Lecture 9

Question 1

MUST LEARN FROM NOTES AND THEN USE THIS TO TEST OR USE THIS TO LEARN AND SOLIDIFY BY LOOKING AT NOTES - BECAUSE EVERYTHING LINKS - IT IS HARD TO SHOW THIS USING FLASHCARDS

Question 2

What is pharmacodynamics?

Answer 2

Pharmacodynamics: (what a drug does to the body) - the biochemical, physiologic, and molecular effects of drugs on the body and involves receptor binding (including receptor sensitivity), post-receptor effects, and chemical interactions.

Question 3

What is pharmokinetics?

Answer 3

Pharmacodynamics, along with pharmacokinetics (what the body does to a drug, or the fate of a drug within the body), helps explain the relationship between the dose and response, ie, the drug’s effects.

Question 4

What does pharmocodynamics and pharmokinetics allow?

Answer 4

• Helps us to better understand physiology and pathology
• Helps us to understand drug action
• Informs clinical decisions
• Allows development of new drug

Question 5

Where does ligands mostly bind?

Answer 5

Endogenous and exogenous ligands exert effects by binding to a TARGET – mainly proteins
Some key concepts - exceptions eg. some antimicrobial & antitumour drugs bind DNA

Question 6

What are the molecular targets responsible for the therapeutic effects of drugs?

Answer 6

Question 7

Briefly how to GPCRs work?

Answer 7

Question 8

What is a superfamily? What is the potential for GPCRs?

Answer 8

Question 9

What receptor does sulbutomal act on?

Answer 9

β₂ adrenoreceptor (it is a selective agonist)

• Asthma

Question 10

What is a ligand?

Answer 10

Ligand something that binds to a receptor eg. drug, hormone, neurotransmitter

• applicable to targets other than GPCRs

Question 11

Drug action is determined by:

Answer 11

The concentration of drug molecules around receptors is critical in determining drug action (at the site of action)

Question 12

Molarity - description and units

Answer 12

M (units for molarity) MOLARITY IS NOT MOLES!

It is the molar concentration

The number of moles of solute per liter of solution

It’s units: mol/dm³ (this is the same as mol/L as dm³=L)

Question 13

What is MWt (molecular weight)

Answer 13

This is the atomic number, e.g. the larger number you see in the periodic table e.g. for oxygen it is 16, for water (H₂O) it is 18

Question 14

What is the molarity formula?

Answer 14

This is changing number of g/L (i.e. concentration in grams) to concentration in moles, using the molecular weight

Question 15

Another formula for molarity

Answer 15

molarity (M) = moles
Volume (either dm³ or L)

Question 16

The MWt of the drug simvastatin is 418.57. How many grams are required in 1 mL to make a 0.5 M solution?

Answer 16

1. Formula to use is: molarity (M) = g/L
   MWt
2. 0.5 = g/L
3. 57
4. 0.5 x 418.57 = 209.285g/L
5. Changing g/L into g: 209.285 / 1000 = 0.209g

Question 17

What is cm³ in dm³?

Answer 17

1000cm³ = 1dm³

Question 18

Need to learn the conversion unit table

Answer 18

Question 19

What are the main bits to remember from the conversion table?

Answer 19

Question 20

What is the Avagadro’s constant?

Answer 20

The Avogadro constant = 6.022 × 10 23 atoms per mole.

Question 21

What is the Avagadro’s formula?

Answer 21

Question 22

Why is it important to consider drug molarity?

Answer 22

Question 23

Recap, why do we need to consider drug concentration in molarity?

Answer 23

Question 24

Describe what happens when a drug binds reversibly

Answer 24

Association

Dissociation

-binding governed by association AND dissociation

Question 25

Draw at a visible representation of drugs binding reversibly

Answer 25

Question 26

Binding to the receptor requires \_\_\_\_\_\_?

Answer 26

To do anything, a ligand (such as a drug) must BIND to the receptor To bind to a receptor a ligand must have AFFINITY for the receptor **binding governed by affinity**

Question 27

Higher affinity =

Answer 27

Higher affinity = stronger binding

Question 28

How can binding be measured?

Answer 28

A common method measures the binding of a radioactively labelled ligand (radioligand) to intact cells or cell membranes. Many cells/many receptors (e.g. 10,000-100,000 per cell) Incubate radioligand and receptors -\> binding At equilibrium (not instant!), separate bound and free: usually measure bound

Question 29

What the graph that is used to measure affinity, what else is on the graph, what do the values mean?

Answer 29

Question 30

What is Bmax?

Answer 30

Maximum binding capacity - information about receptor number

Question 31

What is K_d?

Answer 31

Dissociation constant K_d = the concentration of drug that leads to half of the receptors being bound. Measure of AFFINITY

Question 32

What does a lower K_d value mean?

Answer 32

Lower K_d = higher affinity

Question 33

Describe what a ligand is

Answer 33

​• A ligand is a substance that can interact with a target protein - or receptor • Ligands usually bind to a specific site(s) on the signalling protein ​• Ligands can be endogenous signalling molecules e.g. hormones neurotransmitters or ions such as Ca2+ ​• Ligands can be exogenous molecules – drugs

Question 34

Describe the meaning of affinity and how is it measured?

