Department of Pharmacology
College of Medicine
Our Lady of Fatima University
CASE NO. 24
By:
Ramos Jr., Nicandro and Joseph Yang
INTRODUCTION
A patient with CLL presented with
headache, visual disturbances and stiff
neck. He was admitted to a hospital and
spinal tap was performed. Cryptococcus
neoformans was isolated from the spinal
fluid and the patient was begun on
amphotericin-B. The expected toxicity of
this drug occurred, and in fact, he was
switched to 5-fluorocytosine.
INTRODUCTION
DIAGNOSIS
- Chronic Lymphocytic Leukemia (CLL)
PATIENT SYMPTOMS
- headache
- visual disturbances
- stiff neck
INTRODUCTION
LABORATORY TEST
SPINAL TAP
(+) Cryptococcus neoformans
INTRODUCTION
Prior medication
• Amphotericin- B
Current medication
• 5- Fluorocytosine
CASE: GUIDE QUESTIONS
1. Potential toxicities related to Amphotericin-B
theraphy.
2. Is the therapy describe optimal?
3. Anephric patient – which AF drug might be
choose?
4. If this patient had AIDS with Cryptococcal
meningitis, what would constitute the usual
induction & maintenance therapy?
DEFINITIONS
• CLL - acquired injury to the DNA of
a single cell, a lymphocyte in the bone
marrow that results in “uncontrolled
growth” of CLL cells – Increase Blood
level of Lymphocytes
DEFINITIONS
• Cryptococcus neoformans
-a fungus
-very common in the soil
-can get into your body when you “breathe in”
dust or dried bird droppings
-can travel through the blood to the spinal column
and brain
Nicky’s CLINICAL IMPRESSION
Cryptococcal Meningitis
specific:
Cryptococcus neoformans
Related to:
- CLL
- patient is immunocompromised
Nicky’s CLINICAL IMPRESSION
Cryptococcal Meningitis
•
Moderate-to-Severe
-CSF sample (+)Cryptococcus neoformans.
- Brain-related symptoms of disease
(e.g. severe headaches, vision disturbance)
AMPHOTERICIN-B
•
•
•
•
•
Systemic AF
Produced- Streptomyces nodolus
Amphoteric polyene macrolide
Nearly insoluble in H2O
deoxycholate (Fungizone™) -colloidal
suspension of amphotericin B
• bile salt, deoxycholate -used as the
solubilizing agent.
AMPHOTERICIN-B
PREPARATIONS
Amphotericin B Colloidal Dispersion
(ABCD; Amphocil™ or Amphotec™)
Amphotericin B Lipid Complex
(ABLC; Abelcet™)
Liposomal Amphotericin B
(L-AMB; Ambisome™)
CHEMICAL STRUCTURE
AMPHOTERICIN-B
PHARMACOKINETICS
• GIT – poor absorption
• Oral form-not used for systemic infections
• Serum T1/2 – 15 days
• Intrathecal therapy – Fungal
meningitis
AMPHOTERICIN-B
MECHANISM OF ACTION
• binds to cell membrane sterol,
ergosterol
• binding disrupts osmotic integrity
• result in leakage of intracellular
potassium, magnesium, sugars, and
metabolites
• cellular death
AMPHOTERICIN-B
MECHANISM OF ACTION
AMPHOTERICIN-B
ANTIFUNGAL ACTIVITY
• Broad spectrum
• Candida albicans
• C. neoformans
• H. capsulatum
• B. dermatitis
• C. immitis
• P. boydii
• Aspergilus fumigatus and mucor
AMPHOTERICIN-B
ADVERSE EFFECTS
• Fever, chills, muscle spasm
• Vomiting, headache
• Hypotension
• abnormal liver function
• Seizures
• Chemical arachnoiditis
• NEPHROTOXICITY “did happen to our patient”
AMPHOTERICIN-B
ADVERSE EFFECTS
•
•
•
•
Nephrotoxicity
generally reversible, up to 10%
Irreversible > 4g cumulative dosing
”possible dose for our patient”
dose and duration dependent
two mechanisms:
– 1) the effects on renal blood flow and glomerular
filtration
– 2) the direct toxic effects on (primarily) the distal
tubules.
AMPHOTERICIN-B
ADVERSE EFFECTS
Nephrotoxicity
5 - FLUOROCYTOSINE
•
•
•
•
•
•
•
•
Antimetabolites (only) - AF
1950's -potential antineoplastic agent
A.k.a. -flucytosine (5-FC)
4-amino-5-fluoro-2-pyrimidone
Water soluble
Pyrimidine analog
activated by deamination
marketed - AncobonTM
5 - FLUOROCYTOSINE
PHARMACOKINETICS
•
•
•
•
Oral formulation only
37.5 mg/kg/day 4X/day
Poorly protein bound
Well penetration in all BF
compartments (CSF)
• Renal toxicity
5 - FLUOROCYTOSINE
MECHANISM OF ACTION
• inhibits protein synthesis by replacing uracil
with 5-flurouracil in RNA.
• inhibits thymidylate synthetase via 5fluorodeoxy-uridine monophosphate and
thus interferes with fungal DNA synthesis
5
FLUOROCYTOSINE
MECHANISM OF ACTION
5 - FLUOROCYTOSINE
ANTI FUNGAL ACTIVITY
• Candida spp.
• Cryptococcus neformans
• Aspergillus spp.
• dematiaceous fungi
• Phialophora spp.
