PHAR 1: Intro to Pharm - Pharmacodynamics

Question 1

Define pharmacology

Answer 1

• Pharmacology can be broadly defined as the study of how chemical agents (drugs) can influence the function of living systems

Question 2

Observe the learning outcomes of this session

Answer 2

Question 3

What is pharmacodynamics?

Answer 3

• what the drug does to the body

Question 4

What is pharmacokinetics?

Answer 4

• what the body does to the drug

Question 5

When you consider how individual drugs produce their effects, what three questions should you ask?

Answer 5

1. Where is this effect produced?
2. What is the target for the drug?
3. What is the response that is produced after interaction with this target?

Question 6

Where does cocaine produce its effects?

Answer 6

• drugs can have more than one effect, but if we are talking about the euphoric ‘high’ then the effect is produced at the dopaminergic neurons in the nucleus accumbens

Question 7

What is needed for a drug to produce a measurable effect?

Answer 7

• it must ‘bind’ to a specific target in the body

Question 8

What are drug targets?

How can it be divided into four classes?

Answer 8

• most drug targets are proteins:
  1. receptors
  2. enzymes
  3. ion channels
  4. carrier proteins

Question 9

What do these drugs bind to?

Answer 9

• aspirin: binds to the ‘enzyme’ cyclooxygenase and blocks the production of prostaglandins
• local anaesthetics: blocks sodium ‘ion channels’ and thus prevents nerve conduction
• Prozac (anti-depressant): blocks serotonin ‘carrier proteins’ and prevents serotonin being removed from the synapse
• nicotine: binds to and activates the nicotinic acetylcholine ‘receptor’

Question 10

What are the effects of drugs binding on their targets?

Answer 10

• they can either enhance activation of the target
• stimulate an effect
• prevent activation of the target
• block an effect from being produced

Question 11

Describe why specificity (selectivity) is important

Answer 11

• for a drug to be an effective therapeutic agent it must show a high degree of specificity for a particular drug target.
• If we revisit a concept that you should be familiar with – the lock and key hypothesis.
• Applying this to the concept of drug targets, if we want to see a specific effect, then it is important that the drug (the key in this analogy) only binds to one target (the lock in this analogy).
• Of course, the reality is that a lot of drugs and chemicals are structurally quite similar, and therefore it is very difficult to design a drug that has complete specificity.

Question 12

Observe the chemical structure of dopamine, noradrenaline and serotonin

What are their major differences?

Answer 12

• Dopamine contains a catechol structure (i.e. a benzene ring with two hydroxyl side groups) with one amine group attached via an ethyl side chain.
• Noradrenaline possesses the same structure as dopamine with an additional hydroxyl group on the ethyl side chain.
• 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 13

What is a side effect of a drug that targets specifically dopamine, for example

Observing the structure of dopamine, serotonin and noradrenaline

Answer 13

• There is also a chance that the drug will also interact with serotonin and adrenergic receptors and produce other effects that you don’t want (side-effects).

Question 14

Why is drug dose so important in pharmacology?

Use Pergolide as an example

Answer 14

• For example, imagine a drug is approximately fifty times more selective for drug target A compared to drug target B.
• We start with a very low dose of drug and increase the dose until we first start seeing an effect at target A
• at this point, we know that we will need to increase the dose 50-fold before we start seeing effects at target B.
• Pergolide is a drug we use in the treatment of Parkinson’s disease.
• Pergolide is most selective for dopamine receptors, but like the endogenous chemical dopamine, it can also bind to serotonin receptors and adrenergic receptors.
• Pergolide is most selective for dopamine receptors, but like the endogenous chemical dopamine, it can also bind to serotonin receptors and adrenergic receptors.
• As you can see, at a low dose, the effect you see is more specific, due to the fact that Pergolide will only interact with one target.
• As the dose increases, the effect becomes less specific, because Pergolide starts to interact with other drug targets producing other unwanted effects.

Question 15

Why is it difficult to predict drug dose?

Answer 15

• due to the complex manner in which the body ‘handles’ the drug, it is actually quite difficult to accurately predict how much drug might arrive at your specific drug target.

Question 16

What is the therapeutic window?

How can it be quantified?

Answer 16

• The therapeutic window compares the dose of a drug that produces therapeutic effect with the dose of the drug that produces a toxic effect – this provides an indication of the safety of the drug.
• The therapeutic index quantifies this relationship by directly comparing the dose required to produce toxicity with the dose required to produce the therapeutic effect.
• it can be quantified by the ‘therapeutic index’

Question 17

How do we calculate the therapeutic index?

Answer 17

• To measure a therapeutic effect, we use something called the ED50 – the effective dose to produce a specific therapeutic effect in 50% of the population.
• To measure the toxic effect, we use something called the TD50 – the dose required to produce a specific toxic effect in 50% of the population.
• Therapeutic index is measured by dividing the TD50 by the ED50 i.e.TD50/ED50.

Question 18

Calculate the therapeutic index of these drugs

Answer 18

Question 19

What does the therapeutic index imply?

Answer 19

• the higher the value, the safer the drug

Question 20

Observe these dose response curves

Answer 20

Question 21

Describe this dose response curve and infer the safety of Drug B

Answer 21

• In the case of drug B you can see that there is a wide therapeutic window as shown in the image below, which means the drug is relatively safe.
• Even a dose of drug B that would induce a therapeutic response in nearly 100% of the population (blue circle) would be unlikely to induce a toxic effect at all.

