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Med Chem > Lecture 10 (The Adrenergic System 2) > Flashcards

Lecture 10 (The Adrenergic System 2) Flashcards

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1
Q

What is B1 receptor agonist used for clinically?

A

increase HR and force of contraction

*used for acute heart failure or decreased CO that may occur after surgery

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2
Q

What is B2 receptor agonist used for clinically?

A
  • bronchodilation of lungs
  • relaxation of uterus
  • useful for treatment of asthma and COPD
  • used to prevent premature labor
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3
Q

Most of therapeutically used B agonists are ?

A

secondary amines

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4
Q

Majority of B agonists are ?

A

phenylethylamines

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5
Q

Do any imidazolines act as B agonists?

A

no

*this is another indication that the imidazolines are only alpha agonists

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6
Q

imidazolines are always _____ agonists

A

alpha

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7
Q

As R on the B adrenergic agonist increases. what happens?

A

generally affinity increases for B receptors

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8
Q

Why does the N need to be charged?

A

for receptor binding

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9
Q

What is the H bond on the OH on B more important for?

A

more important for B2 receptor binding

not needed for B1 receptor binding

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10
Q

Large R substituents on the N do what for alpha receptors?

A
  • decrease intrinsic activity at alpha 1 and alpha 2 receptors
  • but affinity increases as R gets very large
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11
Q

Large R substituents on the N do what for beta receptors?

A

-increases affinity for B1 and B2 receptors while keeping intrinsic activity the same or increasing it

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12
Q

isopropyl selective for?

A

B1 and B2 > alpha

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13
Q

t-butyl selective for?

A

B2 > B1

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14
Q

A methyl group on (alpha or 2) does what?

A

selective for alpha 2

but a methyl or ethyl group also increases B2 affinity over B1

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15
Q

An OH on (B or 1) is important for ?

A

it is more important for B2 affinity than B1

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16
Q

What does R1 ring substituents do?

A

usually consists of 2 substitutions capable of forming H-bonds (donor or acceptor)

*anything less tends to reduce B2 and B1 affinity

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17
Q

What does an N-ethylphenol group do?

A

increases both affinity and intrinsic activity at B2 receptors.

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18
Q

What do large hydrophobic 7-11 atom long chains do?

A

also increases affinity and activity at B2 receptors while prolonging duration

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19
Q

Describe the two B2 receptor binding sites

A

1) the nearest site to the N accommodates a t-butyl group

and distal to this

2) is a hydrophobic binding pocket that also seems to require a phenolic OH for optimal binding or a longer hydrophobic chain

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20
Q

N-isopropyl does what?

A

-produces the highest intrinsic activity for B1 receptors

  • has affinity for B1 and B2 receptors
  • low affinity and activity for alpha 1 or alpha 2
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21
Q

What is isoproterenol used for?

A

has limited use as a bronchodilator because it has cardiac stimulatory activities conferred by B1 receptors binding

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22
Q

How does isoproterenol decrease vascular resistance?

A
  • causes vasodilation in muscular blood vessels

- increases CO (HR and SV) and force of contraction.

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23
Q

Absence of OH on a b1-receptor agonist does what?

A

makes it more selective for B1 than B2

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24
Q

What group produces the highest intrinsic activity for B1 receptors?

A

N-isopropyl

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25
Q

What was dobutamine originally thought to be?

A

only a selective B1 receptor agonist

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26
Q

What is dobutamine actually?

A

it is a selective B1 receptor agonist but it is complicated by alpha 1 antagonist and agonist activity

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27
Q

Dobutamine has a chiral centre and it is administered as a _____ mixture

A

racemic

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28
Q

Describe the R-enantiomer of dobutamine

A

it is a potent B1 agonist and a weak alpha 1 antagonist

**these effects appose each other

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29
Q

Describe the S-enantiomer of dobutamine

A

it is a potent alpha 1 agonist that is 10X more potent than the alpha 1 antagonist activity of the R-enantiomer

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30
Q

What is dobutamine used for?

A

acute heart failure
carcinogenic shock
septic shock
cardiac insufficiency after heart surgery

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31
Q

Dobutamine is ______

A

ionotropic

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32
Q

What is an inotropic drug?

A

increases contractile force

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33
Q

does dobutamine increase HR a lot?

A

not really

it modestly increases heart rate but increases contractile force more

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34
Q

Distance of carbons for B1 agonist

A

3

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35
Q

Distance of carbons for B2 agonist

A

2

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36
Q

Isoproterenol and dobutamine have ____ half life and ____ bioavailability

A

short half life and low bioavailability

37
Q

What are isoproterenol and dobutamine rapidly metabolized by?

A

COMT

MAO

38
Q

Why is isoproterenol not appropriate as a bronchodilator for asthma or COPD?

A

Because it targets B1 and B2 receptors therefore it will have unwanted effects on the heart

39
Q

How can dobutamine be given so it’s short half life and low bioavailability are not an issue?

A

by continuous infusion (IV)

*this is most commonly used in hospital setting

40
Q

MAO accepts many substrates including some ?

A

N substituted R groups

41
Q

Because MAO accepts many substrates including some N substituted R groups, what does this mean?

A

this means that many potential B receptor agonists are substrates for MAO

42
Q

What do t-butyl substitutions on the N act as? (On R1)

A

steric block reducing or eliminating the activity of MAO

43
Q

On R2 - an alpha methyl substituent can _____ MAO activity

A

reduce

44
Q

On R2 - an ethyl substituent _____ MAO activity

A

eliminates

45
Q

Substitutions in the 3’ or 5’ positions can be made to ______ COMT metabolism but some part of that substitution should be capable for forming H-bonds. If not the affinity is reduced.

