Lecture 9 (The Adrenergic System) Flashcards
1
Q
alpha 1 stimulates what organs/tissues?
A
- arterioles (peripheral vascular skeletal muscle)
- eye (radial muscle)
- uterus
- intestines
- liver
- urinary
2
Q
What affect does alpha 1 have on:
-arterioles (peripheral vascular skeletal muscle)
A
vasoconstriction
3
Q
What affect does alpha 1 have on:
-eye (radial muscle)
A
contraction of radial muscle to dilate pupils
4
Q
What affect does alpha 1 have on:
-uterus
A
contraction
5
Q
What affect does alpha 1 have on:
-intestines
A
decreased motility
6
Q
What affect does alpha 1 have on:
-liver
A
increased glycogenolysis
7
Q
What affect does alpha 1 have on:
-urinary
A
contracts urinary sphincter
8
Q
beta 1 stimulates what organs/tissues?
A
- kidney
- heart
9
Q
What affect does beta 1 have on:
-kidney
A
renin release
10
Q
What affect does beta 1 have on:
-heart
A
increase HR
increase contractility
11
Q
beta 2 stimulates what organs/tissues?
A
- arterioles (peripheral vascular skeletal muscle)
- lung
- uterus
- intestine
- liver
- urinary
12
Q
What affect does beta 2 have on:
-arterioles (peripheral vascular skeletal muscle)
A
vasodilation
13
Q
What affect does beta 2 have on:
-lung
A
bronchodilation
14
Q
What affect does beta 2 have on:
-uterus
A
relaxation
15
Q
What affect does beta 2 have on:
-intestine
A
decreased motility
16
Q
What affect does beta 2 have on:
-liver
A
increased glycogenolysis
17
Q
What affect does beta 2 have on:
-urinary
A
relax bladder
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
19
Q
You can control selectivity with?
A
changing doses
*see slide 4
20
Q
all adrenergic receptors are ____
A
GPCRs
21
Q
alpha 1 = Galpha__
A
q
22
Q
alpha 2 = Galpha__
A
i
23
Q
Tissue locations for alpha 1?
A
- arterioles
- pupil
- liver
- GI smooth muscle
24
Q
Cellular effects from alpha 1?
A
+PLCy
increase IP3, DAG
increase intracellular [Ca2+]
decrease K+ outflow
Results in:
Excitation
25
Tissue locations for alpha 2?
- presynaptic (autoreceptor)
* presynaptic inhibition
- platelets
* platelet aggregation
26
Cellular effects for alpha 2?
-AC
decrease cAMP
decrease intracellular [Ca2+]
increase K+ outflow
Results in:
Inhibition
27
B1 = Galpha_
s
28
B2 = Galpha_
s
29
B3 = Galpha_
s
30
Tissue locations for B1?
- heart
- GI smooth muscle
- kidney ? pretty sure
31
Cellular effects for B1?
+AC
increase cAMP
increase [Ca2+] stores in ER
Results in:
excitation
32
Tissue locations for B2?
- lungs
- muscle blood vessels
- liver
- GI smooth muscle
- skeletal muscle
33
Cellular effects for B2?
+AC
increase cAMP
Results in:
excitation
34
Tissue locations for B3?
adipose tissue
| *lipolysis
35
Cellular effects for B3?
+AC
increase cAMP
Results in:
excitation
36
Describe the synapse for NA
- 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
37
What are the 3 ways to eliminate the signal from NA?
1) reuptake at synapse
2) COMT
3) MOA
38
COMT
catechol-o-methyl transferase
39
MOA
monoamine oxidase
40
What is the most important mechanism for the elimination of NA signal?
reuptake at synapse
41
Describe the mechanism of COMT
- a major reason that NA and A are not orally bioavailable
| - this is a Phase 2 metabolism enzyme
42
Describe the mechanism of MOA
- this is a phase 1 metabolism enzyme
| - this is NOT a CYP enzyme
43
What are MOPEG and VMA?
- the main metabolites of NA and A
| - they are conjugated before excretion
44
Where is MAO found?
in mitochondria of presynaptic terminal
45
How does MAO metabolize NA and A?
removal of N eliminates activity
46
Where is COMT found?
in the synapse
47
How does COMT metabolize NA and A?
- always adds the methyl group in the meta position
| - this reduces activity
48
NA in the ____ ______ is protected from metabolism
synaptic vesicle
49
Describe the biosynthesis of NA and A
```
tyrosine
DOPA
dopamine
NA
A
```
OR
```
tyrosine
tyramine
octopamine
NA
A
```
OR
tyrosine tyramine
octopamine
synephrine
A
see slide 11
50
Describe the synapse for amphetamine like drugs
*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
Amphetamine works in the monoamine MA synapses: what are they?
noradrenaline (NA)
dopamine (DA)
serotonin (5-HT)
52
Describe amphetamine mechanisms
- 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
VMAT2
vesicular monoamine transporter 2
54
Normally VMAT2 takes ___ up into the vesicle
MA
55
amphetamine blocks _____
VMAT2
| which reduces vesicular uptake of MA
56
_____ is a competitive inhibitor of the MA reuptake transporter
cocaine
57
Because cocaine is a competitive inhibitor of the MA reuptake transporter, what happens?
