Antifungal

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ANTI FUNGAL

Fungi may be classified as

Yeasts: Blastomyces, candida, histoplasma, coccidioides, cryptococcus.

Moulds: Aspergillus spp. Dermatophytes, mucor

Clinically classified as : 1) Superficial mycosis 2)Deep (systemic) mycosis

CLASSIFICATION:
1. Antibiotics
A. Polyenes:AmphotericinB (AMB),Nystatin, Hamycin, Natamycin (Pimaricin)
B. Heterocyclic benzofuran: Griseofulvin
2. Antimetabolite : Flucytosine (5-FC)
3 Azoles
A. lmidazoles (topical): Clotrimazole, Econazole, Miconazole, Oxiconazole
(systemic): Ketoconazole
B. Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole
4. Allylamine : Terbinafine
5. Other topical agents: Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor, Ciclopirox olamine,
Butenafine, Sod. thiosulfate.

POLYENE ANTI BIOTICS : The name polyene is derived from their highly double-bonded structure.

AMPHOTERICIN B (AMB): prototype obtained from Streptomyces nodosus.

Mechanism of Action: It is fungicidal in action.


The polyenes have high affinity for ergosterol present in fungal cell membrane, combine with it, get inserted
into the membrane and several polyene molecules together orient themselves in to form a 'micropore'.
The hydrophilic side forms the interior of the pore through which ions, amino acids and other watersoluble
substances move out reducing cell permeability.The polyenes bind to Cholesterol, present in host cell
membranes, closely resembles ergosterol.

Antifungal spectrum- Blastomyces ,Candida ,Cryptococcus ,Coccidioides ,histoplasma.

Resistance: – Replacement of ergosterol by other sterols in fungal plasma membrane.

Adverse effects:
Acute reaction: – Chills, fever, headache, pain all over, nausea, vomiting, dyspnoea lasting 2-5 hrs because of
release of IL & TNF – can be treated with hydrocortisone 0.6mg/kg
Long term toxicity: – Nephrotoxicity: Azotemia, Hypokalemia, acidosis, Anemia, Hepatotoxicity .
CNS toxicity : intrathecal administration, headache, vomiting, nerve palsies
Uses: Amphotericin B can be applied topically for oral, vaginal and cutaneous candidiasis and otomycosis.
Due to its toxic effects replaced by azoles.
Leishmaniasis: AMB is the most effective drug for resistant cases of kala azar and mucocutaneous
leishmaniasis

PREPARATIONS:
(a) Amphotericin B lipid complex (ABLC)
(b) Amphotericin B colloidal dispersion (ABCD).
(c) Liposomal amphotericin B

NYSTATIN :Obtained from S.Nourse


➢ Similar to AMB in antifungal properties, high systemic toxicity so used locally only.
➢ Poorly absorbed from mucus membrane
➢ Available as ointment ,cream , powder, tablet
Uses:
➢ 5 lac U in intestinal moniliasis TDS
➢ 1 lac U in vaginitis
➢ Prevention of oral candidiasis
➢ Can be used in oral, cutaneous, conjunctival candidiasis
Adverse effects:
Gastointestinal disturbances with oral tablets.

HAMYCIN: obtained from S. Pimprina by Hindustan antibiotics pimpri


More water soluble, fraction absorbed orally but unreliable in systemic infections
Topical use in thrush, cutaneous candidiasis, trichomonas & monilial vaginitis, otomycosis by aspergillus

NATAMYCIN:
Similar to nystatin, broad spectrum
Used topically 1%, 3% ointment in Fusarium solani keratitis, trichomonas & monilial vaginitis

GRISEOFULVIN : One of early antibiotics from penicillium griseofulvum


➢ Fungistatic, systemic drug for superficial fungal infections
➢ Active against most dermatophytes
➢ Resistance: loss of concentrating ability

Mechanism of action: – Griseofulvin interacts with polymerized microtubules and disrupts the mitotic
spindles thus arresting fungal mitosis

Pharmacokinetics: – Oral administration, irregular absorption, increased by fatty food and microfine particles
Gets conc in keratinized tissue , Metabolized in liver, excreted in urine,t1/2=24 hrs.

ADVERSE EFFECTS : – Headache ,GIT disturbances , CNS symptoms: confusion, fatigue, vertigo,
Peripheral neuritis , Rashes, photoallergy , leukopenia, albuminuria
USE : – Systemically only for dermatophytosis, ineffective topically. Duration of treatment depends on site,
thickness of keratin and turnover of keratin.Treatment must be continued till infected tissue is completely
replaced by normal Skin,hair, nail.
➢ Dose: 125-250 mg QID
Duration of treatment:
➢ Body skin = 3 weeks
➢ Palm, soles = 4- 6 weeks
➢ Finger nails = 4- 6months
➢ Toe nails = 8 – 12 months
➢ Griseofulvin should be reserved for nail hair or larger body surface involvement

INTERACTIONS: – Warfarin , OCP, Phenobarbitone.

