Department of Pharmacology

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Department of Pharmacology College of Medicine
Our Lady of Fatima University CASE NO. 24
By Ramos Jr., Nicandro and Joseph Yang
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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.
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INTRODUCTION
DIAGNOSIS - Chronic Lymphocytic Leukemia
(CLL) PATIENT SYMPTOMS - headache - visual
disturbances - stiff neck
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INTRODUCTION
LABORATORY TEST
SPINAL TAP
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() Cryptococcus neoformans
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INTRODUCTION

• Prior medication
• Amphotericin- B
• Current medication
• 5- Fluorocytosine

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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?

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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

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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

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Nickys CLINICAL IMPRESSION

• Cryptococcal Meningitis
• specific
• Cryptococcus neoformans
• Related to
• - CLL
• - patient is immunocompromised

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Nickys CLINICAL IMPRESSION

• Cryptococcal Meningitis
• Moderate-to-Severe
• -CSF sample ()Cryptococcus neoformans.
  - Brain-related symptoms of disease
  (e.g. severe headaches, vision disturbance)
•    

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Anti- Fungal Drugs
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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.

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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

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AMPHOTERICIN-B

• PHARMACOKINETICS
• GIT poor absorption
• Oral form-not used for systemic infections
• Serum T1/2 15 days
• Intrathecal therapy Fungal meningitis

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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

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AMPHOTERICIN-B

• MECHANISM OF ACTION

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AMPHOTERICIN-B

• ANTIFUNGAL ACTIVITY
• Broad spectrum
• Candida albicans
• C. neoformans
• H. capsulatum
• B. dermatitis
• C. immitis
• P. boydii
• Aspergilus fumigatus and mucor

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AMPHOTERICIN-B

• ADVERSE EFFECTS
• Fever, chills, muscle spasm
• Vomiting, headache
• Hypotension
• abnormal liver function
• Seizures
• Chemical arachnoiditis
• NEPHROTOXICITY did happen to our patient

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AMPHOTERICIN-B

• ADVERSE EFFECTS
• Nephrotoxicity
• generally reversible, up to 10
• Irreversible gt 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.

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AMPHOTERICIN-B

• ADVERSE EFFECTS
• Nephrotoxicity

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5 - Fluorocytosine 5-FC 5-Flucytosine
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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

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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

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5 - FLUOROCYTOSINE

• MECHANISM OF ACTION
• inhibits protein synthesis by replacing uracil
  with 5-flurouracil in RNA.
• inhibits thymidylate synthetase via
  5-fluorodeoxy-uridine monophosphate and thus
  interferes with fungal DNA synthesis

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5 - FLUOROCYTOSINE

• MECHANISM OF ACTION

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5 - FLUOROCYTOSINE

• ANTI FUNGAL ACTIVITY
• Candida spp.
• Cryptococcus neformans
• Aspergillus spp.
• dematiaceous fungi
• Phialophora spp.
• Cladosporium spp. causing chromoblastomycosis

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5 - FLUOROCYTOSINE

• ADVERSE EFFECTS
• Gastrointestinal intolerance
• bone marrow depression (anemia, leukopenia,
  thrombocytopenia)
• Rash
• hepatotoxicity
• Headache
• Confusion, hallucinations, sedation, euphoria

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CASE GUIDE QUESTIONS

• Potential toxicities related to Amphotericin-B
  theraphy.

• NEPHROTOXICITY (primary)
• Fever, chills, muscle spasm
• Vomiting, headache
• Hypotension
• abnormal liver function

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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).

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CASE GUIDE QUESTIONS

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• Next reporter

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3. If the patient were anephric, which antifungal
agent might one choose?
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• 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 (5FC) nephrotoxicity is more
  likely to occur in the presence of renal
  insufficiency and in AIDS patients.

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• 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.

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• FLUCONAZOLE
• Excelent CSF penetration
• DOC C. neoformans

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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.

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FLUCONAZOLE Mechanism of Action
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• 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.

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• 4. If this patient had AIDS with cryptococcal
  meningitis, what would constitute the usual
  induction therapy and maintenance therapy?

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• 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

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• 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.

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• Thank You!!

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Any questions?
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CASE GUIDE QUESTIONS

• 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.

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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

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DRUGS USED FOR CLL
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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
  5-fluorouracil - produced from flucytosine by
  intestinal bacteria