Breast Cancer Clinical Therapeutics

1. PROBLEM
1:
BREAST
CANCER
Yang
GOALS
OF
THERAPY:
•
•
The
goals
of
treatment
for
a
patient
with
metastatic
breast
cancer
are
palliation
and
prolongation
of
life.
Since
cure
is
not
the
goal
in
this
setting,
the
easiest,
least
toxic
treatment
regimen
should
be
chosen.
Screening
for
Breast
cancer
Patient
in
our
case
was
previously
diagnosed
with
stage
IIB
Breast
cancer.
In
stage
IIB
tumor:
• Larger
than
2
centimeters
but
not
larger
than
5
cm.
small
clusters
of
breast
cancer
cells
(larger
than
0.2
millimeter
but
not
larger
than
2
millimeters)
are
found
in
the
lymph
nodes
or
• Larger
than
2
centimeters
but
not
larger
than
5
centimeters.
Cancer
has
spread
to
1
to
3
axillary
lymph
nodes
or
to
the
lymph
nodes
near
the
breast
bone
(found
during
a
sentinel
lymph
node
biopsy)
or
• Larger
than
5
centimeters.
Cancer
has
not
spread
to
the
lymph
nodes.
But
now,
our
patient
has
Metastatic
Breast
Cancer
Radiation
therapy,
hormonal
therapy,
and
chemotherapy
have
all
been
used
in
the
treatment
of
metastatic
breast
cancer
to
palliate
the
patient
and
possibly
prolong
survival.
Palliation
is
the
primary
goal
of
therapy:
the
easiest,
least
toxic
treatment
that
can
provide
the
best
possible
response
is
generally
preferred.
•
metastasize
to
virtually
any
site
•
most
common
sites:
bone,
lung,
pleura,
liver,
soft
tissue,
and
the
central
nervous
system.
•
The
choice
of
therapy
for
metastatic
disease
is
based
on
the
site
of
disease
involvement
and
the
presence
or
absence
of
certain
patient
characteristics.
SECTION
3E-­‐–
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
1

2. Treatment:
I.
RADIATION
THERAPY:
Radiation
therapy
is
primarily
used
to
control
symptomatic
disease
such
as
bone
metastases,
metastatic
brain
lesions,
and
spinal
cord
compressions.
II.
HORMONAL
THERAPY
• goal
of
hormonal
therapy
is
to
reduce
the
stimulation
of
the
tumor
cells
by
estrogen.
• Adjuvant
hormonal
therapy
should
be
offered
to
any
patient
whose
tumor
overexpresses
hormone
receptors
[either
ER
or
progesterone
(PgR)],
regardless
of
patient
age,
nodal
status,
or
menopausal
status.
In
our
case,
patient
had
received
Tamoxifen,
a
selective
estro-­‐
gen-­‐receptor
modulator
(SERM),
(adjuvant
hor-­‐
monal
therapy
most
commonly
used)
for
five
years.
• However,
the
benefits
of
tamoxifen
must
be
weighed
against
the
side
effects
of
treatment,
particularly
when
the
drug
is
being
used
in
the
adjuvant
setting.
• The
most
common
side
effects
of
tamoxifen
include
hot
flashes
and
vaginal
discharge,
but
an
increased
risk
of
thromboembolic
events
and
endometrial
cancer
can
also
occur.
• Third-­‐generation
aromatase
inhibitors
have
been
extensively
studied
as
first
and
second-­‐line
therapy
for
metastatic
breast
cancer.
o The
ATAC
(Arimidex,
Tamoxifen
Alone
or
in
Combination)
Trialists’
Group
found
superior
disease-­‐
free
survival
for
anastrozole
as
adjuvant
therapy
in
post-­‐
menopausal
women
with
hormone-­‐
sensitive
disease
when
compared
to
tamoxifen
or
the
combination
of
tamoxifen
and
anastrozole.
As
a
result,
anastrozole
was
granted
accelerated
approval
as
adjuvant
therapy
for
breast
cancer.
• Fulvestrant,
an
injectable
pure
estrogen
antagonist,
has
also
shown
activity
in
patients
with
hormone-­‐
receptor-­‐
positive
disease
progressing
on
hormonal
therapy.
• The
choice
of
hormonal
therapy
is
patient-­‐specific
and
may
be
influenced
by
prior
therapy
in
the
adjuvant
setting,
toxicity
profiles,
cost,
and
ease
of
administration.
***
Tamoxifen
–
acts
like
an
anti-­‐estrogen
in
breast
cells,
it
acts
like
an
estrogen
in
other
tissues,
like
the
uterus
and
the
bones
-­‐
stop
the
growth
and
even
shrink
tumors
in
women
with
metastatic
breast
cancer.
It
can
also
be
used
to
reduce
the
risk
of
developing
breast
cancer
in
women
at
high
risk
Aromatase
inhibitors:
cannot
stop
the
ovaries
from
making
estrogen,
so
they
are
only
effective
in
women
whose
ovaries
aren’t
working
(like
after
menopause)
Fulvestrant
-­‐
first
blocks
the
estrogen
receptor
and
then
also
eliminates
it
temporarily;
acts
like
an
anti-­‐estrogen
throughout
the
body
***

3.
Efficacy
Safety
Suitability
Cost
Anti-­‐
estrogen
Tamoxifen
+++
selective
estrogen
receptor
modulator
or
SERM
++
Disease
flare,
hot
flashes;
rare:
thrombophlebitis,
ocular
abnormalities,
endometrial
cancer
++
premenopausal
and
postmenopausal
women
(and
men)
with
ER-­‐positive
early-­‐
stage
breast
cancer
1,400
Aromatase
Inhibitors
3rd
gen:
anastrazole
+++
Blocking
aromatase
in
fat
tissue
that
is
responsible
for
making
small
amounts
of
estrogen
in
post-­‐
menopausal
women
+++
Hot
flashes,
nausea,
vomiting,
headache,
fatigue;
rare:
bone
fractures,
musculoskeletal
disorders
+++
No
significant
drug
interactions
initial
therapy
for
metastatic
hormone-­‐sensitive
breast
cancer
treat
postmenopausal
women
with
advanced
breast
cancer
whose
disease
has
worsened
after
treatment
with
tamoxifen
+++
2750
Pure
Estrogen
Antagonist
Fulvestrant
+++
+++
Hot
flashes,
headache,
nausea,
vomiting,
injection
site
reactions
++
No
significant
drug
interactions
postmenopausal
women
with
metastatic
ER-­‐positive
breast
cancer
after
treatment
with
other
antiestrogens
+++
28,000
Median
duration
of
response
to
the
first
attempt
at
hormonal
manipulation
is
usually
in
the
range
of
9
to
12
mos.
First-­‐line
hormonal
therapy
should
be
administered
for
at
least
6
to
8
weeks
before
disease
response
is
assessed.
If
a
patient
becomes
refractory
to
hormonal
therapy
at
any
time,
chemotherapy
should
be
given.
III.
CHEMOTHERAPY:
Chemotherapeutic
drugs
are
most
commonly
used
as
palliative
therapy
in
patients
who
would
not
be
expected
to
respond
to
hormonal
therapy
4
GROUPS
OF
CHEMOTHERAPEUTIC
DRUGS
1.
ALKYLATING
AGENTS
The
major
clinically
useful
alkylating
agents
have
a
structure
containing
a
bis(chloroethyl)amine,
ethyleneimine,
or
nitrosourea
moiety,
and
they
are
classified
in
several
different
groups.
Mechanism
of
Action
• exert
their
cytotoxic
effects
via
transfer
of
their
alkyl
groups
to
various
cellular
constituents.
• Alkylations
of
DNA
within
the
nucleus
probably
represent
the
major
interactions
that
lead
to
cell
death.
• The
general
mechanism
of
action
of
these
drugs
involves
intramolecular
cyclization
to
form
an
ethyleneimonium
ion
that
may
directly
or
through
formation
of
a
carbonium
ion
transfer
an
alkyl
group
to
a
cellular
constituent
• a
secondary
mechanism
that
occurs
with
nitrosoureas
involves
carbamoylation
of
lysine
residues
of
proteins
through
formation
of
isocyanates.
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
3

