Introduction to Antifungal Drugs
Antifungal Drugs- Polyene antibiotics
- Polyene is derived from their highly double-bonded structure.
- Prototype: Amphotericin 8B (AMB)
- Source: Streptomyces nodosus
- The polyenes have high affinity for ergosterol present in fungal cell membrane.
- This Polyenes are combine with membrane protein and form a ‘micrgpore‘ and increase the cell permeability (ions, amino acids and other water soluble substances move out through hydrophilic side forms) allowing leakage of a variety of small molecules.
- Cholesterol, present in host cell membranes, closely resembles ergosterol; the polyenes bind to it as well, though with lesser affinity.
Antifungal spectrum/ Activity:
- Active against a wide range of yeasts and fungi
- It is fungicidal at high and static at low concentrations
- Amphotericin B has clinical activity against Candido spp., Cryptococcus neoformans, Blastomyces dermatitidis, Hiskoplasma capsulatum, Sporothrix schenckii, Coccidioides immitis, Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei, and the agents of mucormycosis.
- Amphotericin B active on various species of Leishmania. Amphotericin B has limited activity against the protozoa Leishmonia braziliensis and Noegleria fowleri. The drug has no antibacterial activity.
- Amphotericin B resistant noted in Candida (Candida lusitaniae) in a selected group of leucopenic cancer patients. Aspergillus terreus may be more resistant to amphotericin B than other Aspergillus species
- Amphotericin 8 is not absorbed orally. For intestinal candidiasis it can be given orally. The serum t1/2 is approximately 15 days. About 60% of the drug (amphotericin B) metabolized in liver and is excreted slowly in the bile and urine over a period of several days.
- Broad spectrum of activity and fungicidal action
- Used for the treatment of treatment of systemic fungal disease
- Amphotericin B is most effective drug for resistant cases of kala azar and mucocutaneous leishmaniasis
Liposomal amphotericin B (Antifungal Drugs)
- It has been produced to improve tolerability of iv. infusion, reduce toxicity and achieve targeted delivery.
- produce mild acute reaction on i.v. infusion
- can be used in patients not tolerating infusion of conventional AMB formulation
- lower nephrotoxicity
- minimal anemia
- deliver AMB to reticuloendothelial cells in liver and spleen
- Specially indicated for empirical therapy in febrile neutropenic patients not responding to antibacterial antibiotics.
- Dose: 10 mg, 25 mg per vial inj.: 10 mg/2 ml, 50 mg/10 mi and 100 mg/20 ml inj.
Amphotericin B given orally 50-100 mg QID: intestinal moniliasis epjcally for vaginitis, otomycosis etc.
- Acute reaction:
- Chills, fever, aches, pain all over, nausea, vomiting and dyspnea. Injection of hydrocortisone 0.6 mg/kg with the infusion may reduce the intensity of reaction.
- Thrombophlebitis of the injection vein can occur.
- Long-term reaction:
- CNS toxicity (only on intrathecal injection)
- Acute reaction:
Nystatin (Antifungal Drugs)
- Obtained from S. noursei
- Similar to amphotericin B
- Toxicity high : used only locally in superficial candidiasis
- Dose: 5 lacU TDS
- Monilial vaginitis: 1 lac U tab inserted twice daily
- Oral trush: Crushed & suspended in glycerine for application in mouth
- Corneal, conjunctival & cutaneous candidiasis
- Obtained from Penicillium griseofulvum
- Systemic drug for superficial fungal infections
- Active against most dermatophytes
- Narrow spectrum
- Dermatophytes concentrate it actively hence selective toxicity
- Resistance: loss of drug concentrating ability
- Low water solubility
- Gets deposited in keratin forming cells of skin, hair & nails.
- Esp. concentrated in tinea infected cells.
