Review for the Test
The Test
• 57 Questions/Need to Answer 55
• 27 My Section
• 9.30-11.30p?
– 1-2 minutes/question
COX-2 Physiological Role
• Renin-angiotensin system
• blood pressure and fluid balance
• Ovulation and labor
• Wound healing
• Vascular endothelium
• Vascular remodeling
Modified PGs (mostly)
• Block w-oxidation
– Methyls at 15 and/or 16
– Phenyl in 17-20 range
• Increase Lipophilicity
– Add methyls, phenyls and esters
ADME: Metabolism
b
HO
E
b
HO
CH 3
E
CH 3
CO 2
CO 2
14
13
HO
R
O
OH
O
Travoprost
HO
CF 3
H
N
14
HO
13
R
OH
Prevents Beta-oxidaton
HO
O
G
CH 3
15
CH 3
15
E
Latanoprost
D
CH 2
b
HO
CH 3
CH3
w
CO 2
CH 3
HO
O
OH
O
b
Unoprostone
HO
E
O
R
Bimatoprost
HO
13
14
O
O
F
F
Talfuprost
E=Esterase, O=Oxidation, R=Reduction, b=b-Oxidation, w=w-Oxidation, D=dealkylation, G=glucuronidation
Overview
• Prostaglandins (PGs) and Thromboxanes (TXs)
• NSAIDs
• Gout
PGs and TXs
•
•
•
•
•
•
Structures
Functions
Signaling
Transport
Synthesis and Degradation
PG as drugs
What Prostaglandin is this?
47%
21%
15%
12%
3%
3%
A2
TX
PG
I2
PG
H2
PG
G2
PG
F2
a
lp
ha
0%
PG
E2
PGE1
PGE2
PGF2alpha
PGG2
PGH2
PGI2
TXA2
PG
E1
A.
B.
C.
D.
E.
F.
G.
What Prostaglandin is this?
67%
10%
7%
7%
5%
A2
TX
PG
I2
2%
PG
H2
PG
G2
PG
F2
a
lp
ha
2%
PG
E2
PGE1
PGE2
PGF2alpha
PGG2
PGH2
PGI2
TXA2
PG
E1
A.
B.
C.
D.
E.
F.
G.
What Prostaglandin is this?
PGE1
PGE2
PGF2alpha
PGG2
PGH2
PGI2
TXA2
61%
14%
7%
11%
7%
A2
TX
PG
I2
PG
H2
PG
G2
PG
F2
a
lp
ha
0%
PG
E2
0%
PG
E1
A.
B.
C.
D.
E.
F.
G.
PG and TXs
•
•
•
•
•
•
Structures
Functions
Signaling
Transport
Synthesis and Degradation
PG as drugs
Select the one that is not true
39%
29%
25%
7%
TX
A2
in
re
la
xe
sv
as
cu
la
cr
rs
ea
m
se
PG
...
s
I2
re
pr
na
ot
lb
ec
lo
ts
o.
PG
t
..
h
F2
eg
al
as
ph
tri
a
c..
co
.
PG
nt
ra
F2
ct
al
su
ph
te
a
r i.
ca
.
us
es
br
on
c. .
.
0%
PG
E2
A. PGE2 relaxes vascular
smooth muscle
B. TXA2 increases renal
blood flow
C. PGI2 protects the
gastric mucosa
D. PGF2alpha contracts
uterine smooth
muscles
E. PGF2alpha causes
bronchoconstriction
PG and TXs
•
•
•
•
•
•
Structures
Functions
Signaling
Transport
Synthesis and Degradation
PG as drugs
Prostaglandin signaling within the cell
is?
Endocrine
Autocrine
Paracrine
Intracrine
40%
33%
16%
e
cr
in
In
tra
e
cr
in
Pa
ra
in
e
Au
to
cr
cr
in
e
11%
En
do
A.
B.
C.
D.