4. Adverse
Effects
• generally
dose-­‐related
and
occur
primarily
in
rapidly
growing
tissues
such
as
bone
marrow,
gastrointestinal
tract,
and
reproductive
system.
• Nausea
and
vomiting
can
be
a
serious
issue
• potent
vesicants
and
can
damage
tissues
at
the
site
of
administration
as
well
as
produce
systemic
toxicity.
• carcinogenic
in
nature,
and
there
is
an
increased
risk
of
secondary
malignancies,
especially
acute
myelogenous
leukemia.
Cyclophosphamide
• is
one
of
the
most
widely
used
alkylating
agents.
• One
of
the
potential
advantages:
high
oral
bioavailability
• oral
and
intravenous
routes
with
equal
clinical
efficacy.
• inactive
in
its
parent
form,
and
must
be
activated
to
cytotoxic
forms
by
liver
microsomal
enzymes
A.
NITROSOUREAS
• non-­‐cross-­‐resistant
with
other
alkylating
agents;
all
require
biotransformation,
which
occurs
by
nonenzymatic
decomposition,
to
metabolites
with
both
alkylating
and
carbamoylating
activities
• highly
lipid-­‐soluble
and
are
able
to
cross
the
blood-­‐brain
barrier
B.
NONCLASSIC
ALKYLATING
AGENTS
1. Procarbazine
2. Dacarbazine
3. Bendamustine
C.
PLATINUM
ANALOGS
Three
platinum
analogs
are
currently
used
in
clinical
practice:
cisplatin,
carboplatin,
and
oxaliplatin.
Cisplatin
•
•
is
an
inorganic
metal
complex
that
was
initially
discovered
through
an
observation
that
neutral
platinum
complexes
inhibited
division
and
filamentous
growth
of
Escherichia
coli.
MOA:
kill
tumor
cells
in
all
stages
of
the
cell
cycle
and
bind
DNA
through
the
formation
of
intrastrand
and
interstrand
cross-­‐links,
thereby
leading
to
inhibition
of
DNA
synthesis
and
function.
-­‐
Cisplatin
and
the
other
platinum
analogs
are
extensively
cleared
by
the
kidneys
and
excreted
in
the
urine.
As
a
result,
dose
modification
is
required
in
patients
with
renal
dysfunction.
Carboplatin
• is
a
second-­‐generation
platinum
analog
• MOA,
mechanisms
of
resistance,
and
pharmacology
are
identical
to
cisplatin.
• in
contrast
to
cisplatin,
it
exhibits
significantly
less
renal
toxicity
and
GI
toxicity
• Its
main
dose-­‐limiting
toxicity
is
myelosuppression.
• It
has
therefore
been
widely
used
in
transplant
regimens
to
treat
refractory
hematologic
malignancies.
Oxaliplatin
•
•
third-­‐generation
diaminocyclohexane
platinum
analog.
tumors
that
are
resistant
to
cisplatin
or
carboplatin
on
the
basis
of
mismatch
repair
defects
are
not
cross-­‐
resistant
to
oxaliplatin,

5.
2.
ANTIMETABOLITES
A.
ANTIFOLATES
Methotrexate
is
a
folic
acid
analog
that
binds
with
high
affinity
to
the
active
catalytic
site
of
dihydrofolate
reductase
(DHFR)
à
inhibition
of
the
synthesis
of
tetrahydrofolate
(THF)
Pemetrexed
Pralatrexate
•
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
5

6. B.
FLUOROPYRIMIDINES
5-­‐Fluorouracil
inactive
in
its
parent
form;
requires
activation
via
a
complex
series
of
enzymatic
reactions
to
ribosyl
and
deoxyribosyl
nucleotide
metabolites;
cytotoxicity
of
5-­‐FU
is
thought
to
be
the
result
of
combined
effects
on
both
DNA-­‐
and
RNA-­‐mediated
events.
Capecitabine
•
C.
DEOXYCYTIDINE
ANALOGS
Cytarabine
•
(ara-­‐C)
is
an
S
phase-­‐specific
antimetabolite
that
is
converted
by
deoxycytidine
kinase
to
the
5'-­‐
mononucleotide
(ara-­‐CMP).
Ara-­‐CMP
is
further
metabolized
to
the
diphosphate
and
triphosphate
metabolites,
and
the
ara-­‐CTP
triphosphate
is
felt
to
be
the
main
cytotoxic
metabolite.
Gemcitabine
D.
PURINE
ANTAGONISTS
6-­‐Thiopurines
Fludarabine
Cladribine

7. 3.
NATURAL
PRODUCT
CANCER
CHEMOTHERAPY
DRUGS
A.
VINCA
ALKALOIDS
Vinblastine
•
inhibition
of
tubulin
polymerization,
which
disrupts
assembly
of
microtubules,
an
important
part
of
the
cytoskeleton
and
the
mitotic
spindle.
This
inhibitory
effect
results
in
mitotic
arrest
in
metaphase,
bringing
cell
division
to
a
halt,
which
then
leads
to
cell
death.
Vincristine
•
While
myelosuppression
occurs,
it
is
generally
milder
and
much
less
significant
than
with
vinblastine.
Vinorelbine
B.
TAXANES
&
RELATED
DRUGS
Paclitaxel
•
•
•
drug
functions
as
a
mitotic
spindle
poison
through
high-­‐affinity
binding
to
microtubules
with
enhancement
of
tubulin
polymerization.
This
promotion
of
microtubule
assembly
by
paclitaxel
occurs
in
the
absence
of
microtubule-­‐associated
proteins
and
guanosine
triphosphate
and
results
in
inhibition
of
mitosis
and
cell
division
Hypersensitivity
reactions
may
be
observed
in
up
to
5%
of
patients,
but
the
incidence
is
significantly
reduced
by
premedication
with
dexamethasone,
diphenhydramine,
and
an
H2
blocker.
Abraxane
•
•
A
novel
albumin-­‐bound
paclitaxel
formulation
is
approved
for
use
in
metastatic
breast
cancer.
In
contrast
to
paclitaxel,
this
formulation
is
not
associated
with
hypersensitivity
reactions
B.
EPIPODOPHYLLOTOXINS
Etoposide
•
The
main
site
of
action
is
inhibition
of
the
DNA
enzyme
topoisomerase
II
C.
CAMPTOTHECINS
•
•
inhibit
the
activity
of
topoisomerase
I,
the
key
enzyme
responsible
for
cutting
and
religating
single
DNA
strands.
Inhibition
of
this
enzyme
results
in
DNA
damage
Myelosuppression
and
diarrhea
are
the
two
most
common
adverse
events
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
7