this blocks the reuptake of NA, DA, and 5-HT
58
What does cocaine do?
inhibits reuptake of NA, DA, and 5-HT so it increases these neurotransmitters in the synaptic cleft
59
compare and contrast amphetamine and cocaine
they work by different mechanisms but they both have the same effect on increasing [MA] in the synaptic cleft
60
What is tyramine?
it is a naturally occurring metabolite that has amphetamine activity
61
What kind of foods contain tyramine?
red wine
cheese
fermented foods
62
What are these foods (red wine, cheese, fermented foods) contraindicated with?
these foods are contraindicated while taking irreversible inhibitors of MAO
- phenelzine (Nardil)
- tranylcypromine (Parnate)
63
Reversible MAO inhibitors are ok to eat with red wine, cheese, fermented foods. Give an example of a reversible MAO inhibitor
moclobemide (Manerix)
64
inhibition of MAO while taking tyramine increases ???
[NA]
[DA]
or
[5-HT]
in the synapse
65
sympathomimetics
drugs that mimic the sympathetic nervous system
66
There are 3 basic types of sympathomimetics. Describe them
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
Diversity of mechanism results from the common core structure of _________
phenethylamine
slide 16
68
Aromatic rings of amphetamine like drugs can have a _ OH but never a _ OH
they can have p OH
never have a m OH
69
dexamphetamine is the pure __ isomer of amphetamine
S
70
The __ isomer is more potent
S
71
What about the structure of dexamphetamine suggests that it is an amphetamine like drug?
no substitution on ring
72
What about the structure of dexamphetamine confirms that it is an amphetamine like drug?
no B OH substitution
73
What is dexamphetamine used to treat?
ADHD
| possible narcolepsy
74
Why is amphetamine a drug of abuse?
high doses of this drug releases dopamine in the brain
*this causes hallucinations and psychotic symptoms that are all like scizophrenia
75
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
False
| -we do not know
76
Which isomer of NA and A is preferred?
| Why?
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
no intrinsic activity but has affinity = ?
antagonist
78
What happens as the size of the R substituent increases on an alpha adrenergic agonist?
intrinsic activity at the alpha receptor decreases
but affinity increases
*see slide 22
79
Clonidine:
| ortho substituents favour ?
alpha 2 > alpha 1
80
Clonidine:
| guanidine group favours?
alpha 2 > alpha 1
81
Clonidine has no meta OH: what does that mean?
it means that it cannot be inactivated by COMT
82
Can clonidine cross BBB?
yes
83
Why can it cross BBB?
it is hydrophobic and its pKa is low enough so that a portion is in the unionized form at physiological pH (7.4)
84
Methyldopa is ?
alpha 2 agonist
85
Methyldopa has ___ chiral carbons
2
position 1 = R in the active isomer for all agonists of alpha and beta receptors
position 2 = S where substituent is present
86
alpha 2 agonists were originally marked for ?
hypertension
87
in CNS, alpha 2 agonists do what ?
reduce sympathetic output (because of auto-inhibition)
88
Clonidine (Dixarit) still used for ?
symptoms of menopause
89
Methyldopa is occasionally used for ?
used to treat hypertension during pregnancy (pregnancy risk category B)
90
imidazoline is ?
alpha 1 agonist
91
imidazoline alpha 1 agonists act as ?
topical decongestants
92
decongestants cause ?
vasoconstriction
- in the eyes they reduce appearance of red eyes
- in the nose it reduces swelling in nasal membranes (and decreases nasal secretions)
93
phenylephrine and pseudo ephedrine are ?
oral decongestants
94
does phenylephrine have amphetamine like properties?
no
95
phenylephrine is selective for ?
alpha 1 receptor
96
What about phenylephrine suggests it is an alpha agonist
it has an N-methyl group
97
What about phenylephrine suggests that it has no amphetamine like activity?
presence of meta OH
98
What about phenylephrine confirms no amphetamine like activity?
B OH
99
pseudoephedrine has affinity for what receptor?
alpha 1 and alpha 2
*mixed agonist
100
the alpha CH3 on pseudoephedrine does what?
reduces metabolism by MAO
101
What about pseudoephedrine suggests amphetamine like activity?
lack of ring substitution
102
What about pseudoephedrine confirms that it is not a pure amphetamine but displays mixed activity?
B OH
103
What is the main mechanism of action for pseudoephedrine?
mixed amphetamine like activities
104
psuedoephedrine increases ?
wakefullness
105
Brand for phenylephrine?
Benylin cold and sinus plus
106
Brand for pseudoephedrine?
Sudafed
107
Both phenylephrine and pseudoephedrine can cause?
- vasoconstriction
- increased Hr resulting in hypertension
*only a problem in people with existing hypertension
108
While recommending cough and cold products - always ask about what?
HIGH BLOOD PRESSURE
109
What are nasal spray decongestants good for?
people who cannot tolerate oral decongestants
| -especially those with high blood pressure
110
nasal decongestants can produce?
rebound congestion if they are used for more than 3 days in a row
111
Do oral decongestants produce rebound congestion?
no