What are not involved in Prostaglandin
and Thromboxane signaling
A. Plasma membrane
bound GPCRs
B. Nuclear membrane
bound GPCRs
C. Nuclear Receptors
D. OATP transporter
32%
34%
24%
OA
TP
tra
ns
po
r
te
r
rs
Re
ce
pt
o
Nu
c le
ar
ou
n.
..
eb
m
em
br
an
Nu
c le
ar
Pl
as
m
am
em
br
an
e
bo
un
...
11%
Prostaglandin E2 (PGE2) binds to what
type of receptor
DP1
EP1
FP
IP
TP
63%
14%
16%
IP
FP
EP
1
TP
5%
2%
DP
1
A.
B.
C.
D.
E.
PG and TXs
•
•
•
•
•
•
Structures
Functions
Signaling
Transport
Synthesis and Degradation
PG as drugs
What ways are PG and TX transported
Active Efflux
Active Influx
Passive Diffusion
All the above
79%
e
ab
ov
he
lt
eD
iff
us
io
x
Pa
ss
iv
Ac
t iv
e
In
flu
x
Ef
flu
7%
n
5%
Al
10%
Ac
t iv
e
A.
B.
C.
D.
PG and TXs
•
•
•
•
•
•
Structures
Functions
Signaling
Transport
Synthesis and Degradation
PG as drugs
The substrate of COX 2 is?
Arachidonic Acid
PGE1
PGE2
PGF2alpha
PGG2
PGH2
PGI2
TXA2
57%
24%
9%
2%
2
PG
I2
PG
H2
PG
G2
PG
E2
PG
E1
0%
PG
F2
alp
ha
ac
hi
do
ni
cA
ci d
0%
4%
TX
A
4%
Ar
A.
B.
C.
D.
E.
F.
G.
H.
The product of COX 2 is?
Arachidonic Acid
PGE1
PGE2
PGF2alpha
PGG2
PGH2
PGI2
TXA2
30%
28%
19%
7%
7%
7%
2%
2
TX
A
PG
I2
PG
H2
PG
G2
PG
E2
PG
E1
PG
F2
alp
ha
ac
hi
do
ni
cA
ci d
0%
Ar
A.
B.
C.
D.
E.
F.
G.
H.
What is not a mechanism of
metabolism for PG?
alpha-oxidation
beta-oxidation
omega-oxidation
reduction
alcohol
dehydrogenation
47%
29%
11%
13%
co
re
ho
du
ld
ct
eh
io
n
yd
ro
ge
na
tio
n
al
-o
xid
at
io
io
n
om
eg
a
ox
id
at
io
n
be
ta
-
da
t
-o
xi
ph
a
n
0%
al
A.
B.
C.
D.
E.
How is TXB2 produced
reduction
oxidation
hydrolysis
conjugation
45%
27%
16%
io
n
co
nj
ug
at
ys
is
hy
dr
ol
n
at
io
ox
id
tio
n
11%
re
du
c
A.
B.
C.
D.
Which Cytochrome P450 (CYP) is involved in woxidation?
CYP1A1
CYP2C9
CYP3A4
CYP4A
37%
39%
20%
CY
P4
A
CY
P3
A4
CY
P2
C9
4%
CY
P1
A1
A.
B.
C.
D.
PG and TXs
•
•
•
•
•
•
Structures
Functions
Signaling
Transport
Synthesis and Degradation
PG as drugs
NSAIDs will interfere with PG drugs
because they can
Inhibit PG synthetases
Induce COX 2 expression
Reduce COX 2 expression
Inhibit COX 1
Inhibit COX 2
D and E
96%
PG
it
In
du
c
diclofenac
0%
2%
0%
0%
sy
nt
eC
he
ta
O
se
Re
X
2
s
du
e
xp
ce
re
CO
ss
X
io
2
n
ex
pr
es
sio
In
n
hi
bi
tC
OX
In
1
hi
bi
tC
OX
2
D
an
d
E
2%
In
hi
b
A.
B.
C.
D.
E.
