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_Sem 1. ICCP NOTES > Lecture 9 > Flashcards

Lecture 9 Flashcards

1
Q

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

A
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2
Q

What is pharmacodynamics?

A

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.

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3
Q

What is pharmokinetics?

A

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.

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4
Q

What does pharmocodynamics and pharmokinetics allow?

A
  • Helps us to better understand physiology and pathology
  • Helps us to understand drug action
  • Informs clinical decisions
  • Allows development of new drug
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5
Q

Where does ligands mostly bind?

A

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

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6
Q

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

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7
Q

Briefly how to GPCRs work?

A
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8
Q

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

A
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9
Q

What receptor does sulbutomal act on?

A

β2 adrenoreceptor (it is a selective agonist)

  • Asthma
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10
Q

What is a ligand?

A

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

  • applicable to targets other than GPCRs
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11
Q

Drug action is determined by:

A

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

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12
Q

Molarity - description and units

A

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)

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13
Q

What is MWt (molecular weight)

A

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

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14
Q

What is the molarity formula?

A

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

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15
Q

Another formula for molarity

A

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

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16
Q

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

A
  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
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17
Q

What is cm3 in dm3?

A

1000cm3 = 1dm3

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18
Q

Need to learn the conversion unit table

A
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19
Q

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

A
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20
Q

What is the Avagadro’s constant?

A

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

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21
Q

What is the Avagadro’s formula?

A
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22
Q

Why is it important to consider drug molarity?

A
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23
Q

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

A
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24
Q

Describe what happens when a drug binds reversibly

A

Association

Dissociation

-binding governed by association AND dissociation

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25
Q

Draw at a visible representation of drugs binding reversibly

A
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26
Q

Binding to the receptor requires ______?

A

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

27
Q

Higher affinity =

A

Higher affinity = stronger binding

28
Q

How can binding be measured?

A

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

29
Q

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

A
30
Q

What is Bmax?

A

Maximum binding capacity - information about receptor number

31
Q

What is Kd?

A

Dissociation constant

Kd = the concentration of drug that leads to half of the receptors being bound. Measure of AFFINITY

32
Q

What does a lower Kd value mean?

A

Lower Kd = higher affinity

33
Q

Describe what a ligand is

A

​• 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

34
Q

Describe the meaning of affinity and how is it measured?

A
  • 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 Kd (dissociation constant)
35
Q

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

A

Kd 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.

36
Q

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

A
37
Q

A drug has a Kd 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?

A
38
Q

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?

A

2500

39
Q

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 Kd and Bmax?

A

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

40
Q

Understanding logs - drug concentration vs binding

A
41
Q

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

A
42
Q

Log question:

A

-6

10-6M

43
Q

How to antagonists work?

A

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

44
Q

How do agonists work?

A

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

45
Q

What is intrinsic efficacy?

A

Generating the active form of the receptor

46
Q

Difference between antagonists and agonists?

A

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’)

47
Q

What are the three factors involved in agonism?

A

Affinity

Intrinsic efficacy

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

48
Q

Lock and key analogy for agonists and antagonists

A
49
Q

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

A

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

50
Q

Define agonist

A

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

51
Q

Define antagonist

A
  • 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
52
Q

Define intrinsic efficacy

A

Generate the active form of the receptor (R*)

53
Q

Define ligand efficacy

A

Cause a measurable biological response

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

54
Q

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

A

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

55
Q

What fentanyl?

A

fentanyl driving opioid crisis

  • very high affinity agonist
  • naloxone ineffective

naloxone has a much lower affinity compared to fentanyl, so naloxone will be ineffective

56
Q

Concentration-response curve, what can be derived?

A
57
Q

Emax

A

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

58
Q

EC50

A

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

59
Q

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

A

Left

60
Q

Concentration and dose - difference

A

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

61
Q

Define intrinsic efficacy

A

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

62
Q
A
63
Q

MUST GO THROUGH AND TRY AND ANSWER GROUP WORK QUESTIONS

A

_Sem 1. ICCP NOTES (13 decks)

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