chemotherapy 3 antifungal agents
TRANSCRIPT
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CHEMOTHERAPYHIGHLIGHTS
MOHAMED BAHR; MD, PHD
Antifungal Drugs
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Mohamed Bahr; MD, PhD
ANTIFUNGAL DRUGS
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Mohamed Bahr; MD, PhD
MECHANISMS
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Mohamed Bahr; MD, PhD
CLASSIFICATIONFungal infections could be classified into:
Superficial fungal infections:
Dermatophytes: Tinea capitis (scalp), corporis (body), unguium (nails;
onychomycosis), cruris (crotch), and pedis (foot)
Candida:
• Cutaneous, vaginal, oropharyngeal and gastrointestinal candidiasis.
• Mucocutaneous candidiasis in severely immunodeficient patients and can
spread to deep tissues (disseminated).
Deep fungal infections:
Fungal pneumonia, gastroenteritis, endocarditis or meningitis.
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Mohamed Bahr; MD, PhD
Systemic Drugs for SystemicInfections
Amphotercin-B
Flucytosine
Azoles: ketoconazole - itraconazole - fluconazole - voriconazole
Echinocandins: caspofungin
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Mohamed Bahr; MD, PhD
Drugs for Mucocutaneous Infections Systemic
Drugs
Azoles (candida - dermatophytes)
Griseofulvin (dermatophytes)
Terbinafine (dermatophytes)
Topical Drugs
Azoles (candida - dermatophytes)
Nystatin (candida)
Terbinafine – naftifine (dermatophytes)
Gentian violet (candida) - whitefield ointment (dermatophytes)
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Mohamed Bahr; MD, PhD
Superficial fungal infections are treated first with topical
agents.
Systemic therapy is used in:
• Resistance to topical therapy.
• Wide or inaccessible area.
• Severe infections of hair, skin, and nails.
• Decreased immunity of the patient.
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Mohamed Bahr; MD, PhD
AMPHOTERICIN B
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Mohamed Bahr; MD, PhD
INDICATIONS: MOST IMPORTANT ANTIFUNGAL IN DEEP INFECTIONSSevere life-threatening (IV, not absorbed PO).
Meningitis (intrathecal- does not reach CSF after IVI).
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Mohamed Bahr; MD, PhD
SIDE EFFECTS AND TOXICITY
IVI →
Kidney and Anemia
Heart
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Mohamed Bahr; MD, PhD
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Mohamed Bahr; MD, PhD Illustration ONLY
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Mohamed Bahr; MD, PhD
FLUCYTOSINE (5-FU)Cytotoxic. It is transformed to
fluorouracil (FU)→ inhibits
nucleic acid synthesis.
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Mohamed Bahr; MD, PhD
INDICATIONS: GIVEN PO WITH AMPHOTERICIN
Cryptococcal meningitis.
Disseminated candidiasis.
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Mohamed Bahr; MD, PhD
ADVERSE EFFECTS (CYTOTOXIC DRUG)
1. Bone marrow depression.
2. Hair loss.
3. Hepatotoxic.
4. Enterocolitis.
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Mohamed Bahr; MD, PhD
ADVANTAGES OF COMBINATION OF FLUCYTOSINE WITH AMPHOTERICIN B
↓ Resistance to
flucytosine.
↓ Amphotericin
nephrotoxicity (lower
doses of amphotericin
are used).
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Mohamed Bahr; MD, PhD
AZOLES
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Mohamed Bahr; MD, PhD
Fungistatic. Inhibition of ergosterol
synthesis of cell membrane by inhibiting
cytochrome P450-dependent 14-α-
demethylase responsible for conversion of
lanosterol to ergosterol.
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Mohamed Bahr; MD, PhD
1. KETOCONAZOLE1st oral broad spectrum antifungal for:
1. Deep fungal infections (mild - nonmeningeal): 2nd line to
amphotericin B.
2. Candidal infection.
3. Dermatophytes resistant to griseofulvin and terbinafine
(oral and topical).
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Mohamed Bahr; MD, PhD
INTERACTIONS WITH COMBINATIONS
PK: Avoid Combination with:
Antacids or H2 blockers → ↓ gastric acidity → ↓
ketoconazole absorption.