8. 4.
ANTITUMOR
ANTIBIOTICS
Many
of
these
antibiotics
bind
to
DNA
through
intercalation
between
specific
bases
and
block
the
synthesis
of
RNA,
DNA,
or
both;
cause
DNA
strand
scission;
and
interfere
with
cell
replication.
All
of
the
anticancer
antibiotics
now
being
used
in
clinical
practice
are
products
of
various
strains
of
the
soil
microbe
Streptomyces.
A.
ANTHRACYCLINES
among
the
most
widely
used
cytotoxic
anticancer
drugs.
The
anthracyclines
exert
their
cytotoxic
action
through
four
major
mechanisms:
(1)
inhibition
of
topoisomerase
II;
(2)
high-­‐affinity
binding
to
DNA
through
intercalation,
with
consequent
blockade
of
the
synthesis
of
DNA
and
RNA,
and
DNA
strand
scission;
(3)
generation
of
semiquinone
free
radicals
and
oxygen
free
radicals
through
an
iron-­‐dependent,
enzyme-­‐mediated
reductive
process;
(4)
binding
to
cellular
membranes
to
alter
fluidity
and
ion
transport.
Doxorubicin
•
is
one
of
the
most
important
anticancer
drugs
in
clinical
practice,
with
major
clinical
activity
in
cancers
of
the
breast,
endometrium,
ovary,
testicle,
thyroid,
stomach,
bladder,
liver,
and
lung
Epirubicin
•
•
is
an
anthracycline
analog
initially
approved
for
use
as
a
component
of
adjuvant
therapy
in
early-­‐stage,
node-­‐positive
breast
cancer
but
is
also
used
in
the
treatment
of
metastatic
breast
cancer
and
gastroesophageal
cancer.
B.
MITOMYCIN
•
undergoes
metabolic
activation
through
an
enzyme-­‐mediated
reduction
to
generate
an
alkylating
agent
that
cross-­‐links
DNA.
C.
BLEOMYCIN
•
small
peptide
that
contains
a
DNA-­‐binding
region
and
an
iron-­‐binding
domain
at
opposite
ends
of
the
molecule.
It
acts
by
binding
to
DNA,
which
results
in
single-­‐
and
double-­‐
strand
breaks
following
free
radical
formation,
and
inhibition
of
DNA
biosynthesis.

9.
The
American
Society
of
Clinical
Oncology
(ASCO)
breast
cancer
surveillance
guidelines:
• Women
with
a
history
of
breast
cancer
should
perform
monthly
BSE
and
undergo
annual
mammography
of
both
the
preserved
and
contralateral
breast.
• The
patient
should
also
have
a
complete
history
and
physical
examination
every
3
to
6
months
for
the
first
3
years
after
diagnosis,
then
every
6
to
12
months
for
2
years,
and
then
annually.
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
9

10. NATIONAL
COMPREHENSIVE
CANCER
NETWORK
SUMMARY:
Since
patient
was
diagnosed
6
years
ago
with
Breast
cancer:
Stage
IIB
infiltrating
ductal
carcinoma
of
the
right
breast.
Originally,
the
tumor
was
ER_/PR_
and
did
not
overexpress
HER-­‐2/neu.
The
tumor
was
staged
as
T2N1M0.
She
received
a
lumpectomy
with
axillary
lymph
node
dissection
plus
breast
irradiation,
6
cycles
of
AC
(A=
ADRIAMYCIN
an
anthracycline;
C=Cyclophosphamide),
and
tamoxifen
for
5
years.
NEXT
step
would
be
to
change
tamox
to
anastrazole
and
begin
with
chemotherapy
preferably
combination
since
patient
had
already
a
history
of
being
treated
with
a
combination
chemo
drugs
–AC.
Choice
would
depend
on
patient’s
comorbidities
and
toxicities
from
chemo
drugs.

11. PROBLEM
2:
Bone
Pain
Zepeda
Basis
for
diagnosis:
•
•
•
Chief
Complaint:
Severe
(7
out
of
10)
hip
pain
Bone
scan:
multiple
metastases
to
the
right
pelvis
Medications:
Ibuprofen
200
to
400
mg
PO
q4–6h
PRN,
calcium
carbonate
1,000
mg
PO
TID
with
meals
GOALS
OF
THERAPY:
•
•
•
Decrease
the
severity
of
pain
from
severe
to
moderate
To
minimize
adverse
reactions
or
intolerance
to
pain
management
therapies
Improve
the
patient’s
quality
of
life
and
optimize
ability
to
perform
activities
of
daily
living
Bone
is
the
most
common
site
of
secondary
breast
cancer
or
breast
cancer
recurrence.
Most
commonly
affected
are
the
spine,
skull,
upper
bones
of
the
arms
and
legs
and
pelvis
which
is
the
one
affected
in
our
patient.
Pain
is
defined
as
“an
unpleasant
sensory
and
emotional
experience
associated
with
actual
or
potential
tissue
damage,
or
described
in
terms
of
such
damage”.
It
is
the
most
common
symptom
that
provokes
people
to
seek
medical
attention
Normally,
the
bone
undergoes
a
continuous
process
of
remodeling
by
the
osteoclast
and
osteoblasts
to
maintain
homeostasis.
Disruption
of
this
process,
which
occurs
in
cancer,
will
cause
the
bone
cells
to
proliferate
and
hypertrophy
causing
the
periosteum
to
stretch
or
affect
the
nerves
thereby
resulting
to
pain.
The
World
Health
Organization
developed
a
stepladder
for
relief
of
pain
management
in
adult
cancer
patient.
It
indicates
the
severity
of
pain
which
is
rated
in
1-­‐10
scale
and
will
dictate
what
type
of
medication
is
needed
or
used.
Stage
1:
Mild
(Pain
Scale:
1-­‐3)
Non-­‐opioids
are
the
first
choice
of
treatment.
Medications
include
are
Acetaminophen
or
NSAIDS
like
Ibuprofen.
Stage
2:Moderate
(Pain
Scale:
4-­‐6)
Those
who
are
not
responded
to
the
first
step
should
receive
a
weak
opioid
such
as
codeine,
oxycodone,
hydrocodone
and
Tramadol
Stage
3:
Severe
(Pain
Scale:
7-­‐10)
Those
who
have
not
been
relieved
by
the
previous
recommendation
will
receive
a
stronger
opioid
such
as
Morphine,
Methadone
and
Fentanyl.
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
11

