RVS Chaitanya koppala

ANTIFUNGAL AGENTS

ANTIFUNGAL AGENTS

• common in Diabetes Mellitus, Cancer, AIDS, Pregnancy and in patients on immunosuppressive therapy such as prolonged course of corticosteriods, broad spectrum antibiotics, anticancer drugs, etc.

• Treatment of fungal infections is somewhat difficult than bacterial infection because of various factors.

Antifungal Drugs

• Fungal infectious occur due to :• 1- Abuse of broad spectrum antibiotics• 2- Decrease in the patient immunity

FUNGAL INFECTIONS/CAUSATIVE ORGANISMS

SUPERFICIAL MYCOSIS• Dermatophytes• Epidermophyton • Trichophyton• Microsporum• Candida• Malassezia Furfur

DEEP MYCOSIS

• Asperigillus• Blastomyces• Cryptococcus• Coccidioides• Candida• Histoplasma• Mucormycosis• Sporotrichosis

Types of fungal infections• 1. Superficial : Affect skin – mucous membrane.e.g.• Dermatophytes : Fungi that affect keratin layer of skin,

hair, nail.e.g.tinea pedis ,ring worm infection• Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail

infections.

2- Deep infections• Affect internal organs as : – Lung – Heart – Brain – Endocarditis– Meningitis.

1. ANTIBIOTICSA)Polyenes: amphotericin B, Nystatin, Hamycin, NatamycinB)Heterocyclic Benzofuran: Griseofulvin2. Antimetabolite: Flucytosine (5-FC)3. Azoles: A)Imidazoles (topical): Clotrimazole, Econazole, Miconazole, Oxiconazole. Systemic: ketoconazole.B)Trizoles (systemic): Fluconazole, Itraconazole, Voriconazole.

Classification of Antifungal Drugs

4. Allylamine: Terbinafine

5. Other topical agents: TolnaftateUndecylenic acidBenzoic acidQuiniodochlorCiclopirox olamineButenafineSodium thiosulfate.

Classification According to Route of Administration

• Systemic :• Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine.• Topical• In candidiasis :• Imidazoles : Ketoconazole , Miconazole.• Triazoles : Terconazole.• Polyene macrolides : Nystatin , Amphotericin-B• Gentian violet : Has antifungal & antibacterial.

Amphotericin B• Amphotericin A & B are antifungal antibiotics.• Amphotericin A is not used clinically.• It is a natural polyene macrolide• (polyene = many double bonds )• (macrolide = containing a large lactone ring )

Pharmacokinetics• Poorly absorbed orally, is effective for fungal infection of

gastrointestinal tract.• For systemic infections given as slow I.V.I.• Highly bound to plasma protein .• Poorly crossing BBB.• Metabolized in liver • Excreted slowly in urine over a period of several days.• Half-life 15 days.

Mechanism of action• It is a selective fungicidal drug.• Disrupt fungal cell membrane by binding to ergosterol , so alters the

permeability of the cell membrane leading to leakage of intracellular ions & macromolecules ( cell death ).

Resistance to Amphotericin B

• If ergosterol binding is impaired either by :• Decreasing the membrane concentration of ergosterol.• Or by modyfing the sterol target molecule.

Adverse Effects

1- Immediate reactions ( Infusion –related toxicity ).Fever, muscle spasm, vomiting ,headache, hypotension.

Can be avoided by :A. Slowing the infusionB. Decreasing the daily dose C. Premedication with antipyretics, antihistamincs or corticosteroids.

Slower toxicity• Most serious is renal toxicity (nearly in all patients ).• Hypokalemia• Hypomagnesaemia• Impaired liver functions• Thrombocytopenia• Anemia

Clinical uses

• Has a broad spectrum of activity

• Fungicidal action.

• The drug of choice for life-threatening mycotic infections.

• Also, for chronic therapy & preventive therapy of relapse.

• In cancer patients with neutropenia who remain febrile on broad –spectrum

antibiotics.

Routes of Administration

• 1- Slow I.V.I. For systemic fungal disease.• 2- Intrathecal for fungal C.N.S. infections.• Topical drops & direct subconjunctival injection for Mycotic

corneal ulcers.• 3- Local injection into the joint in fungal arthritis.• 4- Bladder irrigation in Candiduria.

Liposomal preparations of amphotericin B

• Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing :A. NephrotoxicityB. Infusion toxicity

• Also, more effective• More expensive

Azoles• A group of synthetic fungistatic agents with a broad spectrum of

activity .• They have

antibacterial antiprotozoal anthelminthicantifungal activity .

Mechanism of Action

1-Inhibit the fungal cytochrome P450 enzyme, (α-demethylase) which

is responsible for converting lanosterol to ergosterol ( the main sterol

in fungal cell membrane ).

2- Inhibition of mitochondrial cytochrome oxidase leading to

accumulation of peroxides that cause autodigestion of the fungus.

3- Imidazoles may alter RNA& DNA metabolism.

Imidazoles

• Ketoconazole• Miconazole• Clotrimazole• They lack selectivity ,they inhibit human gonadal and steroid

synthesis leading to decrease testosterone & cortisol production.• Also, inhibit human P-450 hepatic enzyme.

Ketoconazole• Well absorbed orally .• Bioavailability is decreased with antacids, H2 blockers , proton pump

inhibitors & food .• Cola drinks improve absorption in patients with achlorhydria.• Half-life increases with the dose , it is (7-8 hrs).• Inactivated in liver & excreted in bile (feces ) & urine.• Does not cross BBB.

Clinical uses Adverse effects

• Used topically or systematic (oral route only ) to treat :

• 1- Oral & vaginal candidiasis.• 2- Dermatophytosis.• 3- Systemic mycoses &

mucocutaneous candidiasis.

• Nausea, vomiting ,anorexia• Hepatotoxic• Inhibits human P 450 enzymes• Inhibits adrenal & gonadal

steroids leading to :• Menstrual irregularities• Loss of libido• Impotence• Gynaecomastia in males

Triazoles

• Fluconazole• Itraconazole• Voriconazole• They are :• Selective• Resistant to degradation• Causing less endocrine disturbance

Fluconazole• Water soluble, Completely absorbed from GIT• Excellent bioavailability after oral administration• Bioavailability is not affected by food or gastric PH• Conc. in plasma is same by oral or IV route• Penetrates well BBB so, it is the drug of choice of cryptococcal

meningitis • Safely given in patients receiving bone marrow transplants (reducing

fungal infections)• Excreted mainly through kidney• Half-life 25-30 hours • Resistance is not a problem

Clinical uses• Candidiasis( is effective in all

forms of mucocutaneous candidiasis)

• Cryptococcus meningitis• Histoplasmosis, blastomycosis,

, ring worm.• Not effective in aspergillosis

Side effects• Nausea, vomiting, headache, skin

rash , diarrhea, abdominal pain , reversible alopecia.

• Hepatic failure may lead to death• Highly teratogenic ( as other

azoles)• Inhibit P450 cytochrome• No endocrine side effects

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