CHEMOTHERAPYHIGHLIGHTS

MOHAMED BAHR; MD, PHD

Antifungal Drugs

Mohamed Bahr; MD, PhD

ANTIFUNGAL DRUGS

Mohamed Bahr; MD, PhD

MECHANISMS

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.

Mohamed Bahr; MD, PhD

Systemic Drugs for SystemicInfections

Amphotercin-B

Flucytosine

Azoles: ketoconazole - itraconazole - fluconazole - voriconazole

Echinocandins: caspofungin

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)

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.

Mohamed Bahr; MD, PhD

AMPHOTERICIN B

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).

Mohamed Bahr; MD, PhD

SIDE EFFECTS AND TOXICITY

IVI →

Kidney and Anemia

Heart

Mohamed Bahr; MD, PhD

Mohamed Bahr; MD, PhD Illustration ONLY

Mohamed Bahr; MD, PhD

FLUCYTOSINE (5-FU)Cytotoxic. It is transformed to

fluorouracil (FU)→ inhibits

nucleic acid synthesis.

Mohamed Bahr; MD, PhD

INDICATIONS: GIVEN PO WITH AMPHOTERICIN

Cryptococcal meningitis.

Disseminated candidiasis.

Mohamed Bahr; MD, PhD

ADVERSE EFFECTS (CYTOTOXIC DRUG)

1. Bone marrow depression.

2. Hair loss.

3. Hepatotoxic.

4. Enterocolitis.

Mohamed Bahr; MD, PhD

ADVANTAGES OF COMBINATION OF FLUCYTOSINE WITH AMPHOTERICIN B

↓ Resistance to

flucytosine.

↓ Amphotericin

nephrotoxicity (lower

doses of amphotericin

are used).

Mohamed Bahr; MD, PhD

AZOLES

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.

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).

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.

Mohamed Bahr; MD, PhD

ADVERSE EFFECTS

1. GIT: nausea - vomiting

2. Hypersensitivity: rash

3. Hepatotoxic (serious)

4. Teratogenic

Mohamed Bahr; MD, PhD Illustration ONLY

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 …

Mohamed Bahr; MD, PhD

2. ITRACONAZOLE AND FLUCONAZOLE (PO - IV)

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

Mohamed Bahr; MD, PhD

CASPOFUNGINBeta Glucan Synthase Inhibitor

Mohamed Bahr; MD, PhD

USES (IV)

Candidiasis and invasive aspergillosis

refractory to amphotericin B.

Mohamed Bahr; MD, PhD

GRISEOFULVIN

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.

Mohamed Bahr; MD, PhD

INDICATIONS

Dermatophyte infections (PO, ↑ absorption by

high-fat diet).

Mohamed Bahr; MD, PhD

ADVERSE EFFECTS (LARGELY REPLACED BY ITRACONAZOLE AND TERBINAFINE)

GIT: nausea - vomiting.

Neurotoxicity: headache - mental confusion.

Hepatotoxic.

Enzyme inducer → ↓ warfarin level.

Mohamed Bahr; MD, PhD

Mohamed Bahr; MD, PhD

TERBINAFINEInhibition of squalene epoxidase enzyme which is

essential for ergosterol synthesis of cell

membrane → accumulation of toxic squalene.

Mohamed Bahr; MD, PhD

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).

Mohamed Bahr; MD, PhD

INDICATIONSSystemic (oral) and topical for dermatophytes.

More effective than griseofulvin.

Mohamed Bahr; MD, PhD

SIDE EFFECTS (SAFE): GIT AND TASTE DISTURBANCES.

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.

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.

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.