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Med Chem > Lecture 9 (The Adrenergic System) > Flashcards

Lecture 9 (The Adrenergic System) Flashcards

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1
Q

alpha 1 stimulates what organs/tissues?

A
  • arterioles (peripheral vascular skeletal muscle)
  • eye (radial muscle)
  • uterus
  • intestines
  • liver
  • urinary
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2
Q

What affect does alpha 1 have on:

-arterioles (peripheral vascular skeletal muscle)

A

vasoconstriction

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3
Q

What affect does alpha 1 have on:

-eye (radial muscle)

A

contraction of radial muscle to dilate pupils

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4
Q

What affect does alpha 1 have on:

-uterus

A

contraction

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5
Q

What affect does alpha 1 have on:

-intestines

A

decreased motility

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6
Q

What affect does alpha 1 have on:

-liver

A

increased glycogenolysis

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7
Q

What affect does alpha 1 have on:

-urinary

A

contracts urinary sphincter

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8
Q

beta 1 stimulates what organs/tissues?

A
  • kidney

- heart

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9
Q

What affect does beta 1 have on:

-kidney

A

renin release

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10
Q

What affect does beta 1 have on:

-heart

A

increase HR

increase contractility

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11
Q

beta 2 stimulates what organs/tissues?

A
  • arterioles (peripheral vascular skeletal muscle)
  • lung
  • uterus
  • intestine
  • liver
  • urinary
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12
Q

What affect does beta 2 have on:

-arterioles (peripheral vascular skeletal muscle)

A

vasodilation

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13
Q

What affect does beta 2 have on:

-lung

A

bronchodilation

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14
Q

What affect does beta 2 have on:

-uterus

A

relaxation

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15
Q

What affect does beta 2 have on:

-intestine

A

decreased motility

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16
Q

What affect does beta 2 have on:

-liver

A

increased glycogenolysis

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17
Q

What affect does beta 2 have on:

-urinary

A

relax bladder

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18
Q

How do you make a drug specific to a certain receptor?

ex. want to make it B1 specific therefore it would not stimulate B2

A

want to:

  • increase potency at desired receptor (B1)
  • decrease potency at undesired receptor (B2)
  • if possible
  • *cannot always do both
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19
Q

You can control selectivity with?

A

changing doses

*see slide 4

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20
Q

all adrenergic receptors are ____

A

GPCRs

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21
Q

alpha 1 = Galpha__

A

q

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22
Q

alpha 2 = Galpha__

A

i

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23
Q

Tissue locations for alpha 1?

A
  • arterioles
  • pupil
  • liver
  • GI smooth muscle
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24
Q

Cellular effects from alpha 1?

A

+PLCy
increase IP3, DAG
increase intracellular [Ca2+]
decrease K+ outflow

Results in:
Excitation

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25
Q

Tissue locations for alpha 2?

A
  • presynaptic (autoreceptor)
  • presynaptic inhibition
  • platelets
  • platelet aggregation
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26
Q

Cellular effects for alpha 2?

A

-AC
decrease cAMP
decrease intracellular [Ca2+]
increase K+ outflow

Results in:
Inhibition

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27
Q

B1 = Galpha_

A

s

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28
Q

B2 = Galpha_

A

s

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29
Q

B3 = Galpha_

A

s

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30
Q

Tissue locations for B1?

A
  • heart
  • GI smooth muscle
  • kidney ? pretty sure
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31
Q

Cellular effects for B1?

A

+AC
increase cAMP
increase [Ca2+] stores in ER

Results in:
excitation

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32
Q

Tissue locations for B2?

A
  • lungs
  • muscle blood vessels
  • liver
  • GI smooth muscle
  • skeletal muscle
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33
Q

Cellular effects for B2?

A

+AC
increase cAMP

Results in:
excitation

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34
Q

Tissue locations for B3?

A

adipose tissue

*lipolysis

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35
Q

Cellular effects for B3?

A

+AC
increase cAMP

Results in:
excitation

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36
Q

Describe the synapse for NA

A
  • voltage gated Ca2+ channel is activated and creates an action potential
  • this triggers NA to leave synaptic vesicle and head into the synaptic cleft and then into the post synaptic cell for receptors or come back onto the presynaptic cell for receptors

*see slide 7

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37
Q

What are the 3 ways to eliminate the signal from NA?