12. Key
Points:
• Oral
route
is
preferred
unless
contraindicated
(parenteral
therapy
may
be
required
for
refractory
pain
or
inability
to
take
per
orem)
• Cancer
pain
is
continuous.
Relief
of
pain
is
only
temporary
and
may
return
in
a
short
time
• Should
be
scheduled
at
regular
intervals
rather
than
prn
• Adjuvant
therapy
is
used
to
decrease
anxiety
and
fear
with
chronic
pain
(e.g.
antidepressants)
• Non-­‐opioids
may
be
given
in
Step
2
and
3
Treatment:
Opioids
-­‐ refers
broadly
to
all
compounds
related
to
opium,
a
natural
product
derived
from
the
poppy
plant
-­‐ reduce
moderate
to
severe
pain,
and
are
unique
in
their
ability
to
do
this
without
producing
loss
of
consciousness
-­‐ produce
analgesia,
affect
mood
and
rewarding
behavior
and
alter
respiratory,
cardiovascular,
GI,
and
neuroendocrine
function
-­‐ All
opioids
have
the
potential
for
tolerance,
habituation,
and
addiction
The
patient
experiences
a
severe
type
of
pain,
therefore
will
be
following
the
Step
3.
Drug
Morphine
Efficacy
++++
Suitability
+++
Safety
++
Hydromorphone
++++
4-­‐5x
more
potent
than
morphine
+++
100x
+++
++
++
Only
available
in
IV,
buccal,
spinal
and
patch
+
Not
available
in
the
Philippines
++
Fentanyl
Methadone
++++
0.3x
++
Cost
++++
Tab
60's
(P1345.00/pack)
++
Tab
28's
(P3640.00/pack)
++
Patch
5
×
1's
(P2513.00/box)
+
Not
available
in
the
Philippines

13. Methadone:
(Diphenylheptanes)
-­‐ long-­‐acting
mu-­‐receptor
agonist
with
properties
qualitatively
similar
to
those
of
morphine.
-­‐ relief
of
chronic
pain,
treatment
of
opioid
abstinence
syndromes,
and
treatment
of
heroin
users.
-­‐ roughly
equivalent
in
potency
to
morphine
on
a
single
dose
basis;
however,
with
repeated
administration
accumulation
in
CNS
and
lipid
tissues
occurs
Fentanyl:
(Phenylpiperidines)
-­‐ is
a
synthetic
opioid
derivative
of
the
4-­‐anilinophenyl-­‐piperidine
class
-­‐ approximately
100
times
more
potent
than
morphine
-­‐ used
clinically
as
an
analgesic;
administered
intraspinally
or
intravenously
and
as
a
preoperative
anesthetic
agent
because
of
its
potency,
rapid
onset,
and
short
duration
of
action
-­‐ Not
suitable
for
rapid
dose
filtration.
Should
be
used
for
relatively
stable
analgesic
requirement.
-­‐ Also
available
as
a
transdermal
patch
which
can
be
given
every
8
days
Hydromorphone:
(Phenanthrenes)
-­‐ Semisyntheticopioid
that
xerts
major
pharmacodynamic
effects
on
mu-­‐receptors
and
kappa-­‐
receptors
-­‐ less
potential
to
produce
nausea,
vomiting,
constipation,
sedation,
or
euphoria
and
has
a
more
rapid
onset
and
shorter
duration
of
action
than
morphine
-­‐ can
be
used
as
a
substitute
when
these
adverse
effects
warrant
a
therapeutic
alternative
Morphine:
(Phenanthrenes)
-­‐ prototype
strong
opioid
agonist
(the
gold
standard
given
for
cancer
patients
with
moderate-­‐severe
pain)
-­‐ Exert
major
pharmacodynamic
effects
on
mu-­‐receptors
(strong)
and
kappa-­‐receptors
-­‐ Interact
w/
opioid
receptors
in
the
CNS
and
GIT
causing
hyperpolarization
of
nerve
cells,
inhibition
of
nerve
firing
and
presynaptic
inhibition
of
transmitter
release
-­‐ Acts
at
κ
receptors
in
lamina
I
and
II
of
the
substantia
gelatinosa
of
the
SC
which
then
decreases
the
release
of
substance
P
-­‐ Main
indication
is
for
preoperative
pain
and
chronic
malignant
pain
*
All
are
efficacious
but
have
different
potency.
Methadone
is
not
available
in
the
Philippines.
All
opioids
have
produce
these
side/adverse
effects:
constipation
(most
common),
nausea,
vomiting,
somnolence,
mood
changes
like
euphoria,
dysphoria,
addiction,
physical
dependence
and
respiratory
depression
(most
dreaded
complication).
Drug
of
Choice:
Morphine
Sulphate
Drug
interactions:
Paroxetine
and
Morphine:
Opioids
may
enhance
effect
of
SSRI.
Additive
effect
to
sedation.
Metformin
and
Morphine:
increase
effects
of
Metformin
Lisinopril
and
Morphine:
may
have
additive
effect
causing
hypotension
*Therefore
it
is
important
to
take
the
medication
as
prescribed
and
strictly
monitor
compliance.
Plan
of
Action
• Initiate
Morphine
Sulphate
immediate
release
15mg
PO
q3-­‐4hours
• If
the
opiate
requirement
is
determined,
switch
to
a
sustained
release
formulation
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
13

14. •
•
•
•
Start
with:
Senna
1
tablet
PO
BID
(stool
softener)
Docusate
sodium
100
mg
PO
BID
(laxative)
*
All
these
adverse
events
(nausea,
vomiting,
sedation,
confusion,
constipation,
or
itching)
except
constipation
will
be
gone.
Should
take
these
two
medications
every
day
to
prevent
constipation
from
morphine)
Ibuprofen
800mg
q8h
with
food
Pamidronate
90
mg
IV
over
2
hours
every
4
weeks
(Check
SCr
prior
to
each
dose)
Monitor
Efficacy
(decrease
pain
scale
and
opiate
requirement)
and
Toxicity
(increase
in
pain,
opiate
requirement,
nausea,
vomiting,
itching,
BP,
constipation,
confusion,
sedation,
respiratory
rate,
renal
function,
platelets,
Hct/Hgb,
signs
and
symptoms
of
bleeding,
calcium,
magnesium,
phosphate
Report
any
prolonged
adverse
events,
severe
confusion/lightheadedness,
or
difficulty
breathing
Important
to
take
the
pain
medication
around
the
clock
to
prevent
the
pain
from
recurring
Non-­‐Pharmacologic
Intervention:
• Relaxation
Techniques,
massage
therapy,
and
exercise
can
be
done
• Counsel
KF
that
the
pain
may
not
completely
resolve
but
that
it
should
substantially
decrease
and
she
should
notice
an
improvement
in
mobility
Problem
3:
Hypercalcemia
of
Malignancy
Secondary
to
Bone
Metastases
Villanueva
Hypercalcemia
in
patients
with
cancer
is
primarily
due
to
increased
bone
resorption
and
release
of
calcium
from
bone.
There
are
three
major
mechanisms
by
which
this
can
occur:
osteolytic
metastases
with
local
release
of
cytokines
(including
osteoclast
activating
factors);
tumor
secretion
of
parathyroid
hormone-­‐related
protein
(PTHrP);
and
tumor
production
of
1,25-­‐dihydroxyvitamin
D
(calcitriol).
In
this
case,
I. Basis
for
diagnosis
•
•
•
•
•
•
•
•
Breast
cancer:
commonly
associated
with
hypercalcemia
Pain
on
right
hip
Decreased
appetite
Increasing
fatigue
Constipation
More
forgetful
Confusion
Ca
level:
12.5
(N:8.5-­‐10.2)
II.
Treatment
objectives
a. To
reduce
serum
calcium
level
b. To
reverse
signs
and
symptoms
of
hypercalcemia
c. avoid
exacerbation
of
hypercalcemia
d. Reduce
gastrointestinal
calcium
absorption