Question 22

Describe drug-receptor interactions

Where do many of the drugs we used produce their effects via?

Answer 22

• Many of the drugs we use, produce their effects via an action at specific receptors – one of the four classical drug target sites mentioned in part 1.
• A large amount of pharmacological theory is directed towards these interactions.
• Suppose you have a piece of smooth muscle tissue from the lung which contains a certain number of receptors for adrenaline.
• If you add a certain concentration of adrenaline to this tissue, then a certain number of receptors will become ‘occupied’ by adrenaline.

This basic reaction can be represented as follows;

Question 23

Describe affinity

Answer 23

• The affinity of a drug determines strength of binding of the drug to the receptor.
• In the diagrams shown above, the strength of each drug-receptor complex is determined by the affinity of the drug.
• As a result, affinity is strongly linked to receptor occupancy.
• It is very important that you understand that each individual drug receptor interaction is transient, with many interactions only lasting milliseconds.
• If you were to focus on one individual drug molecule amongst the many thousands that might be present, then at any given moment that particular drug molecule might be bound to a receptor, or it may have unbound and may currently be free with the potential to bind another receptor.
• It then follows, that if you have two drugs that could be added to the tissue (i.e. same number of receptors available), then the drug with the higher affinity 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 24

Describe efficacy

Answer 24

• Efficacy refers to the ability of an individual drug molecule to produce an effect once bound to a receptor

Question 25

Describe agonists

Answer 25

• an agonist must possess affinity, the ability to bind to the specific receptor, and efficacy, the ability to activate the receptor once bound

Question 26

What type of agonists are most drugs?

Answer 26

• Many drugs are basically exogenous agonists – chemicals that we are using to try and mimic the effects of the endogenous agonists.
• e.g., we might produce a ‘noradrenaline’ like drug that would act to increase your heart rate.
• There are many benefits of using an exogenous agonist, for example you can produce a more powerful effect if you use a high dose and ensure more drug is available to bind receptors than is normally the case with endogenous agonists.
• Of course, there are also disadvantages as well.
• For example, it is very difficult to deliver the drug to its precise site of action as effectively as the body can with endogenous agonists.

Question 27

Why are many drugs termed receptor antagonists?

Answer 27

• many drugs are also termed receptor antagonists.
• In this case, we are trying to block the effects of the endogenous agonists.
• Again, using the example above, we might produce an antagonist for the noradrenaline receptor.
• Since noradrenaline would find it more difficult to access its receptor, then you would see a reduction in heart rate.
• Antagonists must possess affinity for the particular receptor in order to bind to the receptor and block access.
• However, once bound the antagonist has ZERO efficacy i.e. no capacity to activate the receptor.

Question 28

Look at this dose response curve and describe it

What type of agonist is it?

Answer 28

• In this case, once the dose of the drug is high enough, a 100% response is achieved.
• In this case, the drug is considered a FULL AGONIST.
• 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 29

What would a dose response curve look like for a partial agonist?

What are partial agonists?

Answer 29

• Some drug are only classified as PARTIAL AGONISTS.
• In this case, each drug molecule when bound to a receptor CANNOT stimulate the maximal response from that individual receptor (partial efficacy).
• As a result, even when a large number of receptors are bound and activated, the maximal tissue response can never be achieved

Question 30

Describe competitive receptor antagonists

Answer 30

• the competitive receptor antagonist the blockade is transient.
• This means that for each molecule of competitive receptor antagonist, 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.
• If the corresponding agonist is also available, then agonist and antagonist are constantly ‘competing’ for free receptors.
• If you choose to increase the dose of the agonist but do not change the dose of the antagonist, then there will be more molecules of agonist present to out-compete the antagonist.
• Therefore, the blockade produced by the competitive antagonist is surmountable, if you increase the dose of the agonist.

Question 31

Describe irreversible receptor antagonists

Answer 31

• An irreversible receptor antagonist 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.
• Once that individual receptor is blocked, increasing the dose of agonist will have no effect on that particular receptor.
• The more antagonist that is present, the larger the number of receptors that are blocked.
• In this situation, 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 32

Describe the log-dose response curve when there is a competitive and irreversible antagonist

Answer 32

Question 33

Describe potency

Answer 33

• Potency is related to dose.
• The less drug you require to produce a particular effect, the more potent the drug is.
• We often use the ED50 of drugs in order to compare their potencies.
• In this case, the ED50 for drug A is approx. 3mg/kg, the ED50 for drug B is approx. 50mg/kg and the ED50 for drug C is approx. 700mg/kg.
• Therefore drug A is more potent than drug B which is more potent than drug C.
• Students will often get confused as to why drug B would be considered more potent than drug C.
• Drug B is only a partial agonist whilst drug C is a full agonist.
• However, the difference between a partial agonist and a full agonist is a difference in efficacy.
• Therefore, drug B is more potent than drug C, but drug B is not as efficacious as drug C.
• A highly potent drug produces a large response at relatively low concentrations.
• A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration.
• At a very basic level, potency is related to dose, whereas efficacy is not.

Question 34

What is the clinical relevance of the difference between potency and efficacy?

Answer 34

• Efficacy is more important.
• 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.
• If you have two drugs that have equal efficacy, then it doesn’t really matter if one is more potent than the other, since you can still produce the maximal response with the less potent drug – you just need to administer a slightly higher concentration.