A

1) reuptake at synapse
2) COMT
3) MOA

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38
Q

COMT

A

catechol-o-methyl transferase

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39
Q

MOA

A

monoamine oxidase

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40
Q

What is the most important mechanism for the elimination of NA signal?

A

reuptake at synapse

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41
Q

Describe the mechanism of COMT

A
  • a major reason that NA and A are not orally bioavailable

- this is a Phase 2 metabolism enzyme

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42
Q

Describe the mechanism of MOA

A
  • this is a phase 1 metabolism enzyme

- this is NOT a CYP enzyme

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43
Q

What are MOPEG and VMA?

A
  • the main metabolites of NA and A

- they are conjugated before excretion

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44
Q

Where is MAO found?

A

in mitochondria of presynaptic terminal

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45
Q

How does MAO metabolize NA and A?

A

removal of N eliminates activity

46
Q

Where is COMT found?

A

in the synapse

47
Q

How does COMT metabolize NA and A?

A
  • always adds the methyl group in the meta position

- this reduces activity

48
Q

NA in the ____ ______ is protected from metabolism

A

synaptic vesicle

49
Q

Describe the biosynthesis of NA and A

A 
tyrosine 
DOPA
dopamine
NA
A

OR

tyrosine
tyramine
octopamine
NA 
A

OR

tyrosine tyramine
octopamine
synephrine
A

see slide 11

50
Q

Describe the synapse for amphetamine like drugs

A

*Ca2+ channel

amphetamine and amphetamine like drugs cause the release of NA and dopamine from presynaptic vesicles into the synaptic cleft

*this is not mediated by fusion of the vesicle with the presynaptic membrane or by an action potential

slide 12

51
Q

Amphetamine works in the monoamine MA synapses: what are they?

A

noradrenaline (NA)
dopamine (DA)
serotonin (5-HT)

52
Q

Describe amphetamine mechanisms

A
  • amphetamine binds to and inhibits MAO
  • this increases non-vesicular [monoamine]
  • [monoamine] increases so much that the reuptake pump operates in the opposite direction which pumps NA, DA, or 5-HT back into the synaptic cleft
53
Q

VMAT2

A

vesicular monoamine transporter 2

54
Q

Normally VMAT2 takes ___ up into the vesicle

A

MA

55
Q

amphetamine blocks _____

A

VMAT2

which reduces vesicular uptake of MA

56
Q

_____ is a competitive inhibitor of the MA reuptake transporter

A

cocaine

57
Q

Because cocaine is a competitive inhibitor of the MA reuptake transporter, what happens?

A

this blocks the reuptake of NA, DA, and 5-HT

58
Q

What does cocaine do?

A

inhibits reuptake of NA, DA, and 5-HT so it increases these neurotransmitters in the synaptic cleft

59
Q

compare and contrast amphetamine and cocaine

A

they work by different mechanisms but they both have the same effect on increasing [MA] in the synaptic cleft

60
Q

What is tyramine?

A

it is a naturally occurring metabolite that has amphetamine activity

61
Q

What kind of foods contain tyramine?

A

red wine
cheese
fermented foods

62
Q

What are these foods (red wine, cheese, fermented foods) contraindicated with?

A

these foods are contraindicated while taking irreversible inhibitors of MAO

  • phenelzine (Nardil)
  • tranylcypromine (Parnate)
63
Q

Reversible MAO inhibitors are ok to eat with red wine, cheese, fermented foods. Give an example of a reversible MAO inhibitor

A

moclobemide (Manerix)

64
Q

inhibition of MAO while taking tyramine increases ???

A

[NA]
[DA]
or
[5-HT]

in the synapse

65
Q

sympathomimetics

A

drugs that mimic the sympathetic nervous system

66
Q

There are 3 basic types of sympathomimetics. Describe them

A

1) Direct Acting: drugs that bind to the receptors of the sympathetic nervous system (ex. alpha and B receptors)
2) Indirect Acting: drugs that have amphetamine like actions
3) Mixed Acting: drugs that both bind to alpha and or B receptors and have amphetamine like actions

67
Q

Diversity of mechanism results from the common core structure of _________

A

phenethylamine

slide 16

68
Q

Aromatic rings of amphetamine like drugs can have a _ OH but never a _ OH

A

they can have p OH

never have a m OH

69
Q

dexamphetamine is the pure __ isomer of amphetamine

A

S

70
Q

The __ isomer is more potent

A

S

71
Q

What about the structure of dexamphetamine suggests that it is an amphetamine like drug?