• Cladosporium spp. – causing
chromoblastomycosis
5 - FLUOROCYTOSINE
ADVERSE EFFECTS
• Gastrointestinal intolerance
• bone marrow depression (anemia,
leukopenia, thrombocytopenia)
• Rash
• hepatotoxicity
• Headache
• Confusion, hallucinations, sedation, euphoria
CASE: GUIDE QUESTIONS
1. Potential toxicities related to
Amphotericin-B theraphy.
“NEPHROTOXICITY” (primary)
• Fever, chills, muscle spasm
• Vomiting, headache
• Hypotension
• abnormal liver function
CASE: GUIDE QUESTIONS
2. Is the therapy describe optimal?
Ideally :
•First two weeks of treatment, the drug
amphotericin B (Fungizone®) is given
every day through an IV line
• Along with a second drug taken:
•orally flucytosine (Ancobon®).
CASE: GUIDE QUESTIONS
IDEAL THERAPY
1-2 weeks
5-FC amphotericin-B
Lab Test
CSF or Blood
Continue
5-FC amphotericin-B
Lab Test
CSF or Blood
(+) C.neo
(-) C.neo
Discontinue fluconazole (Diflucan®) oral
200mg to prevent recurrence
STOP (6mo)
Good Immune system
(-) C. neo
Next reporter
3. If the patient were anephric,
which antifungal agent might
one choose?
• The choice of antifungal agents could be a
combination of Amphotericin B and
Flucytosine(5-FC) for systemic fungal infection,
such as cryptococcal meningitis. But this
therapy is useful only when the patient had a
normal renal function with hemodialysis, since
both drugs have very strong nephrotoxicity.
• The irreversible form of amphotericin
nephrotoxicity usually occurs in the setting of
prolonged administration.
• The Flucytosine (5–FC) nephrotoxicity is more likely
to occur in the presence of renal insufficiency and in
AIDS patients.
• So, in renal insufficient patients, the
systemic anti-fungal agent of choice is
Azoles, which are relatively nontoxic
and have mostly hepatic elimination
route. The most common adverse
reaction is relatively minor
gastrointestinal upset and abnormalities
in liver enzymes.
Ketocon- Itraconazole
azole
Fluconazole
Voriconazole
Water
low
solubility
low
high
high
Absorption
variable
variable
high
high
Half life
7-10
24-42
23-31
6
CSF:Se- <0.1
rum ratio
<0.01
>0.7
….
ketokona
zole
Itraconazo Fluconaz Voriconaz
le
ole
le
Elimination
hepatic
hepatic
renal
hepatic
Formulations
oral
Oral,IV
Oral,IV
Oral,IV
Azol of
Choice
No more
systemic
use in
USA due
to high
inhibition
of P450
Indermato
phytoses,
onychomy
cosis and
Aspergillus sp.
Cryptoco
ccal
meningitis
Good
against
Candida
species,
including
C. Krusei
and
FLUCONAZOLE
• Excelent CSF penetration
• DOC – C. neoformans
FLUCONAZOLE
Mechanism of Action
• inhibit cytochrome P-450 3-A dependent
enzyme 14-alpha demethylase
• interrupting the synthesis of ergosterol.
• depletion of ergosterol in the cell membrane
and accumulation of toxic intermediate sterols,
• causing increased membrane permeability
and inhibition of fungal growth.
FLUCONAZOLE
Mechanism of Action
• Besides Azoles, Liposomal Amphtericin B
has been developed for less nephrotoxicity,
• It is specially formulated as lipid- vehicled drug
is less likely to bind to the human cholesterol
and more likely to bind into fungal ergosterol in
fungal cell membrane.
4. If this patient had AIDS
with cryptococcal
meningitis, what would
constitute the usual
induction therapy and
maintenance therapy?
• The answer is Fluconazole. The drug of
choice is following reasons.
I. Prophylactic use of Fluconazole has been
demonstrated to reduce fungal diseases in
bone marrow transplant recipients and
AIDS patients.
II. Fluconazole is the azole of choice in the
treatment and secondary prophylaxis of
cryptococcal meningitis because
1. It displays a good cerebrospinal fluid
penetration.
2. Unlike other Azoles (ketoconazole and
itraconazole), its oral bioavailavility is
high.
3. Drug interactions are also less common
because Fluconazole has the least effect
of all the azoles on hepatic microsomal
enzymes.
Thank You!!
Any questions?
CASE: GUIDE QUESTIONS
4. If this patient had AIDS with Cryptococcal
meningitis, what would constitute the usual
induction & maintenance therapy?
Diagnosed early:
• two weeks of amphotericin B followed by oral
fluconazole.
•
fluconazole is continued for life. Without it, the
meningitis is likely to come back.
CASE: GUIDE QUESTIONS
Compromised immune systems (less than 50
T-cells),
•
fluconazole (Diflucan®), an oral pill
(200 mg) taken once a day, to help
prevent cryptococcal meningitis
DRUGS USED FOR CLL
alemtuzumab (Campath®)
chlorambucil (Leukeran®)
cladribine (Leustatin®)
cyclophosphamide (CYTOXAN®)
doxorubicin (Adriamycin®)
fludarabine (Fludara®)
prednisone (Deltasone®)
vincristine (Oncovin®)
5 - FLUOROCYTOSINE
DRUG INTERACTIONS
• flucytosine + amphotericin B
• renal impairment caused by amphotericin B
may increase the flucytosine levels
• thus potentiate its toxicity
• toxicity of flucytosine is presumably due to 5fluorouracil - produced from flucytosine by
intestinal bacteria