- T1/2- 24hrs
- G.L.T. disturbances
- Peripheral neuritis
- Rashes, photo allergy
- Mechanism of Action
Narrow Spectrum Fungistatic:
- Cryptococcus neofomans
Imidazoles & Triazoles (Antifungal Drugs)
Broad spectrum antifungal activity
- Candida, cryptococcosis, coccidiodomycosis
- Not effective against aspergillosis & mucormycosis
Mechanism of action:
- imidazoles and triazoles on fungi is inhibition of 14-a-sterol demethylase_and impair the biosynthesis of ergosterol in cytoplasmic membrane and accumulates the 14-a- methylsterols. These methylsterols may disrupt the close packing of acyl chains of phospholipids, impairing the functions/inhibit the growth of the fungi.
- Some azoles (e.g., clotrimazole) directly increase permeability of the fungal cytoplasmic membrane- topical use.
- Azole resistance (clinical failure) observed in HIV infection and oropharyngeal or esophageal candidiasis. The primary mechanism of resistance in C. albicans is accumulation of mutations in ERG11, the gene coding for the 14-a-sterol demethylase. Increased production of 14-a-sterol demethylase is another potential cause of resistance.
- Topical treatment of tinea infections like ringworms
- Athlete’s foot
- Oropharyngeal candidiasis: 10 mg 3-4 times a day.
- Highly effective in dermatophytosis, otomycosis, oral thrush.
- Local irritation.
- Tinea, candidiasis
- Acidic pH required for the absorption of Ketoconazole.
- bioavailability is reduced in achlorhydria. Such patients should be given acidifying agents (like orange juice) ore ketoconazole administration.
- Plasma half-life is 8-10hours
- penetration into CSF is negligible; hence it is ineffective in the treatment of fungal meningitis
- non -CNS blastomycosis
- Systemic and mucocutaneous infections.
- Prevention of Candida infection in immune suppressed patients.
- Mild side effects: GI digtress and pruritus
- Serious side effects:
- Hepatic toxicity – The drug must be discontinued if hepatitis occurs.
- Gynecomastia – inhibition of testosterone synthesis
- Single 150mg oral dose: vaginal candidiasis
- Oropharyngeal candidiasis: 150mg/day for 2 weeks
- Disseminated candidiasis, cryptococcal meningitis: 200-400mg/day for 4-12 weeks
- Eye drop is useful in fungal keratitis
ITRACONAZOLE (Antifungal Drugs)
- T1/2- 30-64hrs
- Dizziness, prutitus,headache & hypokalemia.
- Systemic mycosis: 200mg OD/BD used for 3 months
- Vaginal candidiasis: 200mg OD for 3 days
- Dermatophytosis:: 100-200mg OD for 7-15
- Onychomycosis: 200mg/day for 3 months
- A synthetic allylamine that is available in an oral formulation.
- It is used in the treatment of dermatophytoses, especially onychomycosis.
- Terbinafine is a keratophilic medication, but unlike griseofulvin, it is fungicidal.
- Like the azole drugs, it interferes with ergosterol biosynthesis, but inhibits the fungal enzyme squalene epoxidase.
- this leads to the accumulation of the sterol squalene, which is toxic to the organism.
- Terbinafine is available for oral and _ topical administration, although its bioavailability is only 40% due to first-pass metabolism.
- It is highly protein bound and is deposited in the skin, nails, and adipose tissue.
- It accumulates in breast milk and should “not be given to nursing mothers.
- A prolonged terminal half-life of 200 to 400 hours may reflect the slow release from these tissues.
- 250 mg OD: tinea pedis/corporis /cruris / capitis for 2-6 weeks
- Onychomycosis: 3-12 months of treatment
Tropical Antifungal agents
- Topical treatment is useful in superficial fungal infections confined to the stratum corneum, squamous mucosa, or cornea, including dermatophytosis (ringworm), candidiasis, tinea versicotor, piedra, tinea nigra, and fungal keratitis.
- Unsuccessful for mycoses of the nails (onychomycosis) and hair (tinea capitis)
- No place in subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis.
- Efficacy of topical agents depends not only on the type of lesion and the mechanism of drug action, but also on the viscosity, hydrophobicity, and acidity of the formulation.
Other Pharmacology Notes:
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