15. III.
Management
A. Therapeutic
B. Non
pharmacologic
Therapeutic
Loop
diuretic
Bisphosphonat
es
Calcitonin
Mechanism
of
action
enhances
urine
flow
but
also
inhibits
calcium
reabsorption
in
the
ascending
limb
of
the
loop
of
Henle
Mimic
pyrophosphat
e's
structure,
inhibiting
activation
of
enzymes
that
utilize
pyrophosphat
e
-­‐
binding
and
blocking
the
enzyme
farnesyldipho
sphate
synthase
(FPPS)
in
the
HMG-­‐CoA
reductase
pathway
Calcitonin
lowers
plasma
Ca2+
and
phosphate
concentration
s
thereby
blocking
bone
resorption,
increases
urinary
calcium
excretion
by
Indications
Adverse
effects
acute
pulmonary
edema,
other
edematous
conditions,
acute
hypercalcemia
.
ototoxicity,
hypovolemia,
K
wasting,
hyperuricemia Oral,
IV
,
hypomagnese
mia
osteoclast-­‐
mediated
bone
resorption,
including
osteoporosis,
steroid-­‐
induced
osteoporosis,
Paget's
disease,
tumor-­‐
associated
osteolysis,
breast
and
prostate
cancer,
and
hypercalcemia
.
upset
stomach
and
inflammation
and
erosions
of
the
esophagus,
IV:
can
give
fever
and
flu-­‐like
symptoms
after
the
first
infusion,
rareosteonecr
osis
of
the
jaw
Oral,
IV
50%
is
excreted
unchanged
by
the
kidney.
The
remainder
has
a
very
high
affinity
for
bone
tissue,
and
is
rapidly
adsorbed
onto
the
bone
surface
nasuea,
vomitting
effect
on
serum
calcium
is
observed
within
4–6
hours
and
lasts
for
6–10
hours,
subcutaneous,
intranasal,
oral
Paget’s
diasease,
osteoporosis
Pharmocokine
tics
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
15

16. inhibiting
renal
calcium
reabsorption
reducing
serum
calcium
nephrotoxicity
Oral,
t1/2:
1
in
cancer
hr
patients
thrombocytop
decreases
enia,
Reduction
in
plasma
Ca2+
hemorrhage,
plasma
Ca2+
concentration
hepatic
and
concentration
hypercalcemia
s
by
inhibiting
renal
toxicity
s
occurs
bone
hypocalcemia,
within
24
to
resorption.
nausea,
and
48
hours
vomiting
IV:
short-­‐
hypocalcemia,
termcalcemic
ectopic
control
of
calcification,
some
patients
acute
renal
Binds
to
Ca
with
primary
failure,
and
Oral
and
IV
ions
hyperparathyr hypotension.
oidism
who
Oral:
ectopic
are
awaiting
calcification
surgery.
and
renal
failure
inhibiting
Gallium
Nitrate
bone
resorption
Plicamycin
(Mithramycin)
Phosphate
Rapid
reduction
of
serum
calcium
is
required.
The
first
steps
include
rehydration
with
saline
and
diuresis
with
furosemide.
Saline
rehydration
is
used
to
dilute
serum
calcium
and
promote
calciuresis.
Most
patients
presenting
with
severe
hypercalcemia
have
a
substantial
component
of
prerenal
azotemia
owing
to
dehydration,
which
prevents
the
kidney
from
compensating
for
the
rise
in
serum
calcium
by
excreting
more
calcium
in
the
urine.
Therefore,
the
initial
infusion
of
500–1000
mL/h
of
saline
to
reverse
the
dehydration
and
restore
urine
flow
can
by
itself
substantially
lower
serum
calcium.
The
addition
of
a
loop
diuretic
such
as
furosemide
following
rehydration
not
only
enhances
urine
flow
but
also
inhibits
calcium
reabsorption
in
the
ascending
limb
of
the
loop
of
Henle.
Monitoring
central
venous
pressure
is
important
to
forestall
the
development
of
heart
failure
and
pulmonary
edema
in
predisposed
subjects.
Calcitonin
Calcitonin
has
proved
useful
as
ancillary
treatment
in
a
large
number
of
patients.
Calcitonin
by
itself
seldom
restores
serum
calcium
to
normal,
and
refractoriness
frequently
develops.
However,
its
lack
of
toxicity
permits
frequent
administration
at
high
doses
(200
MRC
units
or
more).
An
effect
on
serum
calcium
is
observed
within
4–6
hours
and
lasts
for
6–10
hours.
The
drug
has
its
greatest
effect
on
spine
and
is
most
effective
in
patients
who
have
high
bone
turnover
rates.
Calcitonin
also
has
a
significant
analgesic
effect
on
acute
pain
from
vertebral
fracture
that
is
independent
of
its
effects
on
bone
metabolism.Given
by
injection
or
intranasal
spray.
Recommended
injectable
dosage
is
100IU
(SQ
or
IM)
and
the
intranasal
dosage
is
200IU
(one
spray)
per
day
in
alternate
nostrils.
Oral
formulation
is
under
investigation.
Side
effects
of
injectable
calcitonin
include
nausea
and
GI
discomfort.
This
may
be