F.
What prostaglandin is Aprostadil?
77%
10%
8%
2%
PG
I2
y
on
l
lin
cy
c
Pr
os
ta
lin
cy
c
Pr
os
ta
Aprostadil
0%
PG
I2
on
l
y
A2
TX
PG
E2
2%
an
d
PGE1
PGE2
TXA2
Prostacyclin only
PGI2 only
Prostacyclin and PGI2
PG
E1
A.
B.
C.
D.
E.
F.
What is not a use of Aprostadil
A. Erectile dysfunction
B. Congenital hear
defect
C. Hypertension
D. Induce labor
E. A and B
F. C and D
38%
32%
9%
11%
9%
ge
ni
Co
n
Er
ec
t il
ed
D
B
C
an
d
d
an
A
ys
fu
nc
tio
ta
n
lh
ea
rd
ef
ec
Hy
t
pe
rt
en
sio
n
In
du
ce
la
bo
r
2%
Aprostadil binding to a GPCR causes all
but the following
A. Increase
intracellular Ca2+
B. Decrease
intracellular Ca2+
C. Activate adenylate
cyclase
D. Increase cAMP
73%
22%
4%
P
AM
se
In
c
re
as
ec
cla
cy
te
ad
en
yla
e
ra
c
Ac
t iv
at
in
t
ea
se
De
cr
In
c
re
as
ei
nt
ra
ce
llu
el
lu
la
la
rC
rC
a2
+
a2
+
0%
What are not formulations of
Alprostadil?
IV injection
Penile injection
Oral
Urethral
Suppository
78%
13%
9%
y
al
lS
up
po
s it
or
Or
Ur
et
hr
a
io
n
in
je
ct
Pe
ni
le
in
je
ct
io
n
0%
IV
A.
B.
C.
D.
What are ADR of Alprostadil?
A. Pain/Rash
B. Light Headed
C. Bleeding and
Bruising
D. Flu Symptoms
E. All the above
91%
he
lt
m
ab
ov
pt
om
s
e
0%
Sy
Flu
ng
a
nd
Br
ui
si
ng
ed
He
ad
Bl
ee
di
L ig
ht
/R
as
h
Pa
in
2%
Al
4%
2%
HO
HO
CH 3
CH 3
CO 2
CO 2
CH 3
CH 3
HO
O
OH
HO
OH
CF 3
Travoprost
HO
H
N
CH 2
Latanoprost
CH3
HO
CH 3
CO 2
O
CH 3
HO
OH
HO
O
Bimatoprost
Unoprostone
HO
O
O
O
HO
F
Talfluprost
F
The compounds on the previous pageare
modified versions of what prostaglandin?
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
45%
30%
9%
et
hy
l
PG
F2
a
2%
PG
I2
PG
F2
a
A2
TX
PG
E2
2%
15
-m
11%
PG
E1
A.
B.
C.
D.
E.
F.
Overview
• Prostaglandins (PGs) and Thromboxanes (TXs)
• NSAIDs
• Gout
NSAIDs
•
•
•
•
•
COX 1, COX 2 and COX3
COX 1/COX 2 IC50 ratios
COX 1 and COX 2 inhibitor side effects
Cancer
Structural Classes of NSAIDs
NSAIDs will inhibit [blank] in a patient
COX 1
COX 2
COX 3
COX 1 and COX 2
COX 1, COX 2 and
COX 3
87%
13%
CO
X
3
an
d
1,
CO
X
2
1a
nd
CO
X
CO
X
CO
X
2
3
0%
CO
X
2
0%
CO
X
1
0%
CO
X
A.
B.
C.
D.
E.
COX 3 should be considered with
NSAID therapeutic regiments.
A. True
B. False
93%
se
Fa
l
Tr
ue
7%
COX 1 has a larger active site than COX
2.