5 FLUCYTOSINE– Prodrug, pyrimidine analog.


➢ Inactive antimetabolite converted to 5 Flurouracil. Human cells cannot convert it to 5FU
➢ Adverse events: • Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis
➢ Use: in combination with AMB in cryptococcal meningitis

AZOLES
These are presently the most extensively used antifungal drugs.
The imidazoles and triazoles have broadspectrum antifungal activity covering dermatophytes, Candida, other
fungi involved in deep mycosis (except mucor), Nocardia, some grampositive and anaerobic bacteria, e.g.
Staph. aureus, Strep. faecalis and Leishmania.

MECHANISM OF ACTION of imidazoles and triazoles is the same.


➢ They inhibit the fungal cytochrome P450 enzyme 'lanosterol l4--demethylase' and thus impair
ergosterol synthesis leading to a cascade of membrane abnormalities in the fungus.
➢ lower toxicity of triazoles is due to their lower affinity for mammalian CYP450 enzymes and lesser
propensity to inhibit mammalian sterol synthesis.

TRIAZOLES:
CLOTRIMAZOLE: It is effective in the topical treatment of tinea infections like ringworm.
➢ Athletes foot, otomycosis and oral/ cutaneous vaginal candidiasis.
➢ It is well tolerated.
➢ Local irritation with stinging and burning sensation occurs in some.
➢ No systemic toxicity is seen after topical use.

ECONAZOLE : It is similar to clotrimazole; penetrates superficial layers of the skin.


➢ Highly effective in dermatophytosis, otomycosis, oral thrush, inferior to clotrimazole in vaginitis.
➢ No adverse effects
MICONAZOLE: It is a highly efficacious (>90% cure rate) drug for tinea, pityriasis versicolor, otomycosis,
cutaneous and vulvovaginal candidiasis.

KETOCONAZOLE
First orally effective broad-spectrum antifungal
Effective against: Dermatophytosis, Deep mycosis, Candidiasis
Effective orally, acidic environment favours absorption
Adverse effects:
➢ Nausea, vomiting, anorexia
➢ Headache, paresthesia, alopecia
➢ reduced steroid, testosterone & estrogen synthesis – Gynaecomastia, oligospermia , loss of libido &
impotence in males – Menstrual irregularities & amenorrhoea in females•
➢ Elevation of liver enzymes
➢ Hypersensitivity reaction - skin rashes, itching

FLUCONAZOLE
➢ Newer water soluble triazole .
➢ Broad spectrum antifungal activity : Candida, cryptococcosis, coccidiodomycosis, Dermatophytosis,
Blastomycosis, Histoplasmosis, Sporotrichosis
➢ Not effective against aspergillosis & mucormycosis.
Adverse effects : GIT upset, Headache, alopecia, skin rashes, hepatic necrosis,Teratogenic effect
Uses: vaginal candidiasis, Oral candidiasis, Tinea infections & cutaneous candidiasis, systemic fungal
infections, candidiasis, cryptococcal, coccidiodal meningitis Meningitis
Eye drops for fungal keratitis.

ITRACONAZOLE
Broadest spectrum of activity also against aspergillus
Fungistatic but effective in immunocompromised
Does not inhibit steroid hormone synthesis and no serious hepatoxicity
Use : Paracoccidomycosis Chromoblastomycosis, Histoplasmosis, Blastomycosis, Esophageal, oropharyngeal
& vaginal candidiasis.

VORICONAZOLE: II generation triazole. Useful in resistant candida infections.

TERBINAFINE
Orally & topically effective drug against candida & dermatophytes
Fungicidal : shorter courses of therapy required . Negligible effect on CYP450
Adverse effects: Nausea , vomiting , Diarrhoea, Taste disturbances
Topical: erythema , itching , dryness , urticaria, rashes.
Uses: Dermatophytosis, Onychomycosis, Candidiasis
TOLNAFTATE: Tinea, cruris, corporis, 1- 3 weeks treatment.
Not effective in hyperkeratinized lesions
Salicylic acid aids its effect by keratolysis

CICLOPIROX OLAMINE: Tinea infections, pitryasis versicolor ,dermal candidiasis, vaginal candidiasis
Penetrates superficial layers
Acts by inhibiting membrane uptake of precursors of macromolecules needed for fungal growth.

UNDECYCLENIC ACID: 5% (Tineafax) : Generally combined with zinc (20%)


Requires prolonged treatment has high relapse rate
Weaker antifungal action used in tinea cruris and nappy rash

SODIUM THIOSULFATE: (Karpin lotion) : Reducing agent , Effective in pitryasis versicolor

BENZOIC ACID: Used in combination with salicylic acid – Whitfields ointment: ( benzoic acid 6% +
salicyclic acid 3 %) – Salicyclic acid due to its keratolytic action helps to remove infected tissue & promotes
penetration of benzoic acid in fungal infected lesion
Adverse events: irritation & burning sensation (Ring cutter ointment)

QUINIDIOCHLOR : Luminal amoebicide


Weak antifungal & antibacterial
External application : dermatophytosis , mycosis barbae, pityriasis versicolor

SELENIUM SULFIDE: T versicolor

BUTENAFINE :It is a benzylamine congener of terbinafine with the same mechanism of action.

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