A

no substitution on ring

72
Q

What about the structure of dexamphetamine confirms that it is an amphetamine like drug?

A

no B OH substitution

73
Q

What is dexamphetamine used to treat?

A

ADHD

possible narcolepsy

74
Q

Why is amphetamine a drug of abuse?

A

high doses of this drug releases dopamine in the brain

*this causes hallucinations and psychotic symptoms that are all like scizophrenia

75
Q

T of F: In every case where we find an H-bond interaction we know if the receptor or the ligand is the donor or receptor

A

False

-we do not know

76
Q

Which isomer of NA and A is preferred?

Why?

A

R isomer

The S isomer has the Oh in the wrong position production only 4 sites of interaction with the receptor.

The R isomer has the OH in the right position to make the optimum 5 items of interaction with the receptor.

77
Q

no intrinsic activity but has affinity = ?

A

antagonist

78
Q

What happens as the size of the R substituent increases on an alpha adrenergic agonist?

A

intrinsic activity at the alpha receptor decreases

but affinity increases

*see slide 22

79
Q

Clonidine:

ortho substituents favour ?

A

alpha 2 > alpha 1

80
Q

Clonidine:

guanidine group favours?

A

alpha 2 > alpha 1

81
Q

Clonidine has no meta OH: what does that mean?

A

it means that it cannot be inactivated by COMT

82
Q

Can clonidine cross BBB?

A

yes

83
Q

Why can it cross BBB?

A

it is hydrophobic and its pKa is low enough so that a portion is in the unionized form at physiological pH (7.4)

84
Q

Methyldopa is ?

A

alpha 2 agonist

85
Q

Methyldopa has ___ chiral carbons

A

2

position 1 = R in the active isomer for all agonists of alpha and beta receptors

position 2 = S where substituent is present

86
Q

alpha 2 agonists were originally marked for ?

A

hypertension

87
Q

in CNS, alpha 2 agonists do what ?

A

reduce sympathetic output (because of auto-inhibition)

88
Q

Clonidine (Dixarit) still used for ?

A

symptoms of menopause

89
Q

Methyldopa is occasionally used for ?

A

used to treat hypertension during pregnancy (pregnancy risk category B)

90
Q

imidazoline is ?

A

alpha 1 agonist

91
Q

imidazoline alpha 1 agonists act as ?

A

topical decongestants

92
Q

decongestants cause ?

A

vasoconstriction

  • in the eyes they reduce appearance of red eyes
  • in the nose it reduces swelling in nasal membranes (and decreases nasal secretions)
93
Q

phenylephrine and pseudo ephedrine are ?

A

oral decongestants

94
Q

does phenylephrine have amphetamine like properties?

A

no

95
Q

phenylephrine is selective for ?

A

alpha 1 receptor

96
Q

What about phenylephrine suggests it is an alpha agonist

A

it has an N-methyl group

97
Q

What about phenylephrine suggests that it has no amphetamine like activity?

A

presence of meta OH

98
Q

What about phenylephrine confirms no amphetamine like activity?

A

B OH

99
Q

pseudoephedrine has affinity for what receptor?

A

alpha 1 and alpha 2

*mixed agonist

100
Q

the alpha CH3 on pseudoephedrine does what?

A

reduces metabolism by MAO

101
Q

What about pseudoephedrine suggests amphetamine like activity?

A

lack of ring substitution

102
Q

What about pseudoephedrine confirms that it is not a pure amphetamine but displays mixed activity?

A

B OH

103
Q

What is the main mechanism of action for pseudoephedrine?

A

mixed amphetamine like activities

104
Q

psuedoephedrine increases ?

A

wakefullness

105
Q

Brand for phenylephrine?

A

Benylin cold and sinus plus

106
Q

Brand for pseudoephedrine?

A

Sudafed

107
Q

Both phenylephrine and pseudoephedrine can cause?

A
  • vasoconstriction
  • increased Hr resulting in hypertension

*only a problem in people with existing hypertension

108
Q

While recommending cough and cold products - always ask about what?

A

HIGH BLOOD PRESSURE

109
Q

What are nasal spray decongestants good for?

A

people who cannot tolerate oral decongestants

-especially those with high blood pressure

110
Q

nasal decongestants can produce?

A

rebound congestion if they are used for more than 3 days in a row

111
Q

Do oral decongestants produce rebound congestion?

A

no

Med Chem (11 decks)

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