A. True
B. False
57%
se
Fa
l
Tr
ue
43%
NSAIDs
•
•
•
•
•
COX 1, COX 2 and COX3
COX 1/COX 2 IC50 ratios
COX 1 and COX 2 inhibitor side effects
Cancer
Structural Classes of NSAIDs
A new COX inhibitor has a COX-1/COX-2 IC50
ratio of 0.1. What COX enzyme is it selective
for?
A. COX-1
58%
B. COX-2
40%
C. Non-specific
D. COX-3
-3
0%
CO
X
c
sp
ec
ifi
No
n-
-2
CO
X
CO
X
-1
2%
NSAIDs
•
•
•
•
•
COX 1, COX 2 and COX3
COX 1/COX 2 IC50 ratios
COX 1 and COX 2 inhibitor side effects
Cancer
Structural Classes of NSAIDs
Inhibition of PG leads to all but the
following in the GI tract
Increase HCO3
Increase in H+
Increase in mucus
Decrease in mucus
A and B
B and C
A and C
59%
14%
9%
9%
5%
5%
m
uc
us
A
an
d
B
B
an
d
C
A
an
d
C
us
in
ea
se
De
cr
ei
n
m
uc
H+
n
ei
re
as
re
as
In
c
In
c
re
as
eH
CO
3
0%
In
c
A.
B.
C.
D.
E.
F.
G.
What are not COX 1 side effects
GI bleeding
Hypotension
Clotting disorders
Bronchodilation
A and B
B and C
B and D
48%
25%
11%
7%
D
an
d
B
B
an
d
C
B
d
an
A
le
ed
in
7%
2%
Hy
g
po
te
Cl
ot
ns
tin
io
n
gd
is o
Br
rd
on
er
s
ch
od
ila
t io
n
0%
GI
b
A.
B.
C.
D.
E.
F.
G.
PG inhibition leads to
bronchoconstriction through
PGE2
PGE1
PGG2
Leukotrienes (LT)
TXA2
82%
TX
LT
)
tri
en
es
(
PG
G2
A2
5%
2%
Le
uk
o
5%
PG
E1
7%
PG
E2
A.
B.
C.
D.
E.
What type of adverse side effects do you anticipate by interfering
with renin-angiotensin system through COX-2 inhibition?
A. Hypertension
B. Hypertension and
Renal Failure
C. Renal Failure
D. Brain Damage
E. None of the above
76%
22%
Hy
pe
rt
0%
th
e
ab
o
ve
ag
e
No
ne
of
in
Br
a
Re
na
lF
ai
Da
m
lu
re
0%
Re
na
lF
. ..
d
an
en
sio
n
Hy
pe
rt
en
sio
n
2%
NSAIDs
•
•
•
•
•
COX 1, COX 2 and COX3
COX 1/COX 2 IC50 ratios
COX 1 and COX 2 inhibitor side effects
Cancer
Structural Classes of NSAIDs
What are non COX 2 functions for
NSAIDs in Cancer cells?
A. Block NF-kappaB
signaling
B. Activate Peroxisome
proliferator receptor
C. Increase Apoptosis
D. Activate NF-kappaB
signaling
E. A, B and C
F. All the above
71%
14%
oc
k
Bl
0%
0%
NF
-k
Ac
ap
t iv
pa
at
B
e
s ig
Pe
na
ro
xi
lin
so
g
m
ep
In
Ac
cr
ro
ea
t iv
l. .
s
.
at
eA
e
po
NF
pt
-k
os
ap
is
pa
B
s ig
n.
..
A,
B
an
d
Al
C
lt
he
ab
ov
e
0%
14%
Which drug is non-selective for COX 1
and COX 2
Low dose Aspirin
High dose Aspirin
Ibuprofen
Celecoxib
All the above
B and C
68%
23%
7%
B
an
d
C
0%
Ce
le
co
xib
Al
lt
he
ab
ov
e
of
en
Ib
up
r
rin
0%
As
pi
do
se
h
Hi
g
do
se
As
pi
rin
2%
Lo
w
A.
B.
C.
D.
E.
F.
