to the specific receptor and efficacy i.e. the ability to activate the receptor once bound.

Question 25

Can an exogenous or endogenous drug be delivered to its target location more precisely?

Answer 25

endogenous

Question 26

What is an antagonist?

Answer 26

It has affinity for the receptor but zero efficacy

Question 27

What happens to the log dose response curve eventually? Why?

Answer 27

It levels off, because you reach the maximum tissue response

Question 28

What shape do all agonist dose response log curves have?

Answer 28

Sigmoidal shape

Question 29

What is it important to remember about agonist/antagonist - receptor interactions?

Answer 29

It is very transient

Question 30

What is a full agonist?

Answer 30

100% response can be achieved: each drug molecule when bound to a receptor can simulate the maximal response from that individual receptor (full efficacy). Once enough receptors are bound and activated, the maximal tissue response can be achieved

Question 31

What are partial agonists?

Answer 31

Each drug molecule when bound to a receptor CANNOT stimulate the maximal response from that individual receptor (partial efficacy)

Question 32

When a large number of receptors are bound and activated by partial agonists, will the maximal tissue response be achieved?

Answer 32

No the maximal tissue response can never be achieved

Question 33

Where will the partial agonist dose-response curve be in comparison to the full agonist?

Answer 33

Below

Question 34

What is a competitive antagonist?

Answer 34

Blocks the receptor transiently: it can only bind to and block a receptor for a brief period of time. It then detaches from the receptor and is then available to bind to and block another receptor.

Question 35

What is an irreversible receptor agonist?

Answer 35

It produces a long term (possibly permanent) blockade of the receptor. Therefore, for every molecule of irreversible antagonist bound to a receptor, there is one less receptor available to bind the agonist.

Question 36

If the agonist and competitive antagonist are both present in the tissue, and you increase the concentration of the agonist, will you be able to outcompete the competitive antagonist for receptor spaces?

Answer 36

There will be more molecules of agonist present to out-compete the antagonist. Therefore, the blockade produced by the competitive antagonist is surmountable, as the agonist and antagonist are constantly ‘competing’ for free receptors.

Question 37

If the agonist and irreversible antagonist are both present in the tissue, and you increase the concentration of the agonist, will you be able to outcompete the irreversible antagonist for receptor spaces?

Answer 37

Once that individual receptor is blocked, increasing the dose of agonist will have no effect on that particular receptor. Also increasing the agonist will not necessarily increase the response, since the agonist cannot compete with molecules of antagonist that have already bound to and blocked receptors.

Question 38

If a competitive antagonists and agonists are present in the tissue then what will happen to the response in a dose-response log curve?

Answer 38

Lower level of response, because some of the receptors will be blocked by antagonists at any one time

Question 39

If a competitive antagonists and agonists are present in the tissue but you increase the dose of the agonist, then what will happen to the response in a dose-response log curve?

Answer 39

Absolute paralelle shift to the right compared to the curve with no antagonist, (increased dose hence shift to right) but the response can still reach horizontally equal to the response with no antagonist present. Restore the level of response. You can always over compensate.

Question 40

If a irreversible antagonists and agonists are present in the tissue but you increase the dose of the agonist, then what will happen to the response in a dose-response log curve?

Answer 40

Lower sigmoidal curve, the more irreversible antagonist you add the lower the curve gets, eventually you can get a flat line with no response. You cannot outcompete the irreversible antagonist with more agonist.

Question 41

What is potency

Answer 41

Potency is related to dose. The less drug you require to produce a particular effect, the more potent the drug is.

Question 42

What is used to compare potency?

Answer 42

ED50

Question 43

the difference between a partial agonist and a full agonist is a difference in ______.

Answer 43

Efficacy

Question 44

A highly potent drug produces a large response at relatively ___ concentrations

Answer 44

low

Question 45

A highly efficacious drug can produce a ______ response and this effect is not particularly related to drug concentration

Answer 45

maximal

Question 46

Which is more important between efficacy and potency?

Answer 46

Efficacy - You want to know if the drug you are giving can induce a maximal response. The potency simply determines the dose that you will need to administer to produce a response.