Answer 34

* Affinity is a measure of the strength (or avidity) with which a ligand or drug binds to a receptor. * Affinity can also be thought of as the likelihood of how well a ligand will optimally ‘fit’ the receptor or target molecular binding site. * Affinity is measured by K_d (dissociation constant)

Question 35

What is the definition of K_d and how can it be determined from a radioligand saturation binding curve?

Answer 35

K_d is defined as the concentration of ligand at which 50% of all available receptors are bound. This can be determined from a saturation binding curve as 50% binding can be determined and the concentration giving this 50% binding then determined.

Question 36

What of the following drugs has the highest affinity and why?

Answer 36

Question 37

A drug has a K_d of 6.5 x 10-9 M at the b2-adrenoceptor. Under conditions of equilibrium binding to this receptor in airways smooth muscle, how many receptors would be occupied per cell at 6.5 x 10-9 M if there were 12,000 receptors per cell?

Answer 37

Question 38

Binding of the same drug at the b2-adrenoceptor is examined in another tissue with only 5,000 receptors per cell. How many receptors would be occupied per cell at 6.5 x 10-9 M?

Answer 38

2500

Question 39

Why do we often plot drug concentration vs binding using a semi-logarithmic plot? What is the shape of this curve? Can you still derive K_d and B_max?

Answer 39

When we plot eg drug concentration vs. binding – usually a semi logarithmic plot – sigmoidal plot (rather than the rectangular hyperbola shown previously)

Question 40

Understanding logs - drug concentration vs binding

Answer 40

Question 41

How to convert/interpret log graph REALLY IMPORTANT IN THIS - AS NEARLY ALL GRAPHS SHOWN WILL BE LOG SIGMOIDAL GRAPHS

Answer 41

Question 42

Log question:

Answer 42

-6 10^-6M

Question 43

How to antagonists work?

Answer 43

Bind to the receptor and simply block the binding other ligands (endogenous or exogenous) By themselves, these drugs do not cause the receptor to do anything – they are ANTAGONISTS THEY ONLY HAVE AFFINITY

Question 44

How do agonists work?

Answer 44

Some drugs bind and then activate the receptor – they are agonists Agonists have affinity PLUS intrinsic efficacy as they can generate/stabilize an active form (shape) of the receptor R\* - represents the active receptor Agonist has bound to the receptor and caused it to chnage it's conformation

Question 45

What is intrinsic efficacy?

Answer 45

Generating the active form of the receptor

Question 46

Difference between antagonists and agonists?

Answer 46

Agonists have AFFINITY and EFFICACY Antagonists only have AFFINITY (don't have efficacy, as they don't have intrinsic efficacy i.e. don't change the conformation of the receptor, so don't make 'things happen')

Question 47

What are the three factors involved in agonism?

Answer 47

Affinity Intrinsic efficacy Intrinsic efficacy leading to things happening in the cell (cell/tissue-dependent factors, e.g. number of receptors)

Question 48

Lock and key analogy for agonists and antagonists

Answer 48

Question 49

Caution with language when working on the wards -pharmocological efficacy and clinical efficacy

Answer 49

Pharmocological efficacy = i.e. does the drug successfully cause relaxation/dilation Clinical efficacy = i.e. does the drug cause lowering blood pressure, does it cure a headache, MEASURE OF HOW WELL A TREATMENT IS WORKING Left box = pharmacological efficacy Right box = clinical efficacy

Question 50

Define agonist

Answer 50

• An agonist is a substance that binds to a receptor and activates the receptor to then produce a measurable biological response.

Question 51

Define antagonist

Answer 51

* Antagonists are ligands that have affinity for a receptor or target protein but do not produce a biological response. * Antagonists block the effects of agonists

Question 52

Define intrinsic efficacy

Answer 52

Generate the active form of the receptor (R\*)

Question 53

Define ligand efficacy

Answer 53

Cause a measurable biological response In medicine, (clinical) efficacy relates to a response with therapeutic value • Without therapeutic value the intervention is not justified !

Question 54

How is affinity important for a herion overdose? What drug is used?

Answer 54

morphine or heroin (agonists of µ-opioid receptors) overdose -\> respiratory depression -\> death **naloxone** used to treat overdose - high affinity antagonist of µ-opioid receptors (GPCRs) - out-competes opioid

Question 55

What fentanyl?

Answer 55

fentanyl driving opioid crisis - very high affinity agonist - naloxone ineffective naloxone has a much lower affinity compared to fentanyl, so naloxone will be ineffective

Question 56

Concentration-response curve, what can be derived?

Answer 56

Question 57

E_max

Answer 57

E_max = Emax is the maximal effect at high drug concentrations when all the receptors are occupied by the drug

Question 58

EC₅₀

Answer 58

Effective concentration giving 50% of the maximal response. Also known as drug POTENCY.

Question 59

A ligand curve that is more potent will be more to the...

Answer 59

Left

Question 60

Concentration and dose - difference

Answer 60

**Concentration** – known concentration of drug at site of action – e.g. in cells and tissues **Dose** – concentration at site of action generally unknown – e.g. dose to a patient in mg or mg/kg

Question 61

Define intrinsic efficacy

Answer 61

Degree at which a lignad enables the receptor to conformationally change to create an active receptor and cause things to happen

Question 62

Answer 62

Question 63

MUST GO THROUGH AND TRY AND ANSWER GROUP WORK QUESTIONS