What is not a structural class of
NSAIDs?
Salicylates
Profens
Fenacs
Oxicams
Statins
89%
in
s
St
at
s
m
Fe
na
0%
Ox
ic a
2%
cs
2%
Pr
of
en
s
yl
at
es
7%
Sa
lic
A.
B.
C.
D.
E.
Salicylates inhibit by the following
mechanisms
Competitive
Irreversible
Non-competitive
Uncompetitive
A and B
B and C
All the above
56%
26%
7%
2%
5%
5%
0%
Co
m
pe
tit
ive
Irr
ev
No
er
sib
nco
le
m
pe
tit
Un
ive
co
m
pe
tit
iv
e
A
an
d
B
B
an
d
Al
C
lt
he
ab
ov
e
A.
B.
C.
D.
E.
F.
G.
How does low dose Aspirin prevent
stroke and heart attack?
reduce PGE2
reduce PGI2
reduce TXA2
B and C
A, B and C
48%
41%
11%
A,
B
an
d
C
C
B
an
d
2
XA
eT
re
du
c
eP
GI
2
0%
re
du
c
eP
GE
2
0%
re
du
c
A.
B.
C.
D.
E.
Oxicams are acidic by which
mechanism
Reduction
Oxidation
Hydrolysis
Keto-enol
tautomerism
44%
44%
7%
to
m
er
ism
lys
is
en
ol
ta
u
Hy
dr
o
Ke
to
-
n
at
io
Ox
id
n
5%
Re
du
ct
io
A.
B.
C.
D.
What coxib is available in U.S.
markets?
Lumiracoxib
Etoricoxib
Rofecoxib
Celecoxib
Valdecoxib
None of the above
98%
2%
0%
0%
Ro
fe
co
xib
Ce
le
co
xib
Va
ld
No
ec
ne
ox
ib
of
th
e
ab
ov
e
xib
0%
ico
Et
or
co
xib
0%
Lu
m
ir a
A.
B.
C.
D.
E.
F.
Overview
• Prostaglandins (PGs) and Thromboxanes (TXs)
• NSAIDs
• Gout
What is not a strategy for treating
gout?
A. Decrease
inflammation
B. Increase Uric Acid
Reabsorption
C. Inhibit Uric Acid
synthesis
D. None of the above
63%
35%
ab
o
of
No
ne
id
Ac
Ur
ic
it
In
hi
b
th
e
sy
nt
h
s..
.
Re
ab
Ac
id
ric
eU
re
as
In
c
es
is
n
m
at
io
m
in
fla
ea
se
De
cr
ve
2%
0%
The molecule below is?
Uric Acid
Allopurinol
Xanthine
Hypoxanthine
Allopurinol
47%
21%
21%
7%
ol
lo
pu
r in
Al
th
i
ne
e
Hy
po
xa
n
nt
hi
n
Xa
ol
lo
pu
r in
Al
Ac
id
5%
Ur
ic
A.
B.
C.
D.
E.
Colchicine is metabolized by
CYP1A2
CYP2C9
CYP3A4
UGTs
B and D
C and D
24%
24%
22%
16%
9%
D
d
an
C
B
an
d
D
s
UG
T
CY
P3
A4
CY
P2
C9
4%
CY
P1
A2
A.
B.
C.
D.
E.
F.
Why is it bad to take allopurinol or
febuxostat with XO ligands?
A. Increase blood plasma XO
ligand concentration and
toxicity
B. Decrease blood plasma XO
ligand concentration and
increased XO ligand toxicity
C. No effect on blood plasma
XO ligand concentration or
toxicity
D. None of the above
78%
23%
ve
0%
ab
o
s. .
th
e
pl
a
No
ne
of
od
bl
o
on
ef
fe
ct
No
bl
o
ea
se
De
cr
In
c
re
as
eb
lo
od
od
pl
pl
as
m
as
m
a
aX
O.
..
XO
. ..
0%
Good Luck on the Test: Questions