17. minimized
by
bedtime
administration.
Pruritus
at
the
injection
site
is
also
problematic.
To
minimize
these
side
effects,
patients
should
be
instructed
to
administer
calcitonin
SQ
rather
than
IM.
Intranasal
formulation
appears
to
be
better
tolerated;
rhinitis
is
the
most
commonly
reported
side
effect.
Gallium
Nitrate
Gallium
nitrate
is
approved
by
the
FDA
for
the
management
of
hypercalcemia
of
malignancy.
This
drug
acts
by
inhibiting
bone
resorption.
Given
as
continuous
intravenous
infusion
in
5%
dextrose
for
5
days,
gallium
nitrate
proved
superior
to
calcitonin
in
reducing
serum
calcium
in
cancer
patients.
Because
of
potential
nephrotoxicity,
patients
should
be
well
hydrated
and
have
good
renal
output
before
starting
the
infusion.
Plicamycin
(Mithramycin)
Because
of
its
toxicity,
plicamycin
(mithramycin)
is
not
the
drug
of
first
choice
for
the
treatment
of
hypercalcemia.
However,
when
other
forms
of
therapy
fail,
25–50
mcg/kg
given
intravenously
usually
lowers
serum
calcium
substantially
within
24–48
hours.
This
effect
can
last
several
days.
This
dose
can
be
repeated
as
necessary.
The
most
dangerous
toxic
effect
is
sudden
thrombocytopenia
followed
by
hemorrhage.
Hepatic
and
renal
toxicity
can
also
occur.
Hypocalcemia,
nausea,
and
vomiting
may
limit
therapy.
Use
of
this
drug
must
be
accompanied
by
careful
monitoring
of
platelet
counts,
liver
and
kidney
function,
and
serum
calcium
levels.
Phosphate
Giving
intravenous
phosphate
is
probably
the
fastest
and
surest
way
to
reduce
serum
calcium,
but
it
is
a
hazardous
procedure
if
not
done
properly.
Intravenous
phosphate
should
be
used
only
after
other
methods
of
treatment
(bisphosphonates,
calcitonin,
and
saline
diuresis)
have
failed
to
control
symptomatic
hypercalcemia.
The
risks
of
intravenous
phosphate
therapy
include
sudden
hypocalcemia,
ectopic
calcification,
acute
renal
failure,
and
hypotension.
Oral
phosphate
can
also
lead
to
ectopic
calcification
and
renal
failure
if
serum
calcium
and
phosphate
levels
are
not
carefully
monitored,
but
the
risk
is
less
and
the
time
of
onset
much
longer
Biphosphonates
Alendronate
Risedronate
Ibandronate
Zoledronate
Pamidronate
Efficacy
+++
+++
+++
++++
++++
Safety
+++
+++
++
++
+++
Suitability
++++
+++
+++
+++
+++
Cost
+++
P1100
++
P1,800
+
P17,000
+
P24,000
++
P1700
First-­‐generation
bisphosphonates
contain
minimally
modified
side
chains
(R1,
R2)
(medronate,
clodronate,
and
etidronate)
or
contain
a
chlorophenyl
group
(tiludronate).
They
are
the
least
potent
and
in
some
instances
cause
bone
demineralization.
Second-­‐generation
aminobisphosphonates
(e.g.,
alendronate
and
pamidronate)
contain
a
nitrogen
group
in
the
side
chain.
They
are
10
to
100
times
more
potent
than
first-­‐generation
compounds.
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
17

18. Third-­‐generation
bisphosphonates
(e.g.,
risedronate
and
zoledronate)
contain
a
nitrogen
atom
within
a
heterocyclic
ring
and
are
up
to
10,000
times
more
potent
than
first-­‐generation
agents
Alendronate
and
ibandronate
directly
inhibit
multiple
steps
in
the
pathway
from
mevalonate
to
cholesterol
and
isoprenoid
lipids,
such
as
geranylgeranyldiphosphate,
that
are
required
for
the
prenylation
of
proteins
that
are
important
for
osteoclast
function.
The
potency
of
inhibiting
farnesyl
synthase
correlates
directly
with
their
antiresorptive
activity.
They
should
not
be
taken
with
iron
supplements,
vitamins
with
minerals,
or
antacids
containing
calcium,
magnesium,
or
aluminum
because
they
reduce
absorption
of
bisphosphonates.
Pamidronate
is
approved
for
management
of
hypercalcemia
but
also
is
effective
in
other
skeletal
disorders.
Pamidronate
is
available
only
for
parenteral
administration.
For
treatment
of
hypercalcemia,
pamidronate
may
be
given
as
an
intravenous
infusion
of
60
to
90
mg
over
4
to
24
hours.
Electrolyte
imbalances
may
occur
with
pamidronate
use.
Pamidronate
overdose
could
manifest
with
a
low
blood
calcium
level.
Twitching,
anxiety,
muscle
weakness
or
seizures
could
result.Onset:
24-­‐48
hr.
Duration:
Peak
effect:
max
5-­‐7
days.
Absorption:
Poor
absorption.
Excretion:
Elimination
half-­‐life:
21-­‐35
hr.
Excretion:
Biphasic;
urine
(approx
50%
as
unchanged
drug)
within
120
hr.
Zoledronate
has
been
associated
with
renal
toxicity,
deterioration
of
renal
function,
and
potential
renal
failure.
Thus,
the
infusion
should
be
given
over
at
least
15
minutes,
and
the
dose
should
be
4
mg.
Patients
who
receive
zoledronate
should
have
standard
laboratory
and
clinical
parameters
of
renal
function
assessed
prior
to
treatment
and
periodically
after
treatment
to
monitor
for
deterioration
in
renal
function.
It
can
be
administered
at
home
rather
than
in
hospital.
With
monitoring
of
Ca
level,
albumin,
phosphate
level,
K
level,
Mg
level,
Na
level,
hydration
status
(BUN,
SCr,
BP,
HR).
Distribution:
Protein
binding:
Low
(22-­‐56%).
Excretion:
Excreted
unchanged
in
urine
(23-­‐55%),
the
rest
sequestered
to
bone
and
eliminated
very
slowly.The
total
time
between
reconstitution,
dilution,
storage
in
a
refrigerator
at
2-­‐
8°C
and
end
of
administration
must
not
exceed
24
hrs.
First-­‐generation
bisphosphonate
etidronate
was
associated
with
osteomalacia.
Alendronate
and
risedronate
were
well
tolerated
in
clinical
trials,
some
patients
experience
symptoms
of
esophagitis.
If
symptoms
persist
despite
precautions,
use
a
proton
pump
inhibitor
at.
Both
drugs
may
be
better
tolerated
on
a
once-­‐weekly
regimen
with
no
reduction
of
efficacy.
Patients
with
active
upper
gastrointestinal
disease
should
not
be
given
oral
bisphosphonates.
Mild
fever
and
aches
may
attend
the
first
parenteral
infusion
of
pamidronate,
likely
owing
to
cytokine
release.
These
symptoms
are
short-­‐lived
and
generally
do
not
recur
with
subsequent
administration.
All
oral
bisphosphonates
are
very
poorly
absorbed
from
the
intestine
and
have
remarkably
limited
bioavailability
[<1%
(alendronate,
risedronate)
to
6%
(etidronate,
tiludronate)].
Thus
these
drugs
should
be
administered
with
a
full
glass
of
water
following
an
overnight
fast
and
at
least
30
minutes
before
breakfast.
Oral
bisphosphonates
have
not
been
used
widely
in
children
or
adolescents
because
of
uncertainty
of
long-­‐term
effects
of
bisphosphonates
on
the
growing
skeleton.
Bisphosphonates
are
excreted
primarily
by
the
kidneys.
Adjusted
doses
for
patients
with
diminished
renal
function
have
not
been
determined;
bisphosphonates
currently
are
not
recommended
for
patients
with
a
creatinine
clearance
of
less
than
30
ml/min.
Non
pharmacologic
1. Hold
calcium
supplement
Patient
education
1. Confusion,
decreased
appetite,
constipation
are
due
to
high
calcium
level
2. Nausea
and
vomiting
are
side
effects
of
pamidronate
3. Eat
small
frequent
meals
to
help
with
the
nausea
and
vomiting