PD: Amphotericin B: ketoconazole → ↓ amphotericin
effect by ↓ ergosterol.
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Mohamed Bahr; MD, PhD
ADVERSE EFFECTS
1. GIT: nausea - vomiting
2. Hypersensitivity: rash
3. Hepatotoxic (serious)
4. Teratogenic
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Mohamed Bahr; MD, PhD Illustration ONLY
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Mohamed Bahr; MD, PhD
Enzyme inhibitor: human cytochrome P450 (serious)
• ↓ Steroid synthesis which depends on cytochrome P450:
• ↓ Corticosteroids → adrenal suppression (used in Cushing's
disease).
• ↓ Testosterone → gynecomastia, impotence (used in cancer
prostate).
• ↓ Female sex hormones → menstrual irregularities, infertility.
• ↓ Metabolism of drugs → drug interactions:
• ↑ Level of astemizole and terfenadine → arrhythmias.
• ↑ Level of oral anticoagulants, antiepileptics …
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Mohamed Bahr; MD, PhD
2. ITRACONAZOLE AND FLUCONAZOLE (PO - IV)
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Mohamed Bahr; MD, PhD
Ketoconazole Itraconazole Fluconazole
Efficacy Less More More
HepatotoxicityAdrenal SuppressionDrug Interactions
More Less Less
Dosing Single
Plasma protein binding
Extensive Extensive Minimal
CSF distribution Excellent (fungal meningitis)
Renal Excretion Yes
Antacids Stable
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Mohamed Bahr; MD, PhD
CASPOFUNGINBeta Glucan Synthase Inhibitor
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Mohamed Bahr; MD, PhD
USES (IV)
Candidiasis and invasive aspergillosis
refractory to amphotericin B.
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Mohamed Bahr; MD, PhD
GRISEOFULVIN
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Mohamed Bahr; MD, PhD
• Concentrated in newly formed keratin preventing its
infection by:
• Interfering with microtubular function→ interfere
with mitosis.
• Inhibiting nucleic acid synthesis.
• When infected keratin is shed it is replaced by
uninfected one.
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Mohamed Bahr; MD, PhD
INDICATIONS
Dermatophyte infections (PO, ↑ absorption by
high-fat diet).
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Mohamed Bahr; MD, PhD
ADVERSE EFFECTS (LARGELY REPLACED BY ITRACONAZOLE AND TERBINAFINE)
GIT: nausea - vomiting.
Neurotoxicity: headache - mental confusion.
Hepatotoxic.
Enzyme inducer → ↓ warfarin level.
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Mohamed Bahr; MD, PhD
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Mohamed Bahr; MD, PhD
TERBINAFINEInhibition of squalene epoxidase enzyme which is
essential for ergosterol synthesis of cell
membrane → accumulation of toxic squalene.
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Mohamed Bahr; MD, PhD
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Mohamed Bahr; MD, PhD
ADVANTAGES OVER AZOLESSqualene epoxidase enzyme is not present in
human.
No inhibition of cytochrome P450 (no serious
adverse effect of azoles).
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Mohamed Bahr; MD, PhD
INDICATIONSSystemic (oral) and topical for dermatophytes.
More effective than griseofulvin.
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Mohamed Bahr; MD, PhD
SIDE EFFECTS (SAFE): GIT AND TASTE DISTURBANCES.
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Mohamed Bahr; MD, PhD
NYSTATINBinds to ergosterol of fungal cell membrane → formation of
artificial pores → damage of membrane → leakage of
important cell constituents → cell death.
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Mohamed Bahr; MD, PhD
INDICATIONS (TOO TOXIC FOR SYSTEMIC USE)
Used locally in:
Oropharyngeal and GI candida: PO (not absorbed).
Cutaneous candida: topical (nonirritant - rarely causes allergy).
Vaginal candida: given both topically and orally because quite
often vaginal candida is associated with gastrointestinal candida
which acts as a source of reinfection of vagina.
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Mohamed Bahr; MD, PhD
REFERENCESLippincott’s Illustrated Reviews, 5th ed.
Color Atlas of Pharmacology, 2nd ed.
Goodman and Gilman's The Pharmacological Basis of
Therapeutics, 12th ed.