A

reduce

46
Q

Why can the 4’ position remain to have an OH ?

A

because it is not methylated by COMT

47
Q

Why are resorcinol derivatives another COMT block?

A

resorcinol derivatives do not form the right geometry for the Mg2+ coordination complex and therefore resist COMT methylation

48
Q

What are B2 receptor agonists used in treating?

A

asthma and chronic obstructive pulmonary disease (COPD)

49
Q

How do B2 receptor agonists work in asthma?

A

they can temporarily but completely bronchodilator the airway which will temporarily reverse obstruction that results in the disease

50
Q

What are short-acting B2 agonists good for?

A

acute asthma attacks

51
Q

Asthma is primarily a disease of _______ and as a result B2 receptor agonists are never the only treatment

A

inflammation

52
Q

What other treatment should asthmatics have?

A

they should also have an inhaled glucocoorticoid

53
Q

What 2 groups of B2-receptor agonists are there?

A

1) short acting B2 receptor agonists - used only when needed during an attack
2) long acting B2 receptor agonists - used when asthma not controlled

54
Q

Are both types of B2-receptor agonists used in COPD?

A

yes

55
Q

What else is critical to asthma therapy?

A

glucocorticoids

56
Q

How are glucocorticoids taken?

A

must be taken regularly to reduce the frequency and severity of asthmatic attacks

57
Q

Everyone with asthma should have what 2 things?

A

1) short acting B2 receptor agonist

2) glucocorticoid

58
Q

What is the most common short acting B2 agonist? It is supplied as an MDI and a syrup. It also has a propellant.

A

salbutamol (ventolin)

59
Q

What is the second most common short acting B2 agonist? It is sold as a dry powder inhaler and many people tolerate this better.

A

Terbutaline (Bricanyl)

60
Q

_______ is supplied as a syrup for children who cannot use an MDI. Not as B2 selective as salbutamol

A

Orciprenaline

61
Q

_____ is a combination inhaler with ipratropium and can be used with asthma but more often used with COPD

A

Fenoterol (Duovent)

62
Q

Salbutamol, Terbutaline, Orciprenaline, and Fenoterol are all ???

A

short acting B2 receptor agonists

63
Q

______ is given IV or PO to arrest premature labor

A

Ritodrine

64
Q

Ritodrine has ?? (3)

A

No meta OH
No COMT metabolism
Has oral bioavailability

65
Q

Ritodrine does prolong pregnancy, but what else can it do?

A

increase maternal morbidity

66
Q

A high enough dose of any adrenergic agonist could do what?

A

bind to all receptors producing side effects

67
Q

There are B2 receptors on the muscles that cause ____

A

tremor

68
Q

If muscle tremors are occurring in an asthmatic what does that mean? And how can you fix it?

A

probably means that are using their rescue inhaler too much

in this case, add a long acting B2 agonist or increase glucocorticoid dose

69
Q

Along with muscle tremors, what is another side effect?

A

increased HR or irregular heart rate (palpitations)

70
Q

What can happen if B2 agonistic drugs are overused?

A

Desensitization of the bronchial B2 receptors can easily occur

71
Q

Explain what happens when you overuse B2 agonistic drugs

A

the agonist-occupied B2 receptors start to form dysfunctional clusters in the bronchial membranes - the receptors can no longer activate adenylate cyclase

72
Q

Drug tolerance develops and then what happens?

A

a much higher dose of B2 agonists are then required for adequate bronchodilation

73
Q

List 3 LABAs (long acting B2-receptor agonists)

A

1) Salmeterol (Advair or Servant)
2) Formetrol (Oxeze)
3) Indacaterol (Onbrez)

74
Q

Salmeterol is inhaled ___

A

BID

75
Q

What contributes to LABA’s long acting effects?

A

the added lipophilicity conferred by extended N substitution also plays a role in conferring longer duration.

76
Q

What contributes to LABA’s higher affinity for B2 vs. B1 receptors

A

they have extended >7 heavy atom hydrophobic chain sometime with an ether O and an aromatic group

*exception = indacaterol = only 7

77
Q

What is a heavy atom?

A

anything bigger than H+

78
Q

see slide 27 for sure

A

okay girl

79
Q

Why is Salmeterol’s local concentration relative to the receptor high?

A

because salmeterol is always tethered to the receptor it’s local concentration relative to the receptor is high increases the rate of receptor re-association

80
Q

The O on salmeterol acts as a ???

A

hinge

*slide 28

81
Q

Microkinetic model

A
  • The LABA partitions in to the lipid bilayer of the lung membranes because of the highly lipophilic nature of LABAs
  • The membrane acts as a reservoir for the LABA which is continuously released with a first-order rate constant
82
Q

Duration and onset of: Salbutamol

A

Duration:
3-6 hours

Onset:
5 mins (rapid)
83
Q

Duration and onset of:

Formoterol

A

Duration:
12 hours

Onset:
15 mins (slow)
84
Q

Duration and onset of:

Salmeterol

A

Duration:
12 hours

Onset:
20 mins (slowest)
85
Q

Duration and onset of:

Indacaterol

A

Duration:
24 hours

Onset:
5-10 mins (rapid)

86
Q

increasing logP = ____ duration and onset

exception = indacaterol

A

longer

87
Q

Why must we never use Salmeterol or Formoterol for an asthmatic attack?

A

the onset is too slow

88
Q

Why is indacaterol an exception?

A

At physiological pH (7.4) indacterol exists as a zwitterion. Which either gives it the properties of lower and higher logP B2 agonists OR it promotes interaction with the lipid membranes and to the B2 receptor

Med Chem (11 decks)

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