19.
Edward
Philip
I.
Villanueva
FEU-­‐NRMF
Medical
Center
Regalado
Avenue,
West
Fairview,
Quezon
City
Room
416
MWF
–
10:00am-­‐11:00am
Tel
no:
(02)
632-­‐1234
Patient:
Kay
Floyd
January
30,
2014
62
years
old,
female
Address:
#4
Iris
St.,
West
Fairview,
Quezon
City
Description:
D:FEU-­‐NRMFSY
12-­‐13
2nd
semClinical
Therapeutics
3ACase
4
REPORTRx.jpg
Pamidronate
90
mg
Sig:
initiate
pamidronateintravenouslyover
2
hours
Edward
Philip
I.
Villanueva,MD
Lic.
No.
123456
PTR
No.
78910
PROBLEM
4:
DIABETES
MELLITUS
TYPE
2
Zagada
Basis
for
diagnosis:
• Type
2
diabetes
mellitus
for
7
years
• 20
packs
per
year
tobacco
history
• Overweight
• HbA1c=7
Type
2
diabetes
is
characterized
by
tissue
resistance
to
the
action
of
insulin
combined
with
a
relative
deficiency
in
insulin
secretion
GOALS
OF
THERAPY:
•
•
Continue
control
of
blood
sugar
by
maintaining
normal
or
near-­‐normal
ranges
o Keep
HbA1C
of
<7
Prevent
disease
and
drug
related
complications
The
major
goal
of
pharmacologic
therapy
for
diabetes
is
to
normalize
metabolic
parameters,
such
as
blood
sugar,
in
order
to
reduce
the
risk
of
long-­‐term
complications.
Treatment:
The
treatment
of
Type
II
diabetes
is
multifaceted.
First,
obese
patients
should
endeavor
to
reduce
body
weight
and
increase
exercise
in
order
to
improve
insulin
sensitivity.
Some
Type
II
patients
can
achieve
good
control
of
their
diabetes
by
modifying
their
diet
and
exercise
habits.
Pharmacologically,
treatments
include
orally
available
agents
that
act
to
slow
glucose
absorption
from
the
gut
(a-­‐glucosidase
inhibitors),
to
increase
insulin
secretion
by
ß
cells
(sulfonylureas,
meglitinides,
and
GLP-­‐1
mimetics),
or
to
increase
insulin
sensitivity
at
target
tissues
(thiazolidinediones
and
biguanides).
These
agents
are
generally
ineffective
for
patients
with
Type
I
diabetes.
Patients
with
Type
II
diabetes
are
frequently
treated
with
combinations
of
these
drugs
and
are
therefore
utilizing
multiple
strategies.
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
19

20. Class
of
Drugs
used
for
Diabetes
Drug
Class
Action
SULFONYLUREA
AND
MEGLITINIDES
Insulin
secretagogue
BIGUANIDES
Clinical
Application
Effects
Insulin
Sensitizer
•
•
THIAZOLIDINEDIONES
Insulin
Sensitizer
Competitive
inhibitors
•
ALPHA-­‐GLUCDIDASE
of
the
intestinal
INHIBITOR
α-­‐glucosidases
•
•
Glucagon-­‐like
peptide-­‐
•
GLP-­‐1
AGONISTS
1
(GLP-­‐1)
receptor
•
agonist
reduce
circulating
glucose
increase
glycogen,fat,
and
protein
formation
Decreased
endogenous
glucose
production
Reduces
insulin
resistance
Reduce
conversion
of
starch
and
disaccharides
to
monosaccharides
reduce
postprandial
hyperglycemia
enhances
glucose-­‐dependent
insulin
secretion
inhibits
glucagon
secretion
delays
gastric
emptying,
and
decreases
appetite
DM
type
2
DM
type
2
DM
type
2
DM
type
2
DM
type
2
Class
THIAZOLIDINEDIONES
(TZDs)
BIGUANIDES
GLP-­‐1
AGONISTS
Sulfonylureas
A-­‐glucosidase
inhibitors
+++
Efficacy
+++
Safety
Suitability
++++
++
Cost
++++
++++
+++
+++
++++
+++
+++
+++
++++
++++
+++
+++
++++
++
+++
++
1. SULFONYLUREAS
AND
MEGLITINIDES
-­‐inhibit
the
ß
cell
K+/ATP
channel
at
the
SUR1
subunit,
thereby
stimulating
insulin
release
from
pancreatic
ß
cells
and
increasing
circulating
insulin
to
levels
sufficient
to
overcome
insulin
resistance.
First-­‐generation
sulfonylureas:
Second-­‐generation
sulfonylureas:
Acetohexamide
Glimepiride
Chlorpropamide
Glipizide
Tolazamide
Glibenclamide
(Glyburide)
Tolbutamide
Gliclazide
Gliquidone
Sulfonylureas
are
the
mainstay
of
treatment
for
Type
II
diabetes;
orally
available
and
metabolized
by
the
liver.
The
major
adverse
effect
is
hypoglycemia
resulting
from
oversecretion
of
insulin;
Thus,
these
medications
should
be
used
cautiously
in
patients
who
are
unable
to
recognize
or
respond
appropriately
to
hypoglycemia,
such
as
those
with
impaired
sympathetic
function,
mental
status
changes
(our
patient
has
depression),
or
advanced
age.
However
this
agents
can
cause
weight
gain
secondary
to
increased
insulin
activity
in
adipose
tissue;
therefore,
are
better
suited
for
nonobese
patients
(wherein
our
patient
is
already
overweight).
The
adverese
effect
of
hypoglycemia
and
weight
gain
makes
this
drugs
less
suitable
for
our
patient.
As
with
sulfonylureas,
meglitinides
stimulate
insulin
release
by
binding
to
SUR1
and
inhibiting
the
ß
cell
K+/ATP
channel.
Although
both
sulfonylureas
and
meglitinides
act
on
the
SUR1
subunit,
these
two
classes
of
drugs
bind
to
distinct
regions
of
the
SUR1
molecule.
The
absorption,
metabolism,
and
adverse
effect
profiles
of
meglitinides
are
similar
to
those
of
sulfonylureas.

