Department of Pharmacology

College of Medicine

Our Lady of Fatima University

CASE NO. 24

By:

Ramos Jr., Nicandro and Joseph Yang

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

INTRODUCTION

(+) Cryptococcus neoformans

INTRODUCTION

Prior medication

• Amphotericin- B

Current medication

• 5- Fluorocytosine

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?

CASE: GUIDE QUESTIONS

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 IMPRESSIONCryptococcal 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

CHEMICAL STRUCTURE

PREPARATIONS Amphotericin B Colloidal Dispersion

(ABCD; Amphocil™ or Amphotec™) Amphotericin B Lipid Complex

(ABLC; Abelcet™)Liposomal Amphotericin B (L-AMB; Ambisome™)

AMPHOTERICIN-BPHARMACOKINETICS

• GIT – poor absorption

• Oral form-not used for systemic infections

• Serum T1/2 – 15 days

• Intrathecal therapy – Fungal meningitis

AMPHOTERICIN-BMECHANISM 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-BMECHANISM OF ACTION

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

AMPHOTERICIN-BADVERSE EFFECTS• Fever, chills, muscle spasm• Vomiting, headache• Hypotension• abnormal liver function• Seizures • Chemical arachnoiditis• NEPHROTOXICITY “did happen to our patient”

AMPHOTERICIN-BADVERSE 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-BADVERSE 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 5-fluorodeoxy-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 QUESTIONSIDEAL THERAPY

1-2 weeks 5-FC amphotericin-B

Lab Test CSF or Blood (+) C.neo

Continue 5-FC amphotericin-B

Lab Test CSF or Blood (-) 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-azole

Itracon-azole

Flucon-azole

Voricon-azole

Water solubility

low low high high

Absorp-tion

variable variable high high

Half life 7-10 24-42 23-31 6

CSF:Se-rum ratio

<0.1 <0.01 >0.7 ….

ketokonazole

Itraconazole

Fluconazole

Voriconazle

Elimina-tion

hepatic hepatic renal hepatic

Formula-tions

oral Oral,IV Oral,IV Oral,IV

Azol of Choice

No more systemic use in USA due to high inhibition of P450

Indermatophytoses, onychomycosis and Aspergil-lus sp.

Cryptococcal meningi-tis

Good against Candida species, including C. Krusei and aspergil-lus

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 5-

fluorouracil - produced from flucytosine by intestinal bacteria