21. 2. BIGUANIDES
(METFORMIN)
-­‐
activates
AMP-­‐dependent
protein
kinase
(AMPPK)
to
block
breakdown
of
fatty
acids
and
to
inhibit
hepatic
gluconeogenesis
and
glycogenolysis;
increases
insulin
receptor
activity
and
metabolic
responsiveness
in
liver
and
skeletal
muscle.
The
most
common
adverse
effect
is
mild
gastrointestinal
distress,
which
is
usually
transient
and
can
be
minimized
by
slow
titration
of
the
dose.
A
potentially
more
serious
adverse
effect
is
lactic
acidosis.
Because
biguanides
decrease
the
flux
of
metabolic
acids
through
gluconeogenic
pathways,
lactic
acid
can
accumulate
to
dangerous
levels
in
biguanide-­‐treated
patients.
This
drug
is
currently
being
taken
by
the
patient.
3. THIAZOLIDINEDIONES
(TZDS)
-­‐ bind
and
stimulate
the
nuclear
hormone
receptor
peroxisome
proliferator
activated
receptor-­‐γ
(PPARγ),
thereby
increasing
insulin
sensitivity
in
adipose
tissue,
liver,
and
muscle.
The
TZDs
do
not
affect
insulin
secretion,
but
rather
enhance
the
action
of
insulin
at
target
tissues.
Two
thiazolidinediones
are
currently
available:
pioglitazone
and
rosiglitazone.
An
adverse
effect
common
to
both
Tzds
is
fluid
retention,
which
presents
as
a
mild
anemia
and
peripheral
edema,
especially
when
the
drugs
are
used
in
combination
with
insulin
or
insulin
secretagogues.
Both
drugs
increase
the
risk
of
heart
failure.
Many
users
have
a
dose-­‐related
weight
gain
(average
1–3
kg),
which
may
be
fluid
related.
This
is
drug
(Rosiglitazone)
is
currently
being
taken
by
the
patient
but
its
adverse
effect
profile
may
warrant
its
discontinuation.
4. ALPHA-­‐GLUCOSIDASE
INHIBITORS
are
carbohydrate
analogues
that
bind
avidly
to
intestinal
brush
border
a-­‐glucosidase
enzymes,
slowing
breakdown
and
absorption
of
dietary
carbohydrates
such
as
starch,
dextrin,
and
disaccharides.
Flatulence,
bloating,
abdominal
discomfort,
and
diarrhea
are
common
adverse
effects,
all
of
which
result
from
gas
released
by
bacteria
acting
on
undigested
carbohydrates
that
reach
the
large
intestine.
The
patient
is
currently
taking
metformin
which
can
ossibly
cause
GI
distress
and
lactic
acidosis
making
this
drug
less
favorable
addition
to
the
patients
treatment.
Examples
of
this
drugs
are
Acarbose,
Miglitol
and
Voglibose
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
21

22.
5. GLP-­‐1
(GLUCAGON-­‐LIKE
PEPTIDE-­‐1)
MIMETICS
-­‐ are
the
newest
class
of
drugs
developed
for
the
treatment
of
diabetes.
(Ex;
Exanitide
and
Sitagliptin).
Exenatide
is
Glucagon-­‐like
peptide-­‐1
(GLP-­‐1)
receptor
agonist
is
not
orally
available
and
must
be
injected
while
Sitagliptin
(available
orally)
is
a
dipeptidyl
peptidase-­‐IV
(DPP
IV)
inhibitor
that
slows
the
proteolytic
inactivation
of
GLP-­‐1
and
other
incretin
hormones.
This
agents
can
be
used
as
monotherapy
or
in
combination
with
a
TZD
or
metformin.
The
known
physiological
functions
of
GLP-­‐1
include:
• Increases
insulin
secretion
from
the
pancreas
in
a
glucose-­‐dependent
manner.
• Decreases
glucagon
secretion
from
the
pancreas
by
engagement
of
a
specific
G
protein-­‐coupled
receptor.
• increases
insulin-­‐sensitivity
in
both
alpha
cells
and
beta
cells
• Increases
beta
cells
mass
and
insulin
gene
expression,
post-­‐translational
processing
and
incretion.
• Inhibits
acid
secretion
and
gastric
emptying
in
the
stomach.
• Decreases
food
intake
by
increasing
satiety
in
brain
• Promotes
insulin
sensitivity.
Dose
adjustment
is
necessary
in
patients
with
moderate
or
severe
kidney
disease.
This
agents
may
ay
cause
hypoglycemia
in
combination
with
sulfonylureas
and
insulin.
In
this
case,
taking
into
consideration
the
patients
condition,
we
chose
to
give
a
combination
therapy
of
Sitagliptin
and
Metformin.
Drug
of
choice:
Sitagliptin
+
Metformin
(Janumet)
maintenance
50
mg/500
mg
tab
twice
a
day.
Non
pharmacologic
Intervention:
• Counsel
KF
to;
– continue
diabetes
medications
and
self-­‐monitoring.
– Remind
her
of
the
importance
of
diet/exercise
in
the
treatment
of
diabetes.
– Remind
her
to
maintain
all
follow-­‐up
appointments
for
diabetes.
– Report
any
shortness
of
breath
or
swelling
in
the
legs
to
the
physician.

23.
PROBLEM
5:
DEPPRESSION
Basis
for
diagnosis:
• Present
in
patients
medical
history
• Use
of
SSRI-­‐paroxetine
(controlled
under
current
regiment)
• Decreased
appetite
over
the
past
few
weeks
and
increasing
fatigue.
• Slightly
confused
Selectively
inhibit
reuptake
of
serotonin
– increase
synaptic
serotonin
levels
– also
cause
increased
5HT
receptor
activation
and
enhanced
postsynaptic
responses.
At
present,
SSRIs
are
the
most
commonly
prescribed
first-­‐line
agents
in
the
treatment
of
both
MDD
and
anxiety
disorders.
Their
popularity
comes
from
their
ease
of
use,
tolerability,
and
safety
in
overdose.
GOALS
OF
THERAPY:
•
•
Continue
monitoring
for
signs
and
symptoms
of
depression
Continue
therapy
to
avoid
future
episodes
•
Continue
current
regimen
– controlled
with
current
regimen
– Paroxetine,
20
mg
PO
daily
Treatment:
Non-­‐Pharmacologic
Intervention:
• Counsel
KF
to
continue
depression
medication
unless
otherwise
directed
by
her
physician.
•
She
should
seek
a
psychologist
to
discuss
her
new
diagnosis.
She
should
report
any
new/worsened
depression
symptoms
to
her
physician.
SUMMARY:
To
address
the
patients
diabetes,
we
chose
a
combination
therapy
of
Sitagliptin
and
metformin
taking
into
account
the
patients
present
condition.
Sulfonylureas
can
cause
hypoglycemia
and
weight
gain
which
is
not
favorable
since
the
patient
is
already
overweight.
Alpha
glucosidase
inhibitors
causes
abdominal
distention
and
flatulence.
TZD’s
can
cause
fluid
retention
and
edema
and
is
also
known
to
worsen
CVD’s.
Therefore
we
chose
to
retain
Metformin,
a
Biguanide
which
is
currently
used
by
the
patient
and
replace
Rosiglitazone
(TZD’s)
with
GLP-­‐1
mimetics
which
is
a
newer
class
of
drug
with
multiple
effects
mechanism
in
promoting
euglycemia.
There
were
no
changes
in
the
patient’s
medications
for
Depression
because
it
is
currently
controlled
by
the
current
regimen
thus,
paroxetine
was
retained.
SECTION
3E-­‐
CLINICAL
THERAPEUTICS
CASE
12
BREAST
CA
23

24. CLINICAL
THERAPEUTICS
CASE
12
BREAST
CANCER
Proctor:
Dr.
Zenaida
Maglaya
Reporters:
Villanueva,
Edward
Phillip
Yang,
Sheryl
Ray
Zagada,
Timothy
Zepeda,